the federalist essays impact

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Federalist Papers

By: History.com Editors

Updated: June 22, 2023 | Original: November 9, 2009

The Federalist Papers are a collection of essays written in the 1780s in support of the proposed U.S. Constitution and the strong federal government it advocated. In October 1787, the first in a series of 85 essays arguing for ratification of the Constitution appeared in the Independent Journal , under the pseudonym “Publius.” Addressed to “The People of the State of New York,” the essays were actually written by the statesmen Alexander Hamilton , James Madison and John Jay . They would be published serially from 1787-88 in several New York newspapers. The first 77 essays, including Madison’s famous Federalist 10 and Federalist 51 , appeared in book form in 1788. Titled The Federalist , it has been hailed as one of the most important political documents in U.S. history.

Articles of Confederation

As the first written constitution of the newly independent United States, the Articles of Confederation nominally granted Congress the power to conduct foreign policy, maintain armed forces and coin money.

But in practice, this centralized government body had little authority over the individual states, including no power to levy taxes or regulate commerce, which hampered the new nation’s ability to pay its outstanding debts from the Revolutionary War .

In May 1787, 55 delegates gathered in Philadelphia to address the deficiencies of the Articles of Confederation and the problems that had arisen from this weakened central government.

A New Constitution

The document that emerged from the Constitutional Convention went far beyond amending the Articles, however. Instead, it established an entirely new system, including a robust central government divided into legislative , executive and judicial branches.

As soon as 39 delegates signed the proposed Constitution in September 1787, the document went to the states for ratification, igniting a furious debate between “Federalists,” who favored ratification of the Constitution as written, and “Antifederalists,” who opposed the Constitution and resisted giving stronger powers to the national government.

The Rise of Publius

In New York, opposition to the Constitution was particularly strong, and ratification was seen as particularly important. Immediately after the document was adopted, Antifederalists began publishing articles in the press criticizing it.

They argued that the document gave Congress excessive powers and that it could lead to the American people losing the hard-won liberties they had fought for and won in the Revolution.

In response to such critiques, the New York lawyer and statesman Alexander Hamilton, who had served as a delegate to the Constitutional Convention, decided to write a comprehensive series of essays defending the Constitution, and promoting its ratification.

Who Wrote the Federalist Papers?

As a collaborator, Hamilton recruited his fellow New Yorker John Jay, who had helped negotiate the treaty ending the war with Britain and served as secretary of foreign affairs under the Articles of Confederation. The two later enlisted the help of James Madison, another delegate to the Constitutional Convention who was in New York at the time serving in the Confederation Congress.

To avoid opening himself and Madison to charges of betraying the Convention’s confidentiality, Hamilton chose the pen name “Publius,” after a general who had helped found the Roman Republic. He wrote the first essay, which appeared in the Independent Journal, on October 27, 1787.

In it, Hamilton argued that the debate facing the nation was not only over ratification of the proposed Constitution, but over the question of “whether societies of men are really capable or not of establishing good government from reflection and choice, or whether they are forever destined to depend for their political constitutions on accident and force.”

After writing the next four essays on the failures of the Articles of Confederation in the realm of foreign affairs, Jay had to drop out of the project due to an attack of rheumatism; he would write only one more essay in the series. Madison wrote a total of 29 essays, while Hamilton wrote a staggering 51.

Federalist Papers Summary

In the Federalist Papers, Hamilton, Jay and Madison argued that the decentralization of power that existed under the Articles of Confederation prevented the new nation from becoming strong enough to compete on the world stage or to quell internal insurrections such as Shays’s Rebellion .

In addition to laying out the many ways in which they believed the Articles of Confederation didn’t work, Hamilton, Jay and Madison used the Federalist essays to explain key provisions of the proposed Constitution, as well as the nature of the republican form of government.

'Federalist 10'

In Federalist 10 , which became the most influential of all the essays, Madison argued against the French political philosopher Montesquieu ’s assertion that true democracy—including Montesquieu’s concept of the separation of powers—was feasible only for small states.

A larger republic, Madison suggested, could more easily balance the competing interests of the different factions or groups (or political parties ) within it. “Extend the sphere, and you take in a greater variety of parties and interests,” he wrote. “[Y]ou make it less probable that a majority of the whole will have a common motive to invade the rights of other citizens[.]”

After emphasizing the central government’s weakness in law enforcement under the Articles of Confederation in Federalist 21-22 , Hamilton dove into a comprehensive defense of the proposed Constitution in the next 14 essays, devoting seven of them to the importance of the government’s power of taxation.

Madison followed with 20 essays devoted to the structure of the new government, including the need for checks and balances between the different powers.

'Federalist 51'

“If men were angels, no government would be necessary,” Madison wrote memorably in Federalist 51 . “If angels were to govern men, neither external nor internal controls on government would be necessary.”

After Jay contributed one more essay on the powers of the Senate , Hamilton concluded the Federalist essays with 21 installments exploring the powers held by the three branches of government—legislative, executive and judiciary.

Impact of the Federalist Papers

Despite their outsized influence in the years to come, and their importance today as touchstones for understanding the Constitution and the founding principles of the U.S. government, the essays published as The Federalist in 1788 saw limited circulation outside of New York at the time they were written. They also fell short of convincing many New York voters, who sent far more Antifederalists than Federalists to the state ratification convention.

Still, in July 1788, a slim majority of New York delegates voted in favor of the Constitution, on the condition that amendments would be added securing certain additional rights. Though Hamilton had opposed this (writing in Federalist 84 that such a bill was unnecessary and could even be harmful) Madison himself would draft the Bill of Rights in 1789, while serving as a representative in the nation’s first Congress.

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Ron Chernow, Hamilton (Penguin, 2004). Pauline Maier, Ratification: The People Debate the Constitution, 1787-1788 (Simon & Schuster, 2010). “If Men Were Angels: Teaching the Constitution with the Federalist Papers.” Constitutional Rights Foundation . Dan T. Coenen, “Fifteen Curious Facts About the Federalist Papers.” University of Georgia School of Law , April 1, 2007. 

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Course: US history   >   Unit 3

• The Articles of Confederation
• What was the Articles of Confederation?
• Shays's Rebellion
• The Constitutional Convention
• The US Constitution

The Federalist Papers

• The Bill of Rights
• Social consequences of revolutionary ideals
• The presidency of George Washington
• Why was George Washington the first president?
• The presidency of John Adams
• Regional attitudes about slavery, 1754-1800
• Continuity and change in American society, 1754-1800
• Creating a nation
• The Federalist Papers was a collection of essays written by John Jay, James Madison, and Alexander Hamilton in 1788.
• The essays urged the ratification of the United States Constitution, which had been debated and drafted at the Constitutional Convention in Philadelphia in 1787.
• The Federalist Papers is considered one of the most significant American contributions to the field of political philosophy and theory and is still widely considered to be the most authoritative source for determining the original intent of the framers of the US Constitution.

The Articles of Confederation and Constitutional Convention

• In Federalist No. 10 , Madison reflects on how to prevent rule by majority faction and advocates the expansion of the United States into a large, commercial republic.
• In Federalist No. 39 and Federalist 51 , Madison seeks to “lay a due foundation for that separate and distinct exercise of the different powers of government, which to a certain extent is admitted on all hands to be essential to the preservation of liberty,” emphasizing the need for checks and balances through the separation of powers into three branches of the federal government and the division of powers between the federal government and the states. 4 ‍  
• In Federalist No. 84 , Hamilton advances the case against the Bill of Rights, expressing the fear that explicitly enumerated rights could too easily be construed as comprising the only rights to which American citizens were entitled.

What do you think?

• For more on Shays’s Rebellion, see Leonard L. Richards, Shays’s Rebellion: The American Revolution’s Final Battle (Philadelphia: University of Pennsylvania Press, 2002).
• Bernard Bailyn, ed. The Debate on the Constitution: Federalist and Anti-Federalist Speeches, Articles, and Letters During the Struggle over Ratification; Part One, September 1787 – February 1788 (New York: Penguin Books, 1993).
• See Federalist No. 1 .
• See Federalist No. 51 .
• For more, see Michael Meyerson, Liberty’s Blueprint: How Madison and Hamilton Wrote the Federalist Papers, Defined the Constitution, and Made Democracy Safe for the World (New York: Basic Books, 2008).

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Federalist Papers

George Washington  was sent draft versions of the first seven essays on November 18, 1787 by James Madison, who revealed to Washington that he was one of the anonymous writers. Washington agreed to secretly transmit the drafts to his in-law David Stuart in Richmond, Virginia so the essays could be more widely published and distributed. Washington explained in a letter to David Humphreys that the ratification of the Constitution would depend heavily "on literary abilities, & the recommendation of it by good pens," and his efforts to proliferate the Federalist Papers reflected this feeling. 1

Washington was skeptical of Constitutional opponents, known as Anti-Federalists, believing that they were either misguided or seeking personal gain. He believed strongly in the goals of the Constitution and saw The Federalist Papers and similar publications as crucial to the process of bolstering support for its ratification. Washington described such publications as "have thrown new lights upon the science of Government, they have given the rights of man a full and fair discussion, and have explained them in so clear and forcible a manner as cannot fail to make a lasting impression upon those who read the best publications of the subject, and particularly the pieces under the signature of Publius." 2

Although Washington made few direct contributions to the text of the new Constitution and never officially joined the Federalist Party, he profoundly supported the philosophy behind the Constitution and was an ardent supporter of its ratification.

The philosophical influence of the Enlightenment factored significantly in the essays, as the writers sought to establish a balance between centralized political power and individual liberty. Although the writers sought to build support for the Constitution, Madison, Hamilton, and Jay did not see their work as a treatise, per se, but rather as an on-going attempt to make sense of a new form of government.

The Federalist Paper s represented only one facet in an on-going debate about what the newly forming government in America should look like and how it would govern. Although it is uncertain precisely how much The Federalist Papers affected the ratification of the Constitution, they were considered by many at the time—and continue to be considered—one of the greatest works of American political philosophy.

Adam Meehan The University of Arizona

Notes: 1. "George Washington to David Humphreys, 10 October 1787," in George Washington, Writings , ed. John Rhodehamel (New York: Library of America, 1997), 657.

2. "George Washington to John Armstrong, 25 April 1788," in George Washington, Writings , ed. John Rhodehamel (New York: Library of America, 1997), 672.

Bibliography: Chernow, Ron. Washington: A Life . New York: Penguin, 2010.

Epstein, David F. The Political Theory of The Federalist . Chicago: University of Chicago Press, 1984.

Furtwangler, Albert. The Authority of Publius: A Reading of the Federalist Papers . Ithaca: Cornell University Press, 1984.

George Washington, Writings , ed. John Rhodehamel. New York: Library of America, 1997.

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1.6: The Federalist Papers and Constitutional Government

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What is Federalism?

Federalism is the system of government in which sovereignty (the authority and power to govern over a group of people) is constitutionally divided between a central, or national government, and individual regional political units generally referred to as states. It is based upon democratic rules and institutions in which the power to govern is shared between national and state governments, creating a federation.

Debating a Federal System: The Federalist Papers

The most forceful defense of the new Constitution was The Federalist Papers , a compilation of 85 anonymous essays published in New York City to convince the people of the state to vote for ratification. These articles were written by Alexander Hamilton and James Madison. They examined the benefits of the new Constitution and analyzed the political theory and function behind the various articles of the Constitution. Those opposed to the new Constitution became known as the Anti-Federalists. They generally were local rather than cosmopolitan in perspective, oriented to plantations and farms rather than commerce or finance, and wanted strong state governments and a weak national government. The Anti-Federalists believed that the Legislative Branch had too much power, and that they were unchecked. Also, the Executive Branch had too much power, they believed that there was no check on the President. The final belief was that a Bill of Rights should be coupled with the Constitution to prevent a dictator from exploiting citizens. The Federalists argued that it was impossible to list all the rights and those that were not listed could be easily overlooked because they were not in the official Bill of Rights.

What Were The Federalist Papers and Why are They Important?

The Federalist Papers were a series of essays by John Jay, Alexander Hamilton, and James Madison written for the Federalist newspaper.

The convention in Virginia began its debate before nine states had approved the Constitution, but the contest was so close and bitterly fought that it lasted past the point when the technical number needed to ratify had been reached. Nevertheless, Virginia's decision was crucial to the nation. Who can imagine the early history of the United States if Virginia had not joined the union? What if leaders like George Washington, Thomas Jefferson, and James Madison had not been allowed to hold national political office? In the end Virginia approved the Constitution, with recommended amendments, in an especially close vote (89-79). Only one major state remained; the Constitution was close to getting the broad support that it needed to be effective.

Perhaps no state was as deeply divided as New York. The nationalist-urban artisan alliance could strongly carry New York City and the surrounding region while more rural upstate areas were strongly Anti-Federalist. The opponents of the Constitution had a strong majority when the convention began and set a tough challenge for Alexander Hamilton, the leading New York Federalist. Hamilton managed a brilliant campaign that narrowly won the issue (30-27) by combining threat and accommodation. On the one hand, he warned that commercial down state areas might separate from upstate New York if it didn't ratify. On the other hand, he accepted the conciliatory path suggested by Massachusetts; amendments would be acceptable after ratification.

The debate in New York produced perhaps the most famous exploration of American political philosophy, now called The Federalist Papers . Originally they were a series of 85 anonymous letters to newspapers that were co-written by Alexander Hamilton, James Madison, and John Jay. Together, they tried to assure the public of the two key points of the Federalist agenda. First, they explained that a strong government was needed for a variety of reasons, but especially if the United States was to be able to act effectively in foreign affairs. Second, they tried to convince readers that because of the "separation" of powers in the central government, there was little chance of the national government evolving into a tyrannical power. Instead of growing ever stronger, the separate branches would provide a "check and balance" against each other, so that none could rise to complete dominance.

The influence of these newspaper letters in the New York debate is not entirely known, but their status as a classic of American political thought is beyond doubt. Although Hamilton wrote the majority of the letters, James Madison authored the ones that are most celebrated today, especially Federalist No. 10.

Here Madison argued that a larger republic would not lead to greater abuse of power (as had traditionally been thought), but actually could work to make a large national republic a defense against tyranny. Madison explained that the large scope of the national republic would prevent local interests from rising to dominance and therefore the larger scale itself limited the potential for abuse of power. By including a diversity of interests (he identified agriculture, manufacturing, merchants, and creditors, as the key ones), the different groups in a larger republic would cancel each other out and prevent a corrupt interest from controlling all the others.

Madison was one of the first political theorists to offer a profoundly modern vision of self-interest as an aspect of human nature that could be employed to make government better, rather than more corrupt. In this, he represents a key figure in the transition from a traditional Republican vision of America, to a modern Liberal one where self-interest has a necessary role to play in public life.

A Closer Look at the Federalist Papers

Let’s closely examine just three of these important documents.

Federalist #10: In this, the most famous of the Federalist Papers , James Madison begins by stating that one of the strongest arguments in favor of the Constitution is the establishment of a government capable of controlling the violence and damage caused by factions which Madison defines as groups of people who gather together to protect and promote their special economic interests and political opinions (basically political parties and special interests today). Although these factions are at odds with each other, they frequently work against the public interest and infringe upon the rights of others.

Both sides of the Constitutional debate (federalists AND anti-federalists alike) have been concerned with the political instability that these rival factions may cause. Under the Articles of Confederation, the state governments have not succeeded in solving this problem. As a matter of fact, the situation has become such a problem that people have become disillusioned with all politicians and blame the government for their problems (sound familiar?). Consequently, a form of popular government that can deal successfully with this problem has a great deal to recommend it.

Federalist #39: This essay was written to explain and defend the new form of Republican government which the Founding Fathers envisioned to be different than any other “Republic” in Europe. In the mind of Madison and the other founders, no other form of government is suited to the particular genius of the American people; only a Republican form of government can carry forward the principles fought for in the Revolution or demonstrate that self-government is both possible and practical.

Madison sees a Republican form of government as one which derives its powers either directly or indirectly from the people (which distinguishes this new form of republicanism from others that had been used in Europe). This form is administered by people who hold elected public office for a limited period of time or during good behavior. He goes on to say that no government can be called Republican that derives its power from a few people or from a favored and wealthy class (as many governments in Europe did). The Constitution conforms to these Republican principles by ensuring that the people will directly elect the House of Representatives. Additionally, the people indirectly select the senators and the president. Even the judges will reflect the choice of the people since the president appoints them, and the Senate confirms their appointment. The president, senators, and representatives hold office for a specified and limited term. Judges are appointed for life ­but subject to good behavior. The constitutional prohibition against granting titles of nobility and the guarantee to the states that they shall enjoy a republican form of government is further proof that the new government is Republican in nature.

These facts do not satisfy all people. Some people claim that the new Constitution destroyed the federal aspect of the government by taking away too much power from the states. Opponents (anti-federalists) believed that the framers established a national (unitary) form of government where the citizens' are directly acted upon by a central government as citizens of the nation rather than as citizens of the states. But the proposed government (a federal republic) would contain both national and federal characteristics and would allow for a sharing and careful balance of powers between the national government and the states. The principle of federalism (a division of power between the states and the national government) is integrated into the new Constitution and reflected in the suggested method of ratification. The delegates to the ratifying conventions would directly participate (through voting) as citizens of their states, not as citizens of the nation. Madison also points out that this new form of federal republic is also reflected in the structure of the Senate in which the states are equally represented. Since the states would retain certain exclusive and important powers, this is to be considered further proof of the federal nature of the proposed government.

Madison goes on to concede that the new Constitution does exhibit national (central government) features. Madison finishes by reaching the conclusion that the government would be BOTH national and federal. In the operation of its powers, it is a nation; in the extent of its power, it is federal.

Federalist # 51: In this essay, James Madison explains and defends the checks and balances system which would prove to be one of the most important protections and limits included in the Constitution. Each branch of government would be constructed so that its power would have checks over the power of the other two branches. Also, each branch of government is to be subject to the authority of the people who are the legitimate source of authority for the United States government and its new Constitution.

Madison also goes on to discuss the way a republican government can serve as a check on the power of factions, and the tyranny of the majority which would limit the ability of the majority from imposing their will on the minority unjustly (like a tyrant or despot imposing his will over his subjects).

Madison’s conclusion is that all of the Constitution’s checks and balances would serve to preserve liberty by ensuring justice. Madison explained, “Justice is the end of government. It is the end of civil society.” Madison’s political theory is based on Montesquieu’s The Spirit of the Laws on the Founders .

The Impact of the Federalist Papers

The Federalist Papers had an immediate impact on the ratification debate in New York and in the other states. The demand for reprints was so great that one New York newspaper publisher printed the essays together in two volumes entitled The Federalist, A Collection of Essays Written in Favor of the New Constitution, By a Citizen of New York . By this time, the identity of "Publius," never a well-kept secret, was pretty well known. The Federalist , also called The Federalist Papers , has served two very different purposes in American history. The 85 essays succeeded in persuading doubtful New Yorkers to ratify the Constitution. Today, The Federalist Papers help us to more clearly understand what the writers of the Constitution had in mind when they drafted that amazing document over 200 years ago.

From these essays, Americans have received a gift from our Founding Fathers. Whenever we, as a nation, need to consider what the original intent and meaning of the Constitution was more than 200 years ago, we simply can go back to these documents and remind ourselves exactly what our founders were thinking and what was intended without any question as to meaning or design.

Study/Discussion Questions

For each of the following terms, write a sentence which uses or describes the term in your own words.

1. Why has federalism been such a major source of conflict throughout the history of the United States?

2. Why are the Federalist Papers important to our Constitutional system?

3. Compare the views of the Federalists with those of the Anti-Federalists.

4. How do Federalist Papers 10, 39 and 51 contribute to our understanding of the Constitution and the issue of federalism?

5. How would you describe the impact of the Federalist Papers on American government today? What do you think our governmental system would be like without them?

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The Federalist Papers by Keri Holt LAST REVIEWED: 12 January 2022 LAST MODIFIED: 12 January 2022 DOI: 10.1093/obo/9780199827251-0231

The Federalist is widely considered to be one of the most influential political writings in the early United States. Consisting of eighty-five essays in total, the first seventy-seven essays were originally published in New York newspapers between October 1787 and April 1788, and the final eight appeared in the first collected edition of The Federalist in 1788, although they were later republished in New York newspapers as well. The Federalist was written collectively by Alexander Hamilton, James Madison, and John Jay to promote the ratification of the newly drafted Constitution. In keeping with the conventions of 18th-century public political debate, The Federalist was published under the pseudonym “Publius” to present its arguments to the public in anonymous terms, focusing attention on the content of the essays rather than the personal views or personalities of the authors. Although Hamilton, Madison, and Jay would not be formally identified as the authors of The Federalist until the publication of a notice in The Port-Folio on 14 November 1807, their collective authorship was widely known by the 1790s, and their reputations as respected statesmen and innovative political thinkers brought considerable attention and credibility to their arguments. Through the voice of Publius, The Federalist explains and defends the core principles and structure of the new government outlined within the Constitution, while also identifying the flaws and weaknesses of the Articles of Confederation. In doing so, The Federalist provides substantive critical and philosophical discussions of federal governance and its relationship to the principles of plural sovereignty, national unity, republican representation, citizenship, national security, commercial interests, and the separation of powers, all of which had a profound influence, not just on the ratification debates, but also on subsequent interpretations of constitutional language and authority, from the founding period to the present. While scholars have endlessly debated the political, historical, philosophical, literary, and cultural impact of The Federalist , these essays continue to serve as foundational texts for studying the politics and culture of the early United States, as well as contemporary interpretations and revisions of constitutional principles in legal, legislative, and cultural spheres.

Critical studies of The Federalist encompass many disciplinary approaches, including history, political science, law, literature, economics, and philosophy. The essay collections Kesler 1987 and Rakove and Sheehan 2020 provide excellent overviews of the disciplinary range and focus of Federalist scholarship. Allen 2000 stands apart by offering commentary on all eighty-five Federalist essays, providing a comprehensive overview of the central arguments and political and cultural contexts that shaped these essays, drawing on lectures prepared for a summer institute on The Federalist Papers hosted by Louisiana State University. Coenen 2007 provides an equally expansive study, examining The Federalist in relation to biographical and historical contexts, rhetorical structure, thematic content, and impact on US governing principles. Levinson 2015 brings a contemporary focus to The Federalist , examining all eighty-five essays in relation to their relevance and ongoing impact to the political and legal contexts of the present.

Allen, W. B., with Kevin A. Cloonan. The Federalist Papers : A Commentary . New York: Peter Lang, 2000.

While most studies of The Federalist focus more narrowly on several specific essays, Allen’s book provides a comprehensive analysis of all eighty-five Federalist essays, emphasizing the connections and interdependencies that emerge when considering The Federalist as a whole. The appendix includes a useful list of references to The Federalist in Supreme Court cases from 1798 to 1999.

Coenen, Dan T. The Story of The Federalist: How Hamilton and Madison Reconceived America . New York: Twelve Tables Press, 2007.

Although the title of this work suggests a biographic focus, Coenen’s study extends beyond an analysis of Hamilton’s and Madison’s authorial influence to provide an expansive study of The Federalist that addresses its historical contexts, rhetorical structure, theorizations of national security, individual rights, separation of powers, and impact on US national ideology and identity.

Kesler, Charles R., ed. Saving the Revolution : The Federalist Papers and the American Founding . New York: The Free Press, 1987.

Published in commemoration of the Constitution’s bicentennial, this collection explores The Federalist in relation to a range of topics and disciplinary perspectives. While some chapters focus on individual essays, such as No. 10 and No. 51, others take a broader approach, examining The Federalist in relation to the ratification debates, early US foreign policy, and the development of partisan politics. A number of essays also focus on The Federalist’s role in shaping the judicial, executive, and legislative branches of government.

Levinson, Sanford. An Argument Open to All: Reading The Federalist in the Twenty-First Century . New Haven, CT: Yale University Press, 2015.

Levinson examines all eighty-five Federalist essays, summarizing their main arguments and analyzing them in relation to their relevance to 21st-century issues and political contexts.

Rakove, Jack N., and Colleen A. Sheehan. The Cambridge Companion to The Federalist. New York: Cambridge University Press, 2020.

DOI: 10.1017/9781316479865

This collection provides an overview of contemporary approaches to The Federalist , focusing primarily on the fields of political science, history, and law. The book’s content is organized in relation to three thematic areas, the first addressing The Federalist ’s arguments about national security; the second examining Madison’s theorizations of federalism, republicanism, and separation of powers; and the third exploring The Federalist ’s assessments of the three branches of government.

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The Federalist

The Federalist is a collection of short essays written by Alexander Hamilton , James Madison , and John Jay .

Hamilton became Secretary of the Treasury and remained in that position for much of Washington’s Presidency. Madison went on to be a member of the House of Representatives, Secretary of State under Thomas Jefferson, and the fourth President of the United States. John Jay served for a time as Chief Justice of the Supreme Court and then as Governor of the state of New York.

The Federalist was written in order to convince New Yorkers and Americans generally that they should ratify, or give formal consent to, the Constitution, making it officially valid. Many feared that the proposed Constitution created too strong of a central government. Defenders of the Constitution began writing in support of the Constitution, arguing that the Constitution created a stronger central government than existed under the Article of Confederation -- and for good reason -- but also that the new Constitution’s government was still carefully limited by federalism and the separation of powers. In other words, these writers claimed, the Constitution actually created the kind of government sought by its critics. The Federalist has become the most famous of these pro-Constitution writings.

The essays were originally published in the New York press between October 27, 1787 and August 13, 1788, but from the beginning, Hamilton planned to have them printed in book form, which he did in March and May of 1788. As a result, some of the essays appeared in book form even before they appeared in the press. To this day, they remain a touchstone for understanding the Constitution.

Who: Alexander Hamilton, James Madison, and John Jay

Why: To convince New Yorkers and Americans generally that they should ratify, or give formal consent to the Constitution, making it officially valid.

When: March and May of 1788.

Publishing Information: The Federalist : A Collection of Essays, written in Favour of the New Constitution, as Agreed Upon by the Federal Convention, September 17, 1787. First Edition. In Two Volumes. New York: J. and A. M’Lean, 1788. With Michael Zinman bookplate.

Alexander Hamilton

James Madison

Learning Activities

As The Federalist explains, the Constitution tries to combine both energy and safety. It includes institutions like the President meant to provide that energy but also checks and balances to prevent the government from acting oppressively. Do you think they succeeded? Why or why not?  

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On The Site

"Senator Ted Kennedy being interviewed by reporters in the corridors of the U.S. Capitol during the Senate impeachment trial of President Bill Clinton," February 1999; licensed for use on the public domain by the Library of Congress.

The Federalist Papers: On Impeachment

August 2, 2017 | yalepress | American History , Law , Political Science

Sanford Levinson—

Federalist 65 : The Senate’s Confirmation and Impeachment Powers

One of the most important distinction between the Senate and House, with regard to their constitutionally granted powers, concerns the former’s unique role in confirming presidential appointments. It is utterly irrelevant, as a formal matter, what the House thinks about any of the president’s nominees; what is crucial is whether that person can get approved by the requisite majority of senators who are present and voting on a given day (as against an absolute majority of the entire one hundred senators). Anyone aware of contemporary American politics knows this is no easy task, whether one is thinking of nominees to the federal bench or even nominations for cabinet or subcabinet positions. Rather stunningly, Publius mentions this power only to scant any serious discussion of it. He does, to be sure, mention it again in  Federalists  76 and 77, when discussing the president’s power to appoint officials, but one can only wonder at the absence of sustained discussion in the group of essays devoted to the Senate. The answer surely cannot be that appointment and confirmation is without practical interest.

One might ask why the framers of the Twenty-fifth Amendment, added to the Constitution in 1965 to provide a way of filling vacancies in the vice presidency, dictated that  both  the House and Senate must approve the president’s choice. Granted, the vice president, as a prospective president should anything happen to the incumbent, is more important than almost any other political official, but, given the infrequency of such succession and the uncertain powers of the vice president (whose only task under the Constitution is to preside over the Senate), is it really more important to gain the assent of both House and Senate for that office than, say, for the person chosen to be chief justice of the United States, secretary of state, chair of the Joint Chiefs of Staff of the armed forces, or head of the Federal Reserve Board? And it is worth noting as well that under the Succession in Office Act, members of the cabinet, beginning with the secretary of state (if a “natural born Citizen”) would move into the Oval Office in certain extreme circumstances. The vice president may be only a heartbeat away from the presidency, but the secretary of state is only four beats away (with the speaker of the House and the president pro tempore of the Senate, unwisely I believe, being placed by the act between the vice president and the secretary). Were we redesigning our Constitution from scratch, would we again place the confirmation power entirely in the hands of the Senate?

Publius gives a good deal more attention to the Senate’s unique role of determining whether to convict presidents (and other high officials) who have been impeached by the House. One can compare the House to the grand jury, which has only the power to indict. Conviction requires either a trial or a voluntary guilty plea. Some impeached officials have gone quietly into obscurity by resigning their offices, but most (especially federal judges) have insisted on their “day in court,” that is, the Senate, and some have escaped conviction.

Publius is well aware that impeachments stir up popular passion and may reflect partisan or factional disputes. Readers should have little trouble thinking of contemporary examples. Although one might imagine that voters themselves be given the power to acquit or convict, as they do in recall elections, that is obviously not the path taken in Philadelphia, nor is it likely that Publius would have thought that a good idea. He writes, “The convention, it appears, thought the Senate the most fit depositary of this important public trust” to judge impeached officials fairly and impartially, as we would expect ordinary juries to do.

Publius compares the constitutional differentiation between House and Senate to that in Great Britain, where the House of Commons brings charges and the House of Lords assesses their merits. But are there no alternatives, even if one rejects a national “citizen jury” of electors? Publius addresses the possibility that the Supreme Court might be the final judge of an official’s culpability. “It is much to be doubted,” he writes, that the Court would have the “fortitude” necessary “in the execution of so difficult a task.” Far more important, though, is his second concern, which is whether members of the Supreme Court “would possess the degree of credit and authority, which might, on certain occasions, be indispensable towards reconciling the people to a decision that should happen to clash with an accusation brought by their immediate representatives. A deficiency in [fortitude] would be fatal to the accused; in the last, dangerous to the public tranquillity.” Again, the principal concern appears to be taming public passions, which requires that the decision makers have genuine public respect, and Publius apparently doubts whether Supreme Court members will be as highly respected as senators. This too raises empirical questions: One can wonder whether this is true in the contemporary United States. Perhaps, if we polled the public, we would discover that neither institution possesses “enough” respect to still the partisan clashes that at least some impeachments would provoke. Just as much to the point, perhaps, we might want senators to cast “prudential” votes, based on balancing the harm done even by a president’s illegal conduct against his or her ability to serve the nation well by continuing in office (mixed, perhaps, with assessments of the abilities of the vice president, who would take over in case of a conviction). Justices, on the other hand, might be more legalistic in their approach and ask  only  whether the president in fact committed “high Crimes and Misdemeanors.”

Publius points to another problem if we rely on the judiciary instead of the Senate, which is the limited size of the United States Supreme Court. While the Constitution does not specify the Court’s size, Publius was likely not surprised that the first Congress gave it six members (as distinguished from the initial count of twenty-two senators, given that Rhode Island and North Carolina had not yet ratified the Constitution when the new government met for the first time). “The awful discretion which a court of impeachments must necessarily have, to doom to honor or to infamy the most confidential and the most distinguished characters of the community, forbids the commitment of the trust to a small number of persons.” Once again Goldilocks renders her judgment: The Court provides “too few” members, even as the general electorate would undoubtedly have been far too many.

Federalist 66 : The Past Is a Different Country

In Federalist 66 , Publius continues his discussion of the propriety of the Senate’s sitting as the court of impeachment. The primary importance of this essay today is to underscore that the issues of greatest interest to those uncertain about the new Constitution in 1788 were often very different from anything we think about today. Just as reading  Reading Lolita in Tehran , especially after the Islamic Revolution of 1979, might be a different experience from reading it in contemporary New York or Los Angeles, so might we conclude that reading  The Federalist  in the twenty-first century will inevitably provoke different responses than if one had been part of its original audience in 1788.

We have already seen the near-paranoid concern that Congress would take advantage of the Elections Clause to favor urban interests by restricting voting sites to major cities. Sometimes people in 1788 spoke differently, even if the words were the same; the valence attached to the word “democracy,” for example, has certainly shifted dramatically over time, from a term of near opprobrium among many of Publius’s generation to an almost unanalyzed good today. But just as important is the shift with regard even to relatively unambiguous language from a high level of concern to one of indifference. It is difficult for most twenty-first-century readers to understand the depth of concern—what Publius describes as the “vehemence”—about the Senate’s role in impeachment, even if one agrees, as Publius apparently does, that it is not one of the Constitution’s more felicitous aspects. One criticism involved the violation of a “pure” theory of separation of powers, which would deny any legislative institution the ability to play a judicial role. Given Publius’s earlier disdain for such purity, it is not surprising that he defends the “partial intermixture” of legislative and judicial roles. Moreover, he points out—not for the first time—that the constitutions of six states, including New York, Massachusetts, and Pennsylvania, assign decisive powers to one or another branch of the legislature when considering impeachment.

Perhaps the problem is the Senate itself. Some viewed the Senate’s exclusive power over ratification of treaties, the confirmation of federal appointments, and now the resolution of impeachments as “an undue accumulation of powers” and an invitation to aristocracy. Publius not only does not share such fears; he also takes care to note some of the exclusive powers assigned to the House of Representatives. One of them, of course, is initiating impeachment in the first place; the Senate merely reacts to the House’s actions. Another, which has turned out to have little practical importance, is that revenue bills must begin in the House. This could conceivably have been an important feature of our government insofar as it gives the House the ability to prevent any and all tax increases simply by refusing to initiate them. But, as a matter of fact, the Senate has long been accorded the right to amend existing legislative proposals by including provisions requiring tax increases. The House’s third exclusive power has on two occasions, 1801 and 1825, proved extraordinarily important: the ability to choose a president when the Electoral College cannot name a clear winner. That power might have reemerged in 1948, 1968, and 2000, when a shift of relatively few votes in key states would have resulted in no candidate’s gaining a majority of the electoral votes or, in 2000, a tie between George W. Bush and Al Gore.

Publius makes a sagacious observation with regard to the charge that the Senate will be reluctant to convict federal officials whose initial appointments it, after all, confirmed. He notes that the confirmation power is itself a reactive power. The Senate “may defeat one choice of the executive, and oblige him to make another; but they cannot themselves CHOOSE—they can only ratify or reject the choice, he may have made.” Even in the twenty-first century, this remains a key point. Confirmation battles have now become a feature of our polarized political process, and Senate opponents of the president sometimes win. But presidents rarely lose the overall appointment wars inasmuch as they can continue sending nominees, all of whom will presumably be committed to the president’s agenda.

That being said, it may be increasingly relevant that the ability of a partisan Senate to deny confirmation to  any  nominee can disrupt the ordinary operations of administrative agencies. Former Clinton speechwriter Jeff Shesol has caustically described the strategy of the congressional wing of the Republican Party as vindicating “the liberty of the American people to have a non-functioning government.” One would, of course, like to dismiss this as mere partisan hyperbole, but that could be a mistake. At least some Republican senators, angry over President Obama’s declaration of a new policy regarding the treatment of unauthorized aliens who have lived for a substantial time within the United States (and who have children who are indeed “natural born Citizens” of the United States), proclaimed that they would simply refuse to confirm any of Obama’s appointees at least when vital interests of national security are not at stake. The 2015–2017 Senate, firmly controlled by the Republican Party, will offer a natural test of the extent to which a president will be stymied in making practically any appointments that require Senate confirmation.

One “further consideration” reinforces the preference for the Senate over the Court. Impeachment is a special kind of trial in which conviction brings a unique form of punishment: the removal of the miscreant from office and, in certain circumstances, a ban on his holding any public office in the future. But this may not be the end of the matter. An impeached official can also be subjected to criminal trial and punishment, which is the function of the judiciary. “Would it be proper,” Publius asks, “that the persons who had disposed of his fame, and his most valuable rights as a citizen in one trial, should, in another trial, for the same offense, be also the disposers of his life and his fortune?” There is surely something to be said for this concern, but then one wonders why the Constitution assigned the chief justice to preside over impeachment trials of the president. Some readers may recall that William Rehnquist wore special robes of his own design when crossing the street to take his seat as the presiding officer in the trial of President Clinton. Would he have recused himself in any subsequent case involving potential criminal liability of the impeached Clinton?

Publius goes on to consider the creation of what might be termed a “special court of impeachment,” whose members’ only duty is to try those charged by the House with impeachable offenses. He presents reasons both pro and con. What is ultimately most telling is the tepidness of the entire discussion and his reminder, once more, that we should not seek perfection in that human creation called a constitution. He readily concedes that “preferable” alternatives to the system set out in the Constitution might well have been “devised,” but so what? “[I]t will not follow that the Constitution ought for this reason to be rejected. If mankind,” Publius mordantly observes, “were to resolve to agree in no institution of government, until every part of it had been adjusted to the most exact standard of perfection, society would soon become a general scene of anarchy, and the world a desert.” The search for a possibly utopian best—and, he asks, “Where is the standard of perfection to be found?”—would truly become the enemy of an attainably adequate constitution. Thus, he states that “adversaries of the Constitution . . . ought to prove, not merely that particular provisions in it are not the best which might have been imagined,” a proposition to which Publius readily assents, but instead “that the plan upon the whole is bad and pernicious.”

It is one thing to predicate one’s support or opposition to the Constitution on the compromises surrounding slavery or on the demands of small states for equal representation in the Senate. Perhaps they  should  have been deal breakers. But surely only a fanatic would be so concerned about the impeachment process as to reject the Constitution on that basis. We can read in this essay an “anti-fanaticism” principle, a maxim that we should draw lines in the sand only about truly fundamental issues. What might otherwise appear to be an esoteric discussion thus contains a strong and important lesson for twenty-first-century readers.

From An Argument Open to All: Reading “The Federalist” in the 21st Century  by Sanford Levinson ; published by Yale University Press in 2017. Reproduced by permission.

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The Federalist

In part one of Books That Shaped America , an Arizona State University professor and a U.S. Court of Appeals for the Armed Forces judge explo… read more

In part one of Books That Shaped America , an Arizona State University professor and a U.S. Court of Appeals for the Armed Forces judge explored The Federalist , an 1788 collection of essays authored by Alexander Hamilton, James Madison and John Jay under the pseudonym “Publius” to promote the ratification of the U.S. Constitution. Library of Congress historian Julie Miller showed letters between James Madison and Thomas Jefferson. The program also includes a walking tour of the New York City location where Hamilton wrote his essays. Books That Shaped America is a 10-part series, created in partnership with the Library of Congress, that examines major works of literature that have had a significant impact on the country and public policy. close

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The first amendment, the anti-federalists and their important role during the ratification fight.

September 27, 2017 | by Ugonna Eze

On this day in 1787, the debate over the newly written Constitution began in the press after an anonymous writer in the New York Journal warned citizens that the document was not all that it seemed.

Most Americans know of the Federalist Papers, the collection of essays written by Alexander Hamilton, John Jay, and Madison, in defense of the U.S. Constitution. Fewer know of the Anti-Federalist Papers authored by Cato and other incognito writers, their significance to American political history, or their responsibility for producing the Bill of Rights.

When the Constitution was drafted in the summer of 1787, its ratification was far from certain; it still needed to be ratified by at least nine of the 13 state legislatures. The failure of the Articles of Confederation made it clear that America needed a new form of government. Yet there was worry that the Constitution gave too much power to the federal government. The original draft of the Constitution did not have a Bill of Rights, declared all state laws subservient to federal ones, and created a king-like office in the presidency. At the Philadelphia Convention and in the Federalist Papers, James Madison argued against having a Bill of Rights, fearing that they would limit the people’s rights.

Opposition to the Constitution after the Philadelphia Convention began with Elbridge Gerry, Edmund Randolph, and George Mason, the “Three Dissenters” who refused to sign the document. It then grew to include Patrick Henry, Samuel Adams, and Richard Henry Lee, heroes of the Revolutionary War who objected to the Constitution’s consolidation of power. In time, the various opponents to the new Constitution came to be known as the Anti-Federalists. Their collected speeches, essays, and pamphlets later became known as the “Anti-Federalist Papers.”

While each of the Anti-Federalists had their own view for what a new constitution for the United States should look like, they generally agreed on a few things. First, they believed that the new Constitution consolidated too much power in the hands of Congress, at the expense of states. Second, they believed that the unitary president eerily resembled a monarch and that that resemblance would eventually produce courts of intrigue in the nation’s capital. Third, they believed that the liberties of the people were best protected when power resided in state governments, as opposed to a federal one. Lastly, they believed that without a Bill of Rights, the federal government would become tyrannous.

These arguments created a powerful current against adopting the Constitution in each of the states. In state legislatures across the country, opponents of the Constitution railed against the extensive powers it granted the federal government and its detraction from the republican governments of antiquity. In Virginia, Patrick Henry, author of the famous “Give Me Liberty or Give Me Death” speech, called the proposed constitution, “A revolution as radical as that which separated us from Great Britain.” In the Essays of Brutus, an anonymous author worried that without any limitations, the proposed Constitution would make “the state governments… dependent on the will of the general government for their existence.”

The Anti-Federalists mobilized against the Constitution in state legislatures across the country.

Anti-Federalists in Massachusetts, Virginia and New York, three crucial states, made ratification of the Constitution contingent on a Bill of Rights. In Massachusetts, arguments between the Federalists and Anti-Federalists erupted in a physical brawl between Elbridge Gerry and Francis Dana. Sensing that Anti-Federalist sentiment would sink ratification efforts, James Madison reluctantly agreed to draft a list of rights that the new federal government could not encroach.

The Bill of Rights is a list of 10 constitutional amendments that secure the basic rights and privileges of American citizens. They were fashioned after the English Bill of Rights and George Mason’s Virginia Declaration of Rights. They include the right to free speech, the right to a speedy trial, the right to due process under the law, and protections against cruel and unusual punishments. To accommodate Anti-Federalist concerns of excessive federal power, the Bill of Rights also reserves any power that is not given to the federal government to the states and to the people.

Since its adoption, the Bill of Rights has become the most important part of the Constitution for most Americans. In Supreme Court cases, the Amendments are debated more frequently than the Articles. They have been cited to protect the free speech of Civil Rights activists, protect Americans from unlawful government surveillance, and grant citizens Miranda rights during arrest. It is impossible to know what our republic would look like today without the persistence of the Anti-Federalists over two hundred years ago.

Ugonna Eze is a Fellow for Constitutional Studies at the National Constitution Center.

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Chicago students honored for powerful essays on violence impact

'do the write thing' finalists announced in chicago.

There were 100 students honored Tuesday night for writing essays about how violence affects them.

CHICAGO - One hundred students were recognized on Monday for their essays reflecting on the impact of violence in their lives and communities.

The event, known as "Do the Write Thing," is part of a nationwide initiative aimed at curbing violence. The celebratory ceremony unfolded at the University of Illinois at Chicago (UIC), where the young participants were joined by their families, teachers and school principals.

Out of a total of 800 submissions from middle school students across the city, the top ten finalists emerged. From this talented pool, two exceptional individuals were unveiled as the winners.

Rylie Thompson, representing Arthur Dixon Elementary, and Beautiful Pearson, from Parker Community Academy, clinched the coveted titles. 

Alongside their well-deserved trophies, Thompson and Pearson secured an all-expenses-paid journey to the nation's capital, Washington, D.C.

During their visit, the students will have the opportunity to explore the esteemed Library of Congress and, potentially, engage with policymakers. Furthermore, their compelling essays have been immortalized in a book, slated for preservation within the Library of Congress's archives.

Beautiful Pearson's essay can be found HERE or below.

Rylie Thompson's essay can be found HERE or below.

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Policy has tightened a lot. how tight is it (an update).

May 7, 2024

Over the past few years, I have published a series of essays assessing where we are in our inflation fight and highlighting some important questions policymakers are facing. My most recent essay was in February of this year, where I questioned how much monetary policy was actually restraining demand. This essay is an update to that commentary, and I now examine the current stance of monetary policy in more detail. 1

I will argue that the Federal Open Market Committee (FOMC) has tightened policy significantly, compared with prior cycles, both in absolute terms and relative to the market’s understanding of neutral. But I will also observe that the housing market is proving more resilient to that tight policy than it generally has in the past. Given that housing is a key channel through which monetary policy affects the economy, its resilience raises questions about whether policymakers and the market are misperceiving neutral, at least in the near term. It is possible that once the reopening dynamics of the post-COVID economy have concluded, the macro forces that drove the low-rate environment that existed before the pandemic will reemerge, pulling neutral back down. But the FOMC must set policy based on where neutral is in the short run to achieve our dual mandate goals in a reasonable period of time. The uncertainty about where neutral is today creates a challenge for policymakers.

Economic Update

Since my last update in February, two significant economic developments have occurred simultaneously: Inflation appears to have stopped falling and economic activity has proven resilient, continuing the robust activity we saw in the latter half of 2023.

The FOMC targets 12-month headline inflation of 2 percent. While we saw rapid disinflation in the second half of 2023, that progress appears to have stalled in the most recent quarter (see Figure 1). The question we now face is whether the disinflationary process is in fact still underway, merely taking longer than expected, or if inflation is instead settling to around a 3 percent level, suggesting that the FOMC has more work to do to achieve our dual mandate goals.

During this time, economic activity has continued to show remarkable strength, as shown in Figure 2. While the most recent headline GDP appears somewhat weaker than prior quarters, that slowdown was driven largely by inventories and net exports. Underlying domestic demand remained strong.

The labor market, the other half of our dual mandate, has also remained strong with the unemployment rate at a historically low 3.9 percent.

Policy Is Much Tighter than the Pre-pandemic Period

In prior essays I wrote that the single best proxy for the overall stance of monetary policy is the long-term real rate, specifically the 10-year Treasury inflation-protected securities (TIPS) yield. Focusing on a long-term rate incorporates the expected path of both the federal funds rate and balance sheet, not just the current level of the federal funds rate. Moreover, it adjusts the expected path of policy by expected future inflation—the relevant comparison—rather than by recently realized inflation.

As I noted in earlier essays, prior to the pandemic the 10-year real yield was about zero, which I estimate was roughly a neutral policy stance at that time. In response to the pandemic, the FOMC acted aggressively to support the economy by driving the federal funds rate to the effective lower bound and massively expanding our balance sheet. Those combined effects drove the 10-year real yield to roughly -1 percent, as shown in Figure 3. Since we began our tightening cycle two years ago, 10-year real yields have more than fully retraced their pandemic decline and are now around 2.2 percent. Thus, we are clearly in a tighter stance now than immediately before the pandemic.

This Tightening Cycle Appears to Be as Aggressive as the 1994 Cycle

Data from the TIPS market only go back 20 years or so; thus, to evaluate earlier tightening cycles one must make a number of assumptions about the neutral rate and about inflation expectations.

I do not think comparisons to the 1970s and early 1980s are particularly relevant to us today because in those decades, the FOMC had to establish its inflation-fighting credibility, so the required monetary tightening was very large.

The tightening cycle in 1994 might be a better benchmark because at that time, as is true now, the FOMC had a lot of credibility with the public. Inflation was not as high in 1994, however, as it was in this episode. So it is not a perfect comparison either.

Minneapolis Fed staff’s best estimate is that when the FOMC raised the policy rate by 300 basis points in the 1994 tightening cycle, this translated into an increase of about 200 basis points in the 10-year real rate (Figure 4), which was coincidentally also about 200 basis points above the then-neutral 10-year real rate. So that is the key: It seems as though policy drove the 10-year real rate about 200 basis points above neutral.

How does that compare to our current tightening cycle? (See Figure 3.) If my estimate of neutral being zero before the pandemic still holds, then we have accomplished similar or a bit more tightening in this cycle than was achieved in the 1994 tightening cycle.

Yield Curve Suggests Policy Is Tight

As I stated earlier, the underlying inflationary dynamics are quite different today than in 1994, so simply repeating the 1994 tightening might not be enough. And perhaps the unique dynamics of the post-COVID reopening economy have caused neutral to increase.

Another indicator I look at to assess the stance of monetary policy is the shape of the yield curve. Specifically, if the yield curve is inverted, it might indicate that monetary policy is in a contractionary stance. A lot of public attention is given to the yield curve, and there is a robust debate about whether an inverted yield curve is a reliable recession indicator. I wrote about this in 2018. Setting aside its usefulness as a predictor of recessions, the yield curve does seem to give some indication of the stance of monetary policy. The long end of the yield curve should offer some signal of where market participants believe interest rates will settle once current economic and policy shocks have run their course; if markets understand that neutral has moved, it should be reflected in the long end of the curve. If current short rates are higher than long rates, then that might signal an overall tight stance of policy today. Figure 5 shows the history of the (nominal) yield curve with a number of inversions over the past 50 years, including the current inversion. 2

Depending on the specific measures chosen, the yield curve has now been inverted for more than 20 months, which is a relatively long and somewhat deeper inversion than most prior cycles, the Volcker disinflation period being the exception. The current inverted yield curve suggests that policy is in fact tight relative to the market’s understanding of neutral.

The Resilience in the Housing Market Nonetheless Raises Questions

Housing is traditionally the most interest-rate-sensitive sector of the economy. Prior yield curve inversions also coincided with a marked slowdown or even contraction in residential investment, as shown in Figure 6. Curiously, while residential investment fell in the first part of our tightening cycle, it has since reversed and has grown 5 percent over the past year.

What could explain this apparent resilience in residential real estate given monetary policy that has led to an inverted yield curve? We know that following the Global Financial Crisis, the country built far fewer housing units than were needed to keep up with population growth and household formation. Thus, there appears to be a significant shortage of housing that will take a long time to close. In addition, responses to COVID have led to an increase in people working from home, and that has led to increased demand for housing. In recent years there has also been a significant increase in immigration. While the long-run effect of increased immigration on inflation is unclear, immigrants nonetheless need a place to live, and their arrival in the U.S. has likely also increased demand for housing. Policy actions by the FOMC have driven 30-year mortgage rates from around 4.0 percent prior to the pandemic to around 7.5 percent today. Perhaps that level of mortgage rates is not as contractionary for residential investment as it would have been absent these unique factors which are driving housing demand higher. In other words, perhaps a neutral rate for the housing market is higher than before the pandemic.

Other Signals from the Real Economy Are Mixed

Monetary policy is a blunt instrument that eventually affects virtually the entire economy, not only housing. While high interest rates may not be slowing housing as much as in prior tightening cycles, it is nonetheless having an impact on other sectors of the economy. For example, auto loan and credit card delinquencies have increased from very low levels and are now at rates higher than existed before the pandemic, indicating that some consumers are feeling stress from increased borrowing costs. Overall, however, economic activity, consumer spending and the labor market have proven surprisingly resilient.

The FOMC has undeniably tightened policy meaningfully, both relative to the pre-pandemic period and to some prior tightening cycles. Nonetheless, it is hard for me to explain the robust economic activity that has persisted during this cycle. My colleagues and I are of course very happy that the labor market has proven resilient, but, with inflation in the most recent quarter moving sideways, it raises questions about how restrictive policy really is. If policymakers and market participants are misperceiving the neutral policy rate, that could explain the constellation of data we are observing. This is also a communication challenge for policymakers. In my own Summary of Economic Projections (SEP) submission, I have only modestly increased my longer-run nominal neutral funds rate level from 2 percent to 2.5 percent. The SEP does not provide a simple way to communicate the possibility that the neutral rate might be at least temporarily elevated.

1 These comments reflect my own views and may not necessarily represent the views of others in the Federal Reserve System or of the Federal Open Market Committee.

2 Conceptually, the real yield curve is a better measure of the stance of monetary policy than the nominal yield curve. That said, because nominal and real spreads have been quite similar over the past 18 months, the nominal spread in Figure 5 currently provides an equivalent measure of the stance of monetary policy. I plot nominal yields in Figure 5 simply because they are available for a longer time period than TIPS yields.

Related Content

Policy Has Tightened a Lot. How Tight Is It?

Policy Has Tightened a Lot. Is It Enough? (A Second Update)

The Interaction between Inflation and Financial Stability

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When Prison and Mental Illness Amount to a Death Sentence

The downward spiral of one inmate, Markus Johnson, shows the larger failures of the nation’s prisons to care for the mentally ill.

Supported by

By Glenn Thrush

Photographs by Carlos Javier Ortiz

Glenn Thrush spent more than a year reporting this article, interviewing close to 50 people and reviewing court-obtained body-camera footage and more than 1,500 pages of documents.

• Published May 5, 2024 Updated May 7, 2024

Markus Johnson slumped naked against the wall of his cell, skin flecked with pepper spray, his face a mask of puzzlement, exhaustion and resignation. Four men in black tactical gear pinned him, his face to the concrete, to cuff his hands behind his back.

He did not resist. He couldn’t. He was so gravely dehydrated he would be dead by their next shift change.

Listen to this article with reporter commentary

“I didn’t do anything,” Mr. Johnson moaned as they pressed a shield between his shoulders.

It was 1:19 p.m. on Sept. 6, 2019, in the Danville Correctional Center, a medium-security prison a few hours south of Chicago. Mr. Johnson, 21 and serving a short sentence for gun possession, was in the throes of a mental collapse that had gone largely untreated, but hardly unwatched.

He had entered in good health, with hopes of using the time to gain work skills. But for the previous three weeks, Mr. Johnson, who suffered from bipolar disorder and schizophrenia, had refused to eat or take his medication. Most dangerous of all, he had stealthily stopped drinking water, hastening the physical collapse that often accompanies full-scale mental crises.

Mr. Johnson’s horrific downward spiral, which has not been previously reported, represents the larger failures of the nation’s prisons to care for the mentally ill. Many seriously ill people receive no treatment . For those who do, the outcome is often determined by the vigilance and commitment of individual supervisors and frontline staff, which vary greatly from system to system, prison to prison, and even shift to shift.

The country’s jails and prisons have become its largest provider of inpatient mental health treatment, with 10 times as many seriously mentally ill people now held behind bars as in hospitals. Estimating the population of incarcerated people with major psychological problems is difficult, but the number is likely 200,000 to 300,000, experts say.

Many of these institutions remain ill-equipped to handle such a task, and the burden often falls on prison staff and health care personnel who struggle with the dual roles of jailer and caregiver in a high-stress, dangerous, often dehumanizing environment.

In 2021, Joshua McLemore , a 29-year-old with schizophrenia held for weeks in an isolation cell in Jackson County, Ind., died of organ failure resulting from a “refusal to eat or drink,” according to an autopsy. In April, New York City agreed to pay $28 million to settle a lawsuit filed by the family of Nicholas Feliciano, a young man with a history of mental illness who suffered severe brain damage after attempting to hang himself on Rikers Island — as correctional officers stood by.

Mr. Johnson’s mother has filed a wrongful-death suit against the state and Wexford Health Sources, a for-profit health care contractor in Illinois prisons. The New York Times reviewed more than 1,500 pages of reports, along with depositions taken from those involved. Together, they reveal a cascade of missteps, missed opportunities, potential breaches of protocol and, at times, lapses in common sense.

Prison officials and Wexford staff took few steps to intervene even after it became clear that Mr. Johnson, who had been hospitalized repeatedly for similar episodes and recovered, had refused to take medication. Most notably, they did not transfer him to a state prison facility that provides more intensive mental health treatment than is available at regular prisons, records show.

The quality of medical care was also questionable, said Mr. Johnson’s lawyers, Sarah Grady and Howard Kaplan, a married legal team in Chicago. Mr. Johnson lost 50 to 60 pounds during three weeks in solitary confinement, but officials did not initiate interventions like intravenous feedings or transfer him to a non-prison hospital.

And they did not take the most basic step — dialing 911 — until it was too late.

There have been many attempts to improve the quality of mental health treatment in jails and prisons by putting care on par with punishment — including a major effort in Chicago . But improvements have proved difficult to enact and harder to sustain, hampered by funding and staffing shortages.

Lawyers representing the state corrections department, Wexford and staff members who worked at Danville declined to comment on Mr. Johnson’s death, citing the unresolved litigation. In their interviews with state police investigators, and in depositions, employees defended their professionalism and adherence to procedure, while citing problems with high staff turnover, difficult work conditions, limited resources and shortcomings of co-workers.

But some expressed a sense of resignation about the fate of Mr. Johnson and others like him.

Prisoners have “much better chances in a hospital, but that’s not their situation,” said a senior member of Wexford’s health care team in a deposition.

“I didn’t put them in prison,” he added. “They are in there for a reason.”

Markus Mison Johnson was born on March 1, 1998, to a mother who believed she was not capable of caring for him.

Days after his birth, he was taken in by Lisa Barker Johnson, a foster mother in her 30s who lived in Zion, Ill., a working-class city halfway between Chicago and Milwaukee. Markus eventually became one of four children she adopted from different families.

The Johnson house is a lively split level, with nieces, nephews, grandchildren and neighbors’ children, family keepsakes, video screens and juice boxes. Ms. Johnson sits at its center on a kitchen chair, chin resting on her hand as children wander over to share their thoughts, or to tug on her T-shirt to ask her to be their bathroom buddy.

From the start, her bond with Markus was particularly powerful, in part because the two looked so much alike, with distinctive dimpled smiles. Many neighbors assumed he was her biological son. The middle name she chose for him was intended to convey that message.

“Mison is short for ‘my son,’” she said standing over his modest footstone grave last summer.

He was happy at home. School was different. His grades were good, but he was intensely shy and was diagnosed with attention deficit hyperactivity disorder in elementary school.

That was around the time the bullying began. His sisters were fierce defenders, but they could only do so much. He did the best he could, developing a quick, taunting tongue.

These experiences filled him with a powerful yearning to fit in.

It was not to be.

When he was around 15, he called 911 in a panic, telling the dispatcher he saw two men standing near the small park next to his house threatening to abduct children playing there. The officers who responded found nothing out of the ordinary, and rang the Johnsons’ doorbell.

He later told his mother he had heard a voice telling him to “protect the kids.”

He was hospitalized for the first time at 16, and given medications that stabilized him for stretches of time. But the crises would strike every six months or so, often triggered by his decision to stop taking his medication.

His family became adept at reading signs he was “getting sick.” He would put on his tan Timberlands and a heavy winter coat, no matter the season, and perch on the edge of his bed as if bracing for battle. Sometimes, he would cook his own food, paranoid that someone might poison him.

He graduated six months early, on the dean’s list, but was rudderless, and hanging out with younger boys, often paying their way.

His mother pointed out the perils of buying friendship.

“I don’t care,” he said. “At least I’ll be popular for a minute.”

Zion’s inviting green grid of Bible-named streets belies the reality that it is a rough, unforgiving place to grow up. Family members say Markus wanted desperately to prove he was tough, and emulated his younger, reckless group of friends.

Like many of them, he obtained a pistol. He used it to hold up a convenience store clerk for $425 in January 2017, according to police records. He cut a plea deal for two years of probation, and never explained to his family what had made him do it.

But he kept getting into violent confrontations. In late July 2018, he was arrested in a neighbor’s garage with a handgun he later admitted was his. He was still on probation for the robbery, and his public defender negotiated a plea deal that would send him to state prison until January 2020.

An inpatient mental health system

Around 40 percent of the about 1.8 million people in local, state and federal jails and prison suffer from at least one mental illness, and many of these people have concurrent issues with substance abuse, according to recent Justice Department estimates.

Psychological problems, often exacerbated by drug use, often lead to significant medical problems resulting from a lack of hygiene or access to good health care.

“When you suffer depression in the outside world, it’s hard to concentrate, you have reduced energy, your sleep is disrupted, you have a very gloomy outlook, so you stop taking care of yourself,” said Robert L. Trestman , a Virginia Tech medical school professor who has worked on state prison mental health reforms.

The paradox is that prison is often the only place where sick people have access to even minimal care.

But the harsh work environment, remote location of many prisons, and low pay have led to severe shortages of corrections staff and the unwillingness of doctors, nurses and counselors to work with the incarcerated mentally ill.

In the early 2000s, prisoners’ rights lawyers filed a class-action lawsuit against Illinois claiming “deliberate indifference” to the plight of about 5,000 mentally ill prisoners locked in segregated units and denied treatment and medication.

In 2014, the parties reached a settlement that included minimum staffing mandates, revamped screening protocols, restrictions on the use of solitary confinement and the allocation of about $100 million to double capacity in the system’s specialized mental health units.

Yet within six months of the deal, Pablo Stewart, an independent monitor chosen to oversee its enforcement, declared the system to be in a state of emergency.

Over the years, some significant improvements have been made. But Dr. Stewart’s final report , drafted in 2022, gave the system failing marks for its medication and staffing policies and reliance on solitary confinement “crisis watch” cells.

Ms. Grady, one of Mr. Johnson’s lawyers, cited an additional problem: a lack of coordination between corrections staff and Wexford’s professionals, beyond dutifully filling out dozens of mandated status reports.

“Markus Johnson was basically documented to death,” she said.

‘I’m just trying to keep my head up’

Mr. Johnson was not exactly looking forward to prison. But he saw it as an opportunity to learn a trade so he could start a family when he got out.

On Dec. 18, 2018, he arrived at a processing center in Joliet, where he sat for an intake interview. He was coherent and cooperative, well-groomed and maintained eye contact. He was taking his medication, not suicidal and had a hearty appetite. He was listed as 5 feet 6 inches tall and 256 pounds.

Mr. Johnson described his mood as “go with the flow.”

A few days later, after arriving in Danville, he offered a less settled assessment during a telehealth visit with a Wexford psychiatrist, Dr. Nitin Thapar. Mr. Johnson admitted to being plagued by feelings of worthlessness, hopelessness and “constant uncontrollable worrying” that affected his sleep.

He told Dr. Thapar he had heard voices in the past — but not now — telling him he was a failure, and warning that people were out to get him.

At the time he was incarcerated, the basic options for mentally ill people in Illinois prisons included placement in the general population or transfer to a special residential treatment program at the Dixon Correctional Center, west of Chicago. Mr. Johnson seemed out of immediate danger, so he was assigned to a standard two-man cell in the prison’s general population, with regular mental health counseling and medication.

Things started off well enough. “I’m just trying to keep my head up,” he wrote to his mother. “Every day I learn to be stronger & stronger.”

But his daily phone calls back home hinted at friction with other inmates. And there was not much for him to do after being turned down for a janitorial training program.

Then, in the spring of 2019, his grandmother died, sending him into a deep hole.

Dr. Thapar prescribed a new drug used to treat major depressive disorders. Its most common side effect is weight gain. Mr. Johnson stopped taking it.

On July 4, he told Dr. Thapar matter-of-factly during a telehealth check-in that he was no longer taking any of his medications. “I’ve been feeling normal, I guess,” he said. “I feel like I don’t need the medication anymore.”

Dr. Thapar said he thought that was a mistake, but accepted the decision and removed Mr. Johnson from his regular mental health caseload — instructing him to “reach out” if he needed help, records show.

The pace of calls back home slackened. Mr. Johnson spent more time in bed, and became more surly. At a group-therapy session, he sat stone silent, after showing up late.

By early August, he was telling guards he had stopped eating.

At some point, no one knows when, he had intermittently stopped drinking fluids.

‘I’m having a breakdown’

Then came the crash.

On Aug. 12, Mr. Johnson got into a fight with his older cellmate.

He was taken to a one-man disciplinary cell. A few hours later, Wexford’s on-site mental health counselor, Melanie Easton, was shocked by his disoriented condition. Mr. Johnson stared blankly, then burst into tears when asked if he had “suffered a loss in the previous six months.”

He was so unresponsive to her questions she could not finish the evaluation.

Ms. Easton ordered that he be moved to a 9-foot by 8-foot crisis cell — solitary confinement with enhanced monitoring. At this moment, a supervisor could have ticked the box for “residential treatment” on a form to transfer him to Dixon. That did not happen, according to records and depositions.

Around this time, he asked to be placed back on his medication but nothing seems to have come of it, records show.

By mid-August, he said he was visualizing “people that were not there,” according to case notes. At first, he was acting more aggressively, once flicking water at a guard through a hole in his cell door. But his energy ebbed, and he gradually migrated downward — from standing to bunk to floor.

“I’m having a breakdown,” he confided to a Wexford employee.

At the time, inmates in Illinois were required to declare an official hunger strike before prison officials would initiate protocols, including blood testing or forced feedings. But when a guard asked Mr. Johnson why he would not eat, he said he was “fasting,” as opposed to starving himself, and no action seems to have been taken.

‘Tell me this is OK!’

Lt. Matthew Morrison, one of the few people at Danville to take a personal interest in Mr. Johnson, reported seeing a white rind around his mouth in early September. He told other staff members the cell gave off “a death smell,” according to a deposition.

On Sept. 5, they moved Mr. Johnson to one of six cells adjacent to the prison’s small, bare-bones infirmary. Prison officials finally placed him on the official hunger strike protocol without his consent.

Mr. Morrison, in his deposition, said he was troubled by the inaction of the Wexford staff, and the lack of urgency exhibited by the medical director, Dr. Justin Young.

On Sept. 5, Mr. Morrison approached Dr. Young to express his concerns, and the doctor agreed to order blood and urine tests. But Dr. Young lived in Chicago, and was on site at the prison about four times a week, according to Mr. Kaplan. Friday, Sept. 6, 2019, was not one of those days.

Mr. Morrison arrived at work that morning, expecting to find Mr. Johnson’s testing underway. A Wexford nurse told him Dr. Young believed the tests could wait.

Mr. Morrison, stunned, asked her to call Dr. Young.

“He’s good till Monday,” Dr. Young responded, according to Mr. Morrison.

“Come on, come on, look at this guy! You tell me this is OK!” the officer responded.

Eventually, Justin Duprey, a licensed nurse practitioner and the most senior Wexford employee on duty that day, authorized the test himself.

Mr. Morrison, thinking he had averted a disaster, entered the cell and implored Mr. Johnson into taking the tests. He refused.

So prison officials obtained approval to remove him forcibly from his cell.

‘Oh, my God’

What happened next is documented in video taken from cameras held by officers on the extraction team and obtained by The Times through a court order.

Mr. Johnson is scarcely recognizable as the neatly groomed 21-year-old captured in a cellphone picture a few months earlier. His skin is ashen, eyes fixed on the middle distance. He might be 40. Or 60.

At first, he places his hands forward through the hole in his cell door to be cuffed. This is against procedure, the officers shout. His hands must be in back.

He will not, or cannot, comply. He wanders to the rear of his cell and falls hard. Two blasts of pepper spray barely elicit a reaction. The leader of the tactical team later said he found it unusual and unnerving.

The next video is in the medical unit. A shield is pressed to his chest. He is in agony, begging for them to stop, as two nurses attempt to insert a catheter.

Then they move him, half-conscious and limp, onto a wheelchair for the blood draw.

For the next 20 minutes, the Wexford nurse performing the procedure, Angelica Wachtor, jabs hands and arms to find a vessel that will hold shape. She winces with each puncture, tries to comfort him, and grows increasingly rattled.

“Oh, my God,” she mutters, and asks why help is not on the way.

She did not request assistance or discuss calling 911, records indicate.

“Can you please stop — it’s burning real bad,” Mr. Johnson said.

Soon after, a member of the tactical team reminds Ms. Wachtor to take Mr. Johnson’s vitals before taking him back to his cell. She would later tell Dr. Young she had been unable to able to obtain his blood pressure.

“You good?” one of the team members asks as they are preparing to leave.

“Yeah, I’ll have to be,” she replies in the recording.

Officers lifted him back onto his bunk, leaving him unconscious and naked except for a covering draped over his groin. His expressionless face is visible through the window on the cell door as it closes.

‘Cardiac arrest.’

Mr. Duprey, the nurse practitioner, had been sitting inside his office after corrections staff ordered him to shelter for his own protection, he said. When he emerged, he found Ms. Wachtor sobbing, and after a delay, he was let into the cell. Finding no pulse, Mr. Duprey asked a prison employee to call 911 so Mr. Johnson could be taken to a local emergency room.

The Wexford staff initiated CPR. It did not work.

At 3:38 p.m., the paramedics declared Markus Mison Johnson dead.

Afterward, a senior official at Danville called the Johnson family to say he had died of “cardiac arrest.”

Lisa Johnson pressed for more information, but none was initially forthcoming. She would soon receive a box hastily crammed with his possessions: uneaten snacks, notebooks, an inspirational memoir by a man who had served 20 years at Leavenworth.

Later, Shiping Bao, the coroner who examined his body, determined Mr. Johnson had died of severe dehydration. He told the state police it “was one of the driest bodies he had ever seen.”

For a long time, Ms. Johnson blamed herself. She says that her biggest mistake was assuming that the state, with all its resources, would provide a level of care comparable to what she had been able to provide her son.

She had stopped accepting foster care children while she was raising Markus and his siblings. But as the months dragged on, she decided her once-boisterous house had become oppressively still, and let local agencies know she was available again.

“It is good to have children around,” she said. “It was too quiet around here.”

Read by Glenn Thrush

Audio produced by Jack D’Isidoro .

Glenn Thrush covers the Department of Justice. He joined The Times in 2017 after working for Politico, Newsday, Bloomberg News, The New York Daily News, The Birmingham Post-Herald and City Limits. More about Glenn Thrush

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• Published: 01 May 2024

Temporal dynamics of the multi-omic response to endurance exercise training

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Regular exercise promotes whole-body health and prevents disease, but the underlying molecular mechanisms are incompletely understood 1 , 2 , 3 . Here, the Molecular Transducers of Physical Activity Consortium 4 profiled the temporal transcriptome, proteome, metabolome, lipidome, phosphoproteome, acetylproteome, ubiquitylproteome, epigenome and immunome in whole blood, plasma and 18 solid tissues in male and female Rattus norvegicus over eight weeks of endurance exercise training. The resulting data compendium encompasses 9,466 assays across 19 tissues, 25 molecular platforms and 4 training time points. Thousands of shared and tissue-specific molecular alterations were identified, with sex differences found in multiple tissues. Temporal multi-omic and multi-tissue analyses revealed expansive biological insights into the adaptive responses to endurance training, including widespread regulation of immune, metabolic, stress response and mitochondrial pathways. Many changes were relevant to human health, including non-alcoholic fatty liver disease, inflammatory bowel disease, cardiovascular health and tissue injury and recovery. The data and analyses presented in this study will serve as valuable resources for understanding and exploring the multi-tissue molecular effects of endurance training and are provided in a public repository ( https://motrpac-data.org/ ).

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The impact of exercise on gene regulation in association with complex trait genetics

Genome-wide association studies

Regular exercise provides wide-ranging health benefits, including reduced risks of all-cause mortality 1 , 5 , cardiometabolic and neurological diseases, cancer and other pathologies 2 , 6 , 7 . Exercise affects nearly all organ systems in either improving health or reducing disease risk 2 , 3 , 6 , 7 , with beneficial effects resulting from cellular and molecular adaptations within and across many tissues and organ systems 3 . Various ‘omic’ platforms (‘omes’) including transcriptomics, epigenomics, proteomics and metabolomics, have been used to study these events. However, work to date typically covers one or two omes at a single time point, is biased towards one sex, and often focuses on a single tissue, most often skeletal muscle, heart or blood 8 , 9 , 10 , 11 , 12 , with few studies considering other tissues 13 . Accordingly, a comprehensive, organism-wide, multi-omic map of the effects of exercise is needed to understand the molecular underpinnings of exercise training-induced adaptations. To address this need, the Molecular Transducers of Physical Activity Consortium (MoTrPAC) was established with the goal of building a molecular map of the exercise response across a broad range of tissues in animal models and in skeletal muscle, adipose and blood in humans 4 . Here we present the first whole-organism molecular map of the temporal effects of endurance exercise training in male and female rats and provide multiple insights enabled by this MoTrPAC multi-omic data resource.

Multi-omic analysis of exercise training

Six-month-old male and female Fischer 344 rats were subjected to progressive treadmill endurance exercise training (hereafter referred to as endurance training) for 1, 2, 4 or 8 weeks, with tissues collected 48 h after the last exercise bout (Fig. 1a ). Sex-matched sedentary, untrained rats were used as controls. Training resulted in robust phenotypic changes (Extended Data Fig. 1a–d ), including increased aerobic capacity (VO 2 max) by 18% and 16% at 8 weeks in males and females, respectively (Extended Data Fig. 1a ). The percentage of body fat decreased by 5% in males at 8 weeks (Extended Data Fig. 1b ), without a significant change in lean mass (Extended Data Fig. 1c ). In females, the body fat percentage did not change after 4 or 8 weeks of training, whereas it increased by 4% in sedentary controls (Extended Data Fig. 1b ). Body weight of females increased in all intervention groups, with no change for males (Extended Data Fig. 1d ).

a , Experimental design and tissue sample processing. Inbred Fischer 344 rats were subjected to a progressive treadmill training protocol. Tissues were collected from male and female animals that remained sedentary or completed 1, 2, 4 or 8 weeks of endurance exercise training. For trained animals, samples were collected 48 h after their last exercise bout (red pins). b , Summary of molecular datasets included in this study. Up to nine data types (omes) were generated for blood, plasma, and 18 solid tissues, per animal: ACETYL: acetylproteomics; protein site acetylation; ATAC, chromatin accessibility, ATAC-seq data; IMMUNO, multiplexed immunoassays; METAB, metabolomics and lipidomics; METHYL, DNA methylation, RRBS data; PHOSPHO, phosphoproteomics; protein site phosphorylation; PROT, global proteomics; protein abundance; TRNSCRPT, transcriptomics, RNA-seq data; UBIQ, ubiquitylome, protein site ubiquitination. Tissue labels indicate the location, colour code, and abbreviation for each tissue used throughout this study: ADRNL, adrenal gland; BAT, brown adipose tissue; BLOOD, whole blood, blood RNA; COLON, colon; CORTEX, cerebral cortex; HEART, heart; HIPPOC, hippocampus; HYPOTH, hypothalamus; KIDNEY, kidney; LIVER, liver; LUNG, lung; OVARY, ovaries; PLASMA, plasma; SKM-GN, gastrocnemius (skeletal muscle); SKM-VL, vastus lateralis (skeletal muscle); SMLINT, small intestine; SPLEEN, spleen; TESTES, testes; VENACV, vena cava; WAT-SC, subcutaneous white adipose tissue. Icons next to each tissue label indicate the data types generated for that tissue. c , Number of training-regulated features at 5% FDR. Each cell represents results for a single tissue and data type. Colours indicate the proportion of measured features that are differential.

Whole blood, plasma and 18 solid tissues were analysed using genomics, proteomics, metabolomics and protein immunoassay technologies, with most assays performed in a subset of these tissues (Fig. 1b and Extended Data Fig. 1e,f ). Specific details for each omic analysis are provided in Extended Data Fig. 2 , Methods, Supplementary Discussion and Supplementary Table 1 . Molecular assays were prioritized on the basis of available tissue quantity and biological relevance, with the gastrocnemius, heart, liver and white adipose tissue having the most diverse set of molecular assays performed, followed by the kidney, lung, brown adipose tissue and hippocampus (Extended Data Fig. 1e ). Altogether, datasets were generated from 9,466 assays across 211 combinations of tissues and molecular platforms, resulting in 681,256 non-epigenetic and 14,334,496 epigenetic (reduced-representation bisulfite sequencing (RRBS) and assay for transposase-accessible chromatin using sequencing (ATAC-seq)) measurements, corresponding to 213,689 and 2,799,307 unique non-epigenetic and epigenetic features, respectively.

Differential analysis was used to characterize the molecular responses to endurance training (Methods). We computed the overall significance of the training response for each feature, denoted as the training P value, where 35,439 features at 5% false discovery rate (FDR) comprise the training-regulated differential features (Fig. 1c and Supplementary Table 2 ). Timewise summary statistics quantify the exercise training effects for each sex and time point. Training-regulated molecules were observed in the vast majority of tissues for all omes, including a relatively large proportion of transcriptomics, proteomics, metabolomics and immunoassay features (Fig. 1c ). The observed timewise effects were modest: 56% of the per-feature maximum fold changes were between 0.67 and 1.5. Permutation testing showed that permuting the group or sex labels resulted in a significant reduction in the number of selected analytes in most tissues (Extended Data Fig. 3a–d and Supplementary Discussion ). For transcriptomics, the hypothalamus, cortex, testes and vena cava had the smallest proportion of training-regulated genes, whereas the blood, brown and white adipose tissues, adrenal gland and colon showed more extensive effects (Fig. 1c ). For proteomics, the gastrocnemius, heart and liver showed substantial differential regulation in both protein abundance and post-translational modifications (PTMs), with more restricted results in white adipose tissue, lung and kidney protein abundance. For metabolomics, a large proportion of differential metabolites were consistently observed across all tissues, although the absolute numbers were related to the number of metabolomic platforms used (Extended Data Fig. 1e ). The vast number of differential features over the training time course across tissues and omes highlights the multi-faceted, organism-wide nature of molecular adaptations to endurance training.

Multi-tissue response to training

To identify tissue-specific and multi-tissue training-responsive gene expression, we considered the six tissues with the deepest molecular profiling: gastrocnemius, heart, liver, white adipose tissue, lung and kidney. In sum, 11,407 differential features from these datasets were mapped to their cognate gene, for a total of 7,115 unique genes across the tissues (Fig. 2a , Extended Data Fig. 4a and Supplementary Table 3 ). Most of the genes with at least one training-responsive feature were tissue-specific (67%), with the greatest number appearing in white adipose tissue (Fig. 2a ). We identified pathways enriched by these tissue-specific training-responsive genes (Extended Data Fig. 4b ) and tabulated a subset of highly specific genes to gain insight into tissue-specific training adaptation (Supplementary Table 4 ). Focusing on sexually conserved responses revealed tissue-dependent adaptations. These included changes related to immune cell recruitment and tissue remodelling in the lung, cofactor and cholesterol biosynthesis in the liver, ion flux in the heart, and metabolic processes and striated muscle contraction in the gastrocnemius ( Supplementary Discussion ). A detailed analysis of white adipose tissue adaptations to exercise training is provided elsewhere 14 . We also observed ‘ome’-specific responses, with unique transcript and protein responses at the gene and pathway levels (Extended Data Fig. 4c,d , Supplementary Discussion and Supplementary Tables 5 and 6 ).

a , UpSet plot of the training-regulated gene sets associated with each tissue. Bars and dots indicating tissue-specific differential genes are coloured by tissue. Pathway enrichment analysis is shown for selected sets of genes in b , c as indicated by the arrows. b , c , Significantly enriched pathways (10% FDR) corresponding to genes that are differential in both LUNG and WAT-SC datasets ( b ) and the 22 genes that are training-regulated in all six tissues considered in a ( c ). Redundant pathways (those with an overlap of 80% or greater with an existing pathway) were removed. ESR, oestrogen receptor; T H 17, T helper 17.

2,359 genes had differential features in at least two tissues (Fig. 2a ). Lung and white adipose tissue had the largest set of uniquely shared genes ( n  = 249), with predominantly immune-related pathway enrichments (Fig. 2b ); expression patterns suggested decreased inflammation in the lung and increased immune cell recruitment in white adipose tissue (Supplementary Tables 2 and 3 ). Heart and gastrocnemius had the second-largest group of uniquely shared genes, with enrichment of mitochondrial metabolism pathways including the mitochondria fusion genes Opa1 and Mfn1 (Supplementary Table 3 ).

Twenty-two genes were training-regulated in all six tissues, with particular enrichment in heat shock response pathways (Fig. 2c ). Exercise induces the expression of heat shock proteins (HSPs) in various rodent and human tissues 15 . A focused analysis of our transcriptomics and proteomics data revealed HSPs as prominent outliers (Extended Data Fig. 5a and Supplementary Discussion ). Specifically, there was a marked, proteomics-driven up-regulation in the abundance of HSPs, including the major HSPs HSPA1B and HSP90AA1 (Extended Data Fig. 5b,c ). Another ubiquitous endurance training response involved regulation of the kininogenases KNG1 and KNG2 (Supplementary Table 3 ). These enzymes are part of the kallikrein–kininogen system and have been implicated in the hypotensive and insulin-sensitizing effects of exercise 16 , 17 .

Transcription factors and phosphosignalling

We used proteomics and transcriptomics data to infer changes in transcription factor and phosphosignalling activities in response to endurance training through transcription factor and PTM enrichment analyses (Methods). We compared the most significantly enriched transcription factors across tissues (Fig. 3a , Extended Data Fig. 6a and Supplementary Table 7 ). In the blood, we observed enrichment of the haematopoietic-associated transcription factors GABPA, ETS1, KLF3 and ZNF143; haematopoietic progenitors are proposed to be transducers of the health benefits of exercise 18 . In the heart and skeletal muscle, we observed a cluster of enriched Mef2 family transcription factor motifs (Fig. 3a ). MEF2C is a muscle-associated transcription factor involved in skeletal, cardiac and smooth muscle cell differentiation and has been implicated in vascular development, formation of the cardiac loop and neuron differentiation 19 .

a , Transcription factor motif enrichment analysis of the training-regulated transcripts in each tissue. The heat map shows enrichment z -scores across the differential genes for the 13 tissues that had at least 300 genes after mapping transcript IDs to gene symbols. Transcription factors were hierarchically clustered by their enrichment across tissues. CRE, cAMP response element. b , Estimate of activity changes in selected kinases and signalling pathways using PTM signature enrichment analysis on phosphoproteomics data. Only kinases or pathways with a significant difference in at least one tissue, sex or time point ( q value < 0.05) are shown. The heat map shows normalized enrichment score (NES) as colour; tissue, sex and time point combinations as columns, and either kinases or pathways as rows. Kinases are grouped by family; rows are hierarchically clustered within each group. FSH, follicle-stimulating hormone; TSH, thyroid-stimulating hormone.

Phosphorylation signatures of key kinases were altered across many tissues (Fig. 3b and Supplementary Table 8 ). This included AKT1 across heart, kidney and lung, mTOR across heart, kidney and white adipose tissue, and MAPK across heart and kidney. The liver showed an increase in the phosphosignature related to regulators of hepatic regeneration, including EGFR1, IGF and HGF (Extended Data Fig. 6b , Supplementary Discussion ). Increased phosphorylation of STAT3 and PXN, HGF targets involved in cell proliferation, suggest a mechanism for liver regeneration in response to exercise (Extended Data Fig. 6c ). In the heart, kinases showed bidirectional changes in their predicted basal activity in response to endurance training (Extended Data Fig. 6d and Supplementary Discussion ). Several AGC protein kinases showed a decrease in predicted activity, including AKT1, whereas tyrosine kinases, including SRC and mTOR, were predicted to have increased activity. The known SRC target phosphorylation sites GJA1 pY265 and CDH2 pY820 showed significantly increased phosphorylation in response to training (Extended Data Fig. 6e ). Notably, phosphorylation of GJA1 Y265 has previously been shown to disrupt gap junctions, key transducers of cardiac electrical conductivity 20 . This suggests that SRC signalling may regulate extracellular structural remodelling of the heart to promote physiologically beneficial adaptations. In agreement with this hypothesis, gene set enrichment analysis (GSEA) of extracellular matrix proteins revealed a negative enrichment in response to endurance training, showing decreased abundance of proteins such as basement membrane proteins (Extended Data Fig. 6f–h and Supplementary Table 9 ).

Molecular hubs of exercise adaptation

To compare the dynamic multi-omic responses to endurance training across tissues, we clustered the 34,244 differential features with complete timewise summary statistics using an empirical Bayes graphical clustering approach (Methods). By integrating these results onto a graph, we summarize the dynamics of the molecular training response and identify groups of features with similar responses (Extended Data Fig. 7 and Supplementary Table 10 ). We performed pathway enrichment analysis for many graphically defined clusters to characterize putative underlying biology (Supplementary Table 11 ).

We examined biological processes associated with training using the pathway enrichment results for up-regulated features at 8 weeks of training (Extended Data Fig. 8 , Supplementary Table 12 and Supplementary Discussion ). Compared with other tissues, the liver showed substantial regulation of chromatin accessibility, including in the nuclear receptor signalling and cellular senescence pathways. In the gastrocnemius, terms related to peroxisome proliferator-activated receptors (PPAR) signalling and lipid synthesis and degradation were enriched at the protein level, driven by proteins including the lipid droplet features PLIN2, PLIN4 and PLIN5. At the metabolomic level, terms related to ether lipid and glycerophospholipid metabolism were enriched. Together, these enrichments highlight the well-known ability of endurance training to modulate skeletal muscle lipid composition, storage, synthesis and metabolism. The blood displayed pathway enrichments related to translation and organelle biogenesis and maintenance. Paired with the transcription factor analysis (Fig. 3a ), this suggests increased haematopoietic cellular mobilization in the blood. Less studied tissues in the context of exercise training, including the adrenal gland, spleen, cortex, hippocampus and colon, also showed regulation of diverse pathways ( Supplementary Discussion ).

To identify the main temporal or sex-associated responses in each tissue, we summarized the graphical cluster sizes by tissue and time (Extended Data Fig. 7a ). We observed that the small intestine and plasma had more changes at weeks 1 and 2 of training. Conversely, many up-regulated features in brown adipose tissue and down-regulated features in white adipose tissue were observed only at week 8. The largest proportion of opposite effects between males and females was observed at week 1 in the adrenal gland. Other tissues, including the blood, heart, lung, kidney and skeletal muscle (gastrocnemius and vastus lateralis), had relatively consistent numbers of up-regulated and down-regulated features.

We next focused on characterizing shared molecular responses in the three striated muscles (gastrocnemius, vastus lateralis and heart). The three largest graphical clustering paths of differential features in each muscle tissue converged to a sex-consistent response by week 8 (Fig. 4a ). Because of the large number of muscle features that were up-regulated in both sexes at week 8, we further examined the corresponding multi-omic set of analytes (Fig. 4b ). Pathway enrichment analysis of the genes associated with these differential features demonstrated a sex- and muscle-consistent endurance training response that reflected up-regulation of mitochondrial metabolism, biogenesis and translation, and cellular response to heat stress (Fig. 4c and Supplementary Table 11 ).

a , Graphical representation of training-differential features in the three muscle tissues: gastrocnemius (SKM-GN), vastus lateralis (SKM-VL) and heart. Each node represents one of nine possible states (rows) at each of the four training time points (columns). Triangles to the left of row labels map states to symbols used in Fig. 5a . Edges represent the path of differential features over the training time course (see Extended Data Fig. 7 for a detailed explanation). Each graph includes the three largest paths of differential features in that tissue, with edges split by data type. Both node and edge size are proportional to the number of features represented. The node corresponding to features that are up-regulated in both sexes at 8 weeks of training (8w_F1_M1) is circled in each graph. b , Line plots of standardized abundances of all 8w_F1_M1 muscle features. The black line represents the average value across all features. c , Network view of significant pathway enrichment results (10% FDR) corresponding to the features in b . Nodes represent pathways; edges represent functionally similar node pairs (set similarity ≥ 0.3). Nodes are included only if they are significantly enriched in at least two of the muscle tissues, as indicated by node colour. Node size is proportional to the number of differential feature sets (for example, gastrocnemius transcripts) for which the pathway is significantly enriched. High-level biological themes were defined using Louvain community detection of the nodes. d , A subnetwork of a larger cluster identified by network clustering 8w_F1_M1 features from SKM-GN. Mech., mechanical.

We used a network connectivity analysis to study up-regulated features in the gastrocnemius at week 8 (Extended Data Fig. 9a,b , Methods and Supplementary Discussion ). Mapping features to genes revealed overlaps between transcriptomic, chromatin accessibility, and proteomic assays, but no overlaps with methylation. Three molecular interaction networks were compared (Methods), and BioGRID 21 was used for further clustering analysis, which identified three clusters (Extended Data Fig. 9c and Supplementary Table 13 ). The largest cluster was significantly enriched for multiple muscle adaptation processes (Fig. 4d and Supplementary Table 14 ). This analysis illustrates the direct linkage among pathways and putative central regulators, emphasizing the importance of multi-omic data in identifying interconnected networks and understanding skeletal muscle remodelling.

Connection to human diseases and traits

To systematically evaluate the translational value of our data, we integrated our results with extant exercise studies and disease ontology (DO) annotations (Methods). First, we compared our vastus lateralis transcriptomics results to a meta-analysis of long-term training gene-expression changes in human skeletal muscle tissue 8 , demonstrating a significant and direction-consistent overlap (Extended Data Fig. 9d–g and Supplementary Discussion ). We also identified a significant overlap between differential transcripts in the gastrocnemius of female rats trained for 8 weeks and differentially expressed genes identified in the soleus in a study of sedentary and exercise-trained female rats selectively bred for high or low exercise capacity 22 (Extended Data Fig. 9h ). Similarly, adaptations from high-intensity interval training in humans 23 significantly overlapped with the proteomics response in rats (Extended Data Fig. 9i ), particularly for female rats trained for 8 weeks (Extended Data Fig. 9j ). Finally, we performed DO enrichment analysis using the DOSE R package 24 (Supplementary Table 15 and Methods). Down-regulated genes from white adipose tissue, kidney and liver were enriched for several disease terms, suggesting a link between the exercise response and type 2 diabetes, cardiovascular disease, obesity and kidney disease (5% FDR; Extended Data Fig. 9k and Supplementary Discussion ), which are all epidemiologically related co-occurring diseases 25 . Overall, these results support a high concordance of our data from rats with human studies and their relevance to human disease.

Sex-specific responses to exercise

Many tissues showed sex differences in their training responses (Extended Data Fig. 10 ), with 58% of the 8-week training-regulated features demonstrating sex-differentiated responses. Opposite responses between the sexes were observed in adrenal gland transcripts, lung phosphosites and chromatin accessibility features, white adipose tissue transcripts and liver acetylsites. In addition, proinflammatory cytokines exhibited sex-associated changes across tissues (Extended Data Fig. 11a,b and Supplementary Table 16 ). Most female-specific cytokines were differentially regulated between weeks 1 and 2 of training, whereas most male-specific cytokines were differentially regulated between weeks 4 and 8 (Extended Data Fig. 11c ).

We observed extensive transcriptional remodelling of the adrenal gland, with more than 4,000 differential genes. Notably, the largest graphical path of training-regulated features was negatively correlated between males and females, with sustained down-regulation in females and transient up-regulation at 1 week in males (Extended Data Fig. 11d ). The genes in this path were also associated with steroid hormone synthesis pathways and metabolism, particularly those pertaining to mitochondrial function (Supplementary Table 11 ). Further, transcription factor motif enrichment analysis of the transcripts in this path showed enrichment of 14 transcription factors (5% FDR; Supplementary Table 17 ), including the metabolism-regulating factors PPARγ, PPARα and oestrogen-related receptor gamma (ERRγ). The gene-expression levels of several significantly enriched transcription factors themselves followed the same trajectory as this path (Extended Data Fig. 11e ).

In the rat lung, we observed decreased phosphosignalling activity with training primarily in males (Fig. 3b ). Among these, the PRKACA phosphorylation signature showed the largest sex difference at 1 and 2 weeks (Extended Data Fig. 11f–h and Supplementary Table 8 ). PRKACA is a kinase that is involved in signalling within multiple cellular pathways. However, four PRKACA substrates followed this pattern and were associated with cellular structures (such as cytoskeleton and cell–cell junctions): DSP, MYLK, STMN1 and SYNE1 (Extended Data Fig. 11i ). The phosphorylation of these proteins suggests a sex-dependent role of PRKACA in mediating changes in lung structure or mechanical function with training. This is supported as DSP and MYLK have essential roles in alveolar and epithelial cell remodelling in the lung 26 , 27 .

Immune pathway enrichment analysis of training-regulated transcripts at 8 weeks showed limited enrichment in muscle (heart, gastrocnemius and vastus lateralis) and brain (cortex, hippocampus, hypothalamus), down-regulation in the lung and small intestine, and strong up-regulation in brown and white adipose tissue in males only (Fig. 5a , Extended Data Fig. 12a and Supplementary Table 11 ). Many of the same immune pathways (Supplementary Table 18 ) and immune-related transcription factors (Supplementary Table 19 ) were enriched in both adipose tissues in males. Furthermore, correlation between the transcript expression profiles of male-specific up-regulated features in the adipose tissues and immune cell markers from external cell-typing assays revealed a strong positive correlation for many immune cell types, including B, T and natural killer cells, and low correlation with platelets, erythrocytes and lymphatic tissue (Fig. 5b,c , Methods and Supplementary Table 20 ). These patterns suggest recruitment of peripheral immune cells or proliferation of tissue-resident immune cells as opposed to non-biological variation in blood or lymph content. Correlations at the protein level were not as marked (Extended Data Fig. 12b,c ). Complementary analyses using CIBERTSORTx produced similar results (Extended Data Fig. 12d,e ). In summary, our data suggest an important role of immune cell activity in the adaptation of male adipose tissue to endurance training.

a , Enrichment analysis results of the training-differential transcripts at 8 weeks in Kyoto Encyclopedia of Genes and Genomes (KEGG) immune system pathways (10% FDR). NK, natural killer. b , Line plots of standardized abundances of selected training-differential transcripts. Brown and white adipose tissue show male-specific up-regulation at week 8 (8w_F0_M1). The small intestine (SMLINT) shows down-regulation in females and partial down-regulation in males at week 8 (8w_F-1_M0 or 8w_F-1_M-1). c , Box plots of the sample-level Pearson correlation between markers of immune cell types, lymphatic tissue or cell proliferation and the average value of features in b at the transcript level. A pink dot indicates that the marker is also one of the differential features plotted in b . A pound sign indicates that the distribution of Pearson correlations for a set of at least two markers is significantly different from 0 (two-sided one-sample t -test, 5% FDR). When only one marker is used to define a category on the y axis, the gene name is provided in parentheses. In box plots, the centre line represents median, box bounds represent 25th and 75th percentiles, whiskers represent minimum and maximum excluding outliers and blue dots represent outliers.

The small intestine was among the tissues with the highest enrichment in immune-related pathways (Extended Data Fig. 12a ), with down-regulation of transcripts at 8 weeks, and a more robust response in females (Fig. 5b ). This transcript set was significantly enriched with pathways related to gut inflammation (Supplementary Table 11 ). We observed positive associations between these transcripts and markers of several immune cell types, including B, T, natural killer and dendritic cells, suggesting decreased abundance (Fig. 5c and Supplementary Discussion ). Endurance training also decreased the expression of transcripts with genetic risk loci for inflammatory bowel disease (IBD), including major histocompatability complex class II 28 , a finding that also emerged through the DO enrichment analysis (Supplementary Table 15 ). Endurance training is suggested to reduce systemic inflammation, in part by increasing gut microbial diversity and gut barrier integrity 29 . In accordance, we observed decreases in Cxcr3 and Il1a with training (Extended Data Fig. 12f ), both of which are implicated in the pathogenesis of IBD 30 , 31 . Together, these data suggest that endurance training improves gut homeostasis, potentially conferring systemic anti-inflammatory effects.

Multi-tissue changes in mitochondria and lipids

We summarized the organism-wide metabolic changes for metabolomic datasets using RefMet metabolite classes (Fig. 6a and Supplementary Table 21 ) and for non-metabolomics datasets using metabolic subcategories of KEGG pathways (10% FDR; Extended Data Fig. 13a and Supplementary Table 11 ). The liver showed the greatest number of significantly enriched metabolite classes, followed by the heart, lung and hippocampus (Fig. 6a and Supplementary Discussion ). Inspection of individual metabolites and acylcarnitine groups revealed changes associated with functional alterations in response to training (Extended Data Fig. 13b–d and Supplementary Discussion ). Of particular interest, trimethylamine- N -oxide has been associated with cardiovascular disease 32 . We observed up-regulation of 1-methylhistidine, a marker of muscle protein turnover, in the kidney at 1, 2 and 4 weeks, which may indicate muscle breakdown and clearance through the kidney during early training time points. Cortisol levels were increased as expected from the physiological stress of training, and we observed a substantial increase in the kidney, again probably owing to renal clearance 33 . The liver showed up-regulation of 1-methylnicotinamide, which may have a role in inflammation 34 , at 8 weeks.

a , RefMet metabolite class enrichment calculated using GSEA with the −log 10 training P value. Significant chemical class enrichments (5% FDR) are shown as black circles with size is proportional to FDR. Small grey circles are chemical class enrichments that were not significant, and blank cells were not tested owing to low numbers of detected metabolites. TCA, tricarboxylic acid cycle. b , GSEA results using the MitoCarta MitoPathways gene set database and proteomics (PROT) or acetylome (ACETYL) timewise summary statistics for training. NESs are shown for significant pathways (10% FDR). Mitochondrial pathways shown as rows are grouped using the parental group in the MitoPathways hierarchy. OXPHOS, oxidative phosphorylation. c , Line plots of standardized abundances of liver training-differential features across all data types that are up-regulated in both sexes, with a later response in females (LIVER: 1w_F0_M1 − >2w_F0_M1 − >4w_F0_M1 − >8w_F1_M1). The black line represents the average value across all features. d , Network view of pathway enrichment results corresponding to features in c . Nodes indicate significantly enriched pathways (10% FDR); edges connect nodes if there is a similarity score of at least 0.375 between the gene sets driving each pathway enrichment. Node colours indicate omes in which the enrichment was observed. e , log 2 fold changes (logFC) relative to sedentary controls for metabolites within the ‘Lipids and lipid related compounds’ category in the 8-week liver. Heat map colour represents fold change (red, positive; blue, negative). Compounds are grouped into columns based on category (coloured bars).

The heart showed enrichment of various carbohydrate metabolism subcategories across many omes (Extended Data Fig. 13a ), and remarkably, all enzymes within the glycolysis–gluconeogenesis pathway showed a consistent increase in abundance, except for GPI, FBP2 and DLAT (Extended Data Fig. 13e ). Oxidative phosphorylation was enriched in most tissues and is consistent with the joint analyses of the muscle tissues (Fig. 4c ), suggesting potential changes in mitochondria biogenesis. We estimated proportional mitochondrial changes to endurance training using mitochondrial RNA-sequencing (RNA-seq) reads (Extended Data Fig. 14a–c ) and changes of mitochondrial functions through GSEA using gene expression, protein abundance and protein PTMs (Fig. 6b , Extended Data Fig. 14d and Supplementary Tables 22 – 25 ). Increased mitochondrial biogenesis was observed in skeletal muscle, heart and liver across these analyses. Moreover, sex-specific mitochondrial changes were observed in the adrenal gland, as described above, and in the colon, lung and kidney. These results highlight a highly adaptive and pervasive mitochondrial response to endurance training; a more in-depth analysis of this response is provided elsewhere 35 .

In the liver, we observed substantial regulation of metabolic pathways across the proteome, acetylome and lipidome (Fig. 6a,b and Extended Data Fig. 13a ). For example, there was significant enrichment in 12 metabolite classes belonging to ‘lipids and lipid-related compounds’ (Fig. 6a and Supplementary Table 26 ). We therefore focused on the large group of features that increased in abundance over time for both sexes (Fig. 6c ). Most of these liver features corresponded to protein abundance and protein acetylation changes in the mitochondrial, amino acid and lipid metabolic pathways (Fig. 6d and Supplementary Table 27 ). We also observed an increase in phosphatidylcholines and a concomitant decrease in triacylglycerols (Fig. 6e ). Finally, there was increased abundance and acetylation of proteins from the peroxisome, an organelle with key functions in lipid metabolism (Extended Data Fig. 14e ). To our knowledge, these extensive changes in protein acetylation in response to endurance training have not been described previously. Together, these molecular adaptations may constitute part of the mechanisms underlying exercise-mediated improvements in liver health, particularly protection against excessive intrahepatic lipid storage and steatosis 36 .

Mapping the molecular exercise responses across a whole organism is critical for understanding the beneficial effects of exercise. Previous studies are limited to a few tissues, a narrow temporal range, or a single sex. Substantially expanding on the current work in the field, we used 25 distinct molecular platforms in as many as 19 tissues to study the temporal changes to endurance exercise training in male and female rats. Accordingly, we identified thousands of training-induced changes within and across tissues, including temporal and sex-biased responses, in mRNA transcripts, proteins, post-translational modifications and metabolites. Each omic dataset provides unique insights into exercise adaptation, where a holistic understanding requires multi-omic analysis. This work illustrates how mining our data resource can both recapitulate expected mechanisms and provide novel biological insights.

This work can be leveraged to deepen our understanding of exercise-related improvement of health and disease management. The global heat shock response to exercise may confer cytoprotective effects, including in pathologies related to tissue damage and injury recovery 37 . Increased acetylation of liver mitochondrial enzymes and regulation of lipid metabolism may link exercise to protection against non-alcoholic fatty liver disease and steatohepatitis 36 . Similarly, exercise-mediated modulation of cytokines, receptors and transcripts linked to intestinal inflammation or IBD may be associated with improved gut health. These examples highlight unique training responses illuminated by a multi-omics approach that can be leveraged for future hypothesis-driven research on how exercise improves whole-body and tissue-specific health.

We note limitations in our experimental design, datasets and analyses ( Supplementary Discussion ). In short, samples were collected 48 h after the last exercise bout to capture sustained alterations, thereby excluding acute responses. Our assays were performed on bulk tissue and do not cover single-cell platforms. Our resource has limited omic characterization for certain tissues, and additional platforms with emerging biological relevance were not utilized, including microbiome profiling. Moreover, our results are hypothesis-generating and require biological validation; supporting this, we have established a publicly accessible tissue bank from this study.

This MoTrPAC resource provides future opportunities to enhance and refine the molecular map of the endurance training response. We expect that this dataset will remain an ongoing platform to translate tissue- and sex-specific molecular changes in rats to humans. MoTrPAC has made extensive efforts to facilitate access, exploration and interpretation of this resource. We developed the MoTrPAC Data Hub to easily explore and download data ( https://motrpac-data.org/ ), software packages to provide reproducible source code and facilitate data retrieval and analysis in R (MotrpacRatTraining6mo and MotrpacRatTraining6moData 38 , 39 ), and visualization tools for data exploration ( https://data-viz.motrpac-data.org ). Altogether, this multi-omic resource serves as a broadly useful reference for studying the milieu of molecular changes in endurance training adaptation and provides new opportunities to understand the effects of exercise on health and disease.

All methods are included in the  Supplementary Information .

Reporting summary

Further information on research design is available in the  Nature Portfolio Reporting Summary linked to this article.

Data availability

MoTrPAC data are publicly available via http://motrpac-data.org/data-access . Data access inquiries should be sent to [email protected]. Additional resources can be found at http://motrpac.org and https://motrpac-data.org/ . Interactive data visualizations are provided through a website ( https://data-viz.motrpac-data.org ) and HTML reports summarizing the multi-omic graphical analysis results in each tissue 40 . Processed data and analysis results are additionally available in the MotrpacRatTraining6moData R package 39 ( https://github.com/MoTrPAC/MotrpacRatTraining6moData ). Raw and processed data for were deposited in the appropriate public repositories as follows. RNA-seq, ATAC-seq and RRBS data were deposited at the Sequence Read Archive under accession PRJNA908279 and at the Gene Expression Omnibus under accession GSE242358 ; multiplexed immunoassays were deposited at IMMPORT under accession SDY2193 ; metabolomics data were deposited at Metabolomics Workbench under project ID PR001020 ; and proteomics data were deposited at MassIVE under accessions MSV000092911 , MSV000092922 , MSV000092923 , MSV000092924 , MSV000092925 and MSV000092931 . We used the following external datasets: release 96 of the Ensembl R. norvegicus (rn6) genome ( https://ftp.ensembl.org/pub/release-96/fasta/rattus_norvegicus/dna/ ) and gene annotation ( https://ftp.ensembl.org/pub/release-96/gtf/rattus_norvegicus/Rattus_norvegicus.Rnor_6.0.96.gtf.gz ); RefSeq protein database ( https://ftp.ncbi.nlm.nih.gov/refseq/R_norvegicus/ , downloaded 11/2018); the NCBI gene2refseq mapping files ( https://ftp.ncbi.nlm.nih.gov/gene/DATA/gene2refseq.gz , accessed 18 December 2020); RGD rat gene annotation ( https://download.rgd.mcw.edu/data_release/RAT/GENES_RAT.txt , accessed 12 November 2021); BioGRID v4.2.193 ( https://downloads.thebiogrid.org/File/BioGRID/Release-Archive/BIOGRID-4.2.193/BIOGRID-ORGANISM-4.2.193.tab3.zip ); STRING v11.5 ( https://stringdb-downloads.org/download/protein.physical.links.v11.5/10116.protein.physical.links.v11.5.txt.gz ); GENCODE release 39 metadata and annotation files ( https://ftp.ebi.ac.uk/pub/databases/gencode/Gencode_human/release_39/ , accessed 20 January 2022); MatrisomeDB ( https://doi.org/10.1093/nar/gkac1009 ); MitoPathways database available through MitoCarta ( https://personal.broadinstitute.org/scalvo/MitoCarta3.0/ ); PTMSigDB v1.9.0 PTM set database ( https://doi.org/10.1074/mcp.TIR118.000943 ); UniProt human proteome FASTA for canonical protein sequences (UniProtKB query “reviewed:true AND proteome:up000005640”, download date 3 March 2021); the CIBERSORT LM22 leukocyte gene signature matrix ( https://doi.org/10.1007/978-1-4939-7493-1_12 ); published results from Amar et al. 8 , Bye et al. 22 and Hostrup et al. 23 ; and GTEx v8 gene-expression data (dbGaP Accession phs000424.v8.p2). Details are provided in the Supplementary Information , Methods.

Code availability

Code for reproducing the main analyses is provided in the MotrpacRatTraining6mo R package 38 ( https://motrpac.github.io/MotrpacRatTraining6mo/ ). MoTrPAC data processing pipelines for RNA-seq, ATAC-seq, RRBS and proteomics are available in the following Github repositories: https://github.com/MoTrPAC/motrpac-rna-seq-pipeline 41 , https://github.com/MoTrPAC/motrpac-atac-seq-pipeline 42 , https://github.com/MoTrPAC/motrpac-rrbs-pipeline 43 and https://github.com/MoTrPAC/motrpac-proteomics-pipeline 44 . Normalization and quality control scripts are available at https://github.com/MoTrPAC/MotrpacRatTraining6moQCRep 45 .

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Acknowledgements

Funding: The MoTrPAC Study is supported by NIH grants U24OD026629 (Bioinformatics Center), U24DK112349, U24DK112342, U24DK112340, U24DK112341, U24DK112326, U24DK112331, U24DK112348 (Chemical Analysis Sites), U01AR071133, U01AR071130, U01AR071124, U01AR071128, U01AR071150, U01AR071160, U01AR071158 (Clinical Centers), U24AR071113 (Consortium Coordinating Center), U01AG055133, U01AG055137 and U01AG055135 (PASS/Animal Sites). This work was also supported by other funding sources: NHGRI Institutional Training Grant in Genome Science 5T32HG000044 (N.R.G.), National Science Foundation Graduate Research Fellowship Grant No. NSF 1445197 (N.R.G.), National Heart, Lung, and Blood Institute of the National Institute of Health F32 postdoctoral fellowship award F32HL154711 (P.M.J.B.), the Knut and Alice Wallenberg Foundation (M.E.L.), National Science Foundation Major Research Instrumentation (MRI) CHE-1726528 (F.M.F.), National Institute on Aging P30AG044271 and P30AG003319 (N.M.), and NORC at the University of Chicago grant no. P30DK07247 (E.R.). Parts of this work were performed in the Environmental Molecular Science Laboratory, a US Department of Energy national scientific user facility at Pacific Northwest National Laboratory in Richland, WA. The views expressed are those of the authors and do not necessarily reflect those of the NIH or the US Department of Health and Human Services. Some figures were created using Biorender.com. Fig. 1b was modified with permission from ref. 46 .

Author information

These authors contributed equally: David Amar, Nicole R. Gay, Pierre M. Jean-Beltran

These authors jointly supervised this work: Sue C. Bodine, Steven A. Carr, Karyn A. Esser, Stephen B. Montgomery, Simon Schenk, Michael P. Snyder, Matthew T. Wheeler

Authors and Affiliations

Department of Medicine, Stanford University, Stanford, CA, USA

David Amar, David Jimenez-Morales, Malene E. Lindholm, Shruti Marwaha, Archana Natarajan Raja, Jimmy Zhen, Euan Ashley, Matthew T. Wheeler, Karen P. Dalton, Steven G. Hershman, Mihir Samdarshi & Christopher Teng

Department of Genetics, Stanford University, Stanford, CA, USA

Nicole R. Gay, Bingqing Zhao, Jose J. Almagro Armenteros, Nasim Bararpour, Si Wu, Stephen B. Montgomery, Michael P. Snyder, Clarisa Chavez, Roxanne Chiu, Krista M. Hennig, Chia-Jui Hung, Christopher A. Jin & Navid Zebarjadi

Proteomics Platform, Broad Institute of MIT and Harvard, Cambridge, MA, USA

Pierre M. Jean-Beltran, Hasmik Keshishian, Natalie M. Clark, Steven A. Carr, D. R. Mani, Charles C. Mundorff & Cadence Pearce

Department of Internal Medicine, University of Iowa, Iowa City, IA, USA

Dam Bae, Ana C. Lira, Sue C. Bodine, Michael Cicha, Luis Gustavo Oliveira De Sousa, Bailey E. Jackson, Kyle S. Kramer, Andrea G. Marshall & Collyn Z-T. Richards

Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN, USA

Surendra Dasari

Metabolomics Platform, Broad Institute of MIT and Harvard, Cambridge, MA, USA

Courtney Dennis, Julian Avila-Pacheco & Clary B. Clish

Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA

Charles R. Evans & Charles F. Burant

School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, GA, USA

David A. Gaul, Evan M. Savage & Facundo M. Fernández

Department of Medicine, Duke University, Durham, NC, USA

Olga Ilkayeva, William E. Kraus & Kim M. Huffman

Duke Molecular Physiology Institute, Duke University, Durham, NC, USA

Olga Ilkayeva, Michael J. Muehlbauer, William E. Kraus, Christopher Newgard, Kim M. Huffman & Megan E. Ramaker

Emory Integrated Metabolomics and Lipidomics Core, Emory University, Atlanta, GA, USA

Anna A. Ivanova, Xueyun Liu & Kristal M. Maner-Smith

BRCF Metabolomics Core, University of Michigan, Ann Arbor, MI, USA

Maureen T. Kachman, Alexander (Sasha) Raskind & Tanu Soni

Division of Endocrinology, Nutrition, and Metabolism, Mayo Clinic, Rochester, MN, USA

Ian R. Lanza

Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, USA

Venugopalan D. Nair, Gregory R. Smith, Yongchao Ge, Stuart C. Sealfon, Mary Anne S. Amper, Kristy Guevara, Nada Marjanovic, German Nudelman, Hanna Pincas, Irene Ramos, Stas Rirak, Aliza B. Rubenstein, Frederique Ruf-Zamojski, Nitish Seenarine, Sindhu Vangeti, Mital Vasoya, Alexandria Vornholt, Xuechen Yu & Elena Zaslavsky

Environmental Molecular Sciences Division, Pacific Northwest National Laboratory, Richland, WA, USA

Paul D. Piehowski

Department of Pathology and Laboratory Medicine, University of Vermont, Burlington, VT, USA

Jessica L. Rooney, Russell Tracy, Elaine Cornell, Nicole Gagne & Sandy May

Department of Pathology, Stanford University, Stanford, CA, USA

Kevin S. Smith, Nikolai G. Vetr, Stephen B. Montgomery & Daniel Nachun

Department of Biostatistics and Data Science, Wake Forest University School of Medicine, Winston-Salem, NC, USA

Cynthia L. Stowe, Fang-Chi Hsu, Scott Rushing & Michael P. Walkup

Biological Sciences Division, Pacific Northwest National Laboratory, Richland, WA, USA

Gina M. Many, James A. Sanford, Joshua N. Adkins, Wei-Jun Qian, Marina A. Gritsenko, Joshua R. Hansen, Chelsea Hutchinson-Bunch, Matthew E. Monroe, Ronald J. Moore, Michael D. Nestor, Vladislav A. Petyuk & Tyler J. Sagendorf

Department of Biochemistry, Emory University, Atlanta, GA, USA

Tiantian Zhang, Zhenxin Hou & Eric A. Ortlund

Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Boston, MA, USA

David M. Presby, Laurie J. Goodyear, Brent G. Albertson, Tiziana Caputo, Michael F. Hirshman, Nathan S. Makarewicz, Pasquale Nigro & Krithika Ramachandran

Department of Human Genetics, University of Michigan, Ann Arbor, MI, USA

Alec Steep & Jun Z. Li

Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA

Yifei Sun & Martin J. Walsh

Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA

Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA

• Sue C. Bodine

Department of Physiology and Aging, University of Florida, Gainesville, FL, USA

Karyn A. Esser & Marco Pahor

Department of Orthopaedic Surgery, School of Medicine, University of California, San Diego, La Jolla, CA, USA

Simon Schenk

Department of Biomedical Data Science, Stanford University, Stanford, CA, USA

Stephen B. Montgomery

Department of Biostatistics, University of Alabama at Birmingham, Birmingham, AL, USA

Gary Cutter

Division of Cardiovascular Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA

Robert E. Gerszten & Jeremy M. Robbins

Division of Public Health Sciences, Wake Forest University School of Medicine, Winston-Salem, NC, USA

Michael E. Miller

Department of Medicine, Mayo Clinic, Rochester, MN, USA

K. Sreekumaran Nair

Department of Statistics, Stanford University, Stanford, CA, USA

Trevor Hastie & Rob Tibshirani

Department of Biomedical Data Sciences, Stanford University, Stanford, CA, USA

Rob Tibshirani

Department of Aging and Geriatric Research, University of Florida, Gainesville, FL, USA

Brian Bouverat, Christiaan Leeuwenburgh & Ching-ju Lu

Section on Gerontology and Geriatric Medicine, Wake Forest University School of Medicine, Winston-Salem, NC, USA

• Barbara Nicklas

Department of Health and Exercise Science, Wake Forest University School of Medicine, Winston-Salem, NC, USA

W. Jack Rejeski

National Institute on Aging, National Institutes of Health, Bethesda, MD, USA

• John P. Williams

National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA

Applied Physiology and Kinesiology, University of Florida, Gainesville, FL, USA

Elisabeth R. Barton

Department of Biomedical Sciences, University of Missouri, Columbia, MO, USA

Frank W. Booth

Department of Medical Pharmacology and Physiology, University of Missouri, Columbia, MO, USA

Department of Nutrition and Exercise Physiology, University of Missouri, Columbia, MO, USA

Frank W. Booth & R. Scott Rector

Dalton Cardiovascular Research Center, University of Missouri, Columbia, MO, USA

Department of Kinesiology and Health Education, University of Texas, Austin, TX, USA

Roger Farrar

Department of Medicine, Division of Endocrinology and Diabetes, University of California, Los Angeles, CA, USA

Andrea L. Hevener

Center for Public Health Genomics, University of Virginia School of Medicine, Charlottesville, VA, USA

Benjamin G. Ke & Chongzhi Zang

Section on Clinical, Behavioral, and Outcomes Research, Joslin Diabetes Center, Boston, MA, USA

Sarah J. Lessard

Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, USA

Andrea G. Marshall

Department of Health Sciences, Stetson University, Deland, FL, USA

Scott Powers

Department of Medicine, University of Missouri, Columbia, MO, USA

R. Scott Rector

NextGen Precision Health, University of Missouri, Columbia, MO, USA

Cell Biology and Physiology, Internal Medicine, University of Kansas Medical Center, Kansas City, KS, USA

John Thyfault

Center for Skeletal Muscle Research at Robert M. Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, VA, USA

Department of Medicine, University of Virginia School of Medicine, Charlottesville, VA, USA

Department of Pharmacology, University of Virginia School of Medicine, Charlottesville, VA, USA

Department of Molecular Physiology and Biological Physics, University of Virginia School of Medicine, Charlottesville, VA, USA

Fralin Biomedical Research Institute, Center for Exercise Medicine Research at Virginia Tech Carilion, Roanoke, VA, USA

Department of Human Nutrition, Foods, and Exercise, College of Agriculture and Life Sciences, Virginia Tech, Blacksburg, VA, USA

Department of Computational and Systems Biology, University of Pittsburgh, Pittsburgh, PA, USA

Ali Tugrul Balci & Maria Chikina

Petit Institute of Bioengineering and Biosciences, Georgia Institute of Technology, Atlanta, GA, USA

Samuel G. Moore

Department of Medicine, Emory University, Atlanta, GA, USA

Karan Uppal

Department of Cell, Developmental, and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL, USA

Marcas Bamman & Anna Thalacker-Mercer

Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA

Bryan C. Bergman, Daniel H. Bessesen, Wendy M. Kohrt, Edward L. Melanson, Kerrie L. Moreau, Irene E. Schauer & Robert S. Schwartz

Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA

Thomas W. Buford

Human Performance Laboratory, Ball State University, Muncie, IN, USA

Toby L. Chambers, Bridget Lester, Scott Trappe & Todd A. Trappe

Translational Research Institute, AdventHealth, Orlando, FL, USA

Paul M. Coen, Bret H. Goodpaster & Lauren M. Sparks

Department of Pediatrics, University of California, Irvine, CA, USA

Dan Cooper, Fadia Haddad & Shlomit Radom-Aizik

Pennington Biomedical Research Center, Baton Rouge, LA, USA

Kishore Gadde, Melissa Harris, Neil M. Johannsen, Tuomo Rankinen & Eric Ravussin

College of Nursing, University of Colorado Anschutz Medical Campus, Aurora, CO, USA

Catherine M. Jankowski

Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA

Nicolas Musi

Population and Public Health, Pennington Biomedical Research Center, Baton Rouge, LA, USA

Robert L. Newton Jr

Biochemistry and Structural Biology, Center for Metabolic Health, Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center, San Antonio, TX, USA

Blake B. Rasmussen

Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center, San Antonio, TX, USA

Elena Volpi

MoTrPAC Study Group

• Primary authors

Lead Analysts

• , Nicole R. Gay
• , Pierre M. Jean-Beltran

Lead Data Generators

• , Surendra Dasari
• , Courtney Dennis
• , Charles R. Evans
• , David A. Gaul
• , Olga Ilkayeva
• , Anna A. Ivanova
• , Maureen T. Kachman
• , Hasmik Keshishian
• , Ian R. Lanza
• , Ana C. Lira
• , Michael J. Muehlbauer
• , Venugopalan D. Nair
• , Paul D. Piehowski
• , Jessica L. Rooney
• , Kevin S. Smith
• , Cynthia L. Stowe
•  & Bingqing Zhao
• Natalie M. Clark
• , David Jimenez-Morales
• , Malene E. Lindholm
• , Gina M. Many
• , James A. Sanford
• , Gregory R. Smith
• , Nikolai G. Vetr
• , Tiantian Zhang
• , Bingqing Zhao
• , Jose J. Almagro Armenteros
• , Julian Avila-Pacheco
• , Nasim Bararpour
• , Yongchao Ge
• , Zhenxin Hou
• , Shruti Marwaha
• , David M. Presby
• , Archana Natarajan Raja
• , Evan M. Savage
• , Alec Steep
• , Yifei Sun
• , Si Wu
•  & Jimmy Zhen

Animal Study Leadership

• , Karyn A. Esser
• , Laurie J. Goodyear
•  & Simon Schenk

Manuscript Writing Group Leads

• Nicole R. Gay
•  & David Amar

Manuscript Writing Group

• Malene E. Lindholm
• , Simon Schenk
• , Stephen B. Montgomery
• , Sue C. Bodine
• , Facundo M. Fernández
• , Stuart C. Sealfon
• , Michael P. Snyder
•  & Tiantian Zhang

Senior Leadership

• Joshua N. Adkins
• , Euan Ashley
• , Charles F. Burant
• , Steven A. Carr
• , Clary B. Clish
• , Gary Cutter
• , Robert E. Gerszten
• , William E. Kraus
• , Jun Z. Li
• , Michael E. Miller
• , K. Sreekumaran Nair
• , Christopher Newgard
• , Eric A. Ortlund
• , Wei-Jun Qian
• , Russell Tracy
• , Martin J. Walsh
•  & Matthew T. Wheeler

Co-corresponding Authors

Bioinformatics center.

• , Karen P. Dalton
• , Trevor Hastie
• , Steven G. Hershman
• , Mihir Samdarshi
• , Christopher Teng
• , Rob Tibshirani
• , Matthew T. Wheeler

Biospecimens Repository

• Elaine Cornell
• , Nicole Gagne
• , Sandy May
•  & Russell Tracy

Administrative Coordinating Center

• Brian Bouverat
• , Christiaan Leeuwenburgh
• , Ching-ju Lu
•  & Marco Pahor

Data Management, Analysis, and Quality Control Center

• Fang-Chi Hsu
• , Scott Rushing
•  & Michael P. Walkup

Exercise Intervention Core

•  & W. Jack Rejeski
•  & Ashley Xia

Preclinical Animal Study Sites

• Brent G. Albertson
• , Dam Bae
• , Elisabeth R. Barton
• , Frank W. Booth
• , Tiziana Caputo
• , Michael Cicha
• , Luis Gustavo Oliveira De Sousa
• , Roger Farrar
• , Andrea L. Hevener
• , Michael F. Hirshman
• , Bailey E. Jackson
• , Benjamin G. Ke
• , Kyle S. Kramer
• , Sarah J. Lessard
• , Nathan S. Makarewicz
• , Andrea G. Marshall
• , Pasquale Nigro
• , Scott Powers
• , Krithika Ramachandran
• , R. Scott Rector
• , Collyn Z-T. Richards
• , John Thyfault
• , Zhen Yan
•  & Chongzhi Zang

Chemical Analysis Sites

• , Mary Anne S. Amper
• , Ali Tugrul Balci
• , Clarisa Chavez
• , Maria Chikina
• , Roxanne Chiu
• , Natalie M. Clark
• , Marina A. Gritsenko
• , Kristy Guevara
• , Joshua R. Hansen
• , Krista M. Hennig
• , Chia-Jui Hung
• , Chelsea Hutchinson-Bunch
• , Christopher A. Jin
• , Xueyun Liu
• , Kristal M. Maner-Smith
• , D. R. Mani
• , Nada Marjanovic
• , Matthew E. Monroe
• , Ronald J. Moore
• , Samuel G. Moore
• , Charles C. Mundorff
• , Daniel Nachun
• , Michael D. Nestor
• , German Nudelman
• , Cadence Pearce
• , Vladislav A. Petyuk
• , Hanna Pincas
• , Irene Ramos
• , Alexander (Sasha) Raskind
• , Stas Rirak
• , Jeremy M. Robbins
• , Aliza B. Rubenstein
• , Frederique Ruf-Zamojski
• , Tyler J. Sagendorf
• , Nitish Seenarine
• , Tanu Soni
• , Karan Uppal
• , Sindhu Vangeti
• , Mital Vasoya
• , Alexandria Vornholt
• , Xuechen Yu
• , Elena Zaslavsky
• , Navid Zebarjadi

Clinical Sites

• Marcas Bamman
• , Bryan C. Bergman
• , Daniel H. Bessesen
• , Thomas W. Buford
• , Toby L. Chambers
• , Paul M. Coen
• , Dan Cooper
• , Fadia Haddad
• , Kishore Gadde
• , Bret H. Goodpaster
• , Melissa Harris
• , Kim M. Huffman
• , Catherine M. Jankowski
• , Neil M. Johannsen
• , Wendy M. Kohrt
• , Bridget Lester
• , Edward L. Melanson
• , Kerrie L. Moreau
• , Nicolas Musi
• , Robert L. Newton Jr
• , Shlomit Radom-Aizik
• , Megan E. Ramaker
• , Tuomo Rankinen
• , Blake B. Rasmussen
• , Eric Ravussin
• , Irene E. Schauer
• , Robert S. Schwartz
• , Lauren M. Sparks
• , Anna Thalacker-Mercer
• , Scott Trappe
• , Todd A. Trappe
•  & Elena Volpi

Contributions

All authors reviewed and revised the manuscript. Detailed author contributions are provided in the  Supplementary Information .

Corresponding authors

Correspondence to Sue C. Bodine , Karyn A. Esser , Simon Schenk , Stephen B. Montgomery , Michael P. Snyder , Steven A. Carr or Matthew T. Wheeler .

Ethics declarations

Competing interests.

S.C.B. has equity in Emmyon, Inc. G.R.C. sits on data and safety monitoring boards for AI Therapeutics, AMO Pharma, Astra-Zeneca, Avexis Pharmaceuticals, Biolinerx, Brainstorm Cell Therapeutics, Bristol Meyers Squibb/Celgene, CSL Behring, Galmed Pharmaceuticals, Green Valley Pharma, Horizon Pharmaceuticals, Immunic, Mapi Pharmaceuticals, Merck, Mitsubishi Tanabe Pharma Holdings, Opko Biologics, Prothena Biosciences, Novartis, Regeneron, Sanofi-Aventis, Reata Pharmaceuticals, NHLBI (protocol review committee), University of Texas Southwestern, University of Pennsylvania, Visioneering Technologies, Inc.; serves on consulting or advisory boards for Alexion, Antisense Therapeutics, Biogen, Clinical Trial Solutions LLC, Genzyme, Genentech, GW Pharmaceuticals, Immunic, Klein-Buendel Incorporated, Merck/Serono, Novartis, Osmotica Pharmaceuticals, Perception Neurosciences, Protalix Biotherapeutics, Recursion/Cerexis Pharmaceuticals, Regeneron, Roche, SAB Biotherapeutics; and is the president of Pythagoras Inc., a private consulting company. S.A.C. is a member of the scientific advisory boards of Kymera, PrognomiQ, PTM BioLabs, and Seer. M.P.S. is a cofounder and scientific advisor to Personalis, Qbio, January AI, Filtricine, SensOmics, Protos, Fodsel, Rthm, Marble and scientific advisor to Genapsys, Swaz, Jupiter. S.B.M. is a consultant for BioMarin, MyOme and Tenaya Therapeutics. D.A. is currently employed at Insitro, South San Francisco, CA. N.R.G. is currently employed at 23andMe, Sunnyvale, CA. P.M.J.B. is currently employed at Pfizer, Cambridge, MA. Insitro, 23andMe and Pfizer had no involvement in the work presented here.

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Extended data figures and tables

Extended data fig. 1 animal phenotyping and data availability..

a-d) Clinical measurements before and after the training intervention in untrained control rats (SED), 4-week trained rats (4w), and 8-week trained rats (8w). Data are displayed pre and post for each individual rat (connected by a line), with males in blue and females in pink. Filled symbols (n = 5 per sex and time point) represent rats used for all omics analyses, whereas the rat utilized for proteomics only (n = 1 per sex and time point) is represented by a non-filled symbol. Significant results by ANOVA of the overall group effect (#, p < 0.05; ##, p < 0.01) and interaction between group and time (§, p < 0.05; §§ p < 0.01) are indicated. Significant within-group differential responses from a Bonferroni post hoc test are indicated (*, q-value < 0.05; **, q-value < 0.01). a) Aerobic capacity through a VO 2 max test until exhaustion. Data are reported in ml/(kg.min) for all individual rats and time points. b) Body fat percentage. c) Percent lean mass. ( b-c ) were assessed through nuclear magnetic resonance spectroscopy. d) Body weight (in grams). e) Description of available datasets. Colored cells indicate that data are available for that tissue and assay. Individual panels and platforms are shown for metabolomics and the multiplexed immunoassays. f) Detailed availability of sample-level data across assays. Each column represents an individual animal, ordered by training group and colored by sex. Gray cells indicate that data were generated for that animal and assay; black cells indicate that data were not generated. Rows are ordered by ome and colored by assay and tissue.

Extended Data Fig. 2 Quality control metrics for omics data.

a) Proteomics multiplexing design using TMT11 reagents for isobaric tagging and a pooled reference sample. The diagram describes processing of a single tissue. Following multiplexing, peptides were used for protein abundance analysis, serial PTM enriched for phosphosite and optional acetylsite quantification, or ubiquitylsite quantification through enrichment of lysine-diglycine ubiquitin remnants. b) Total number of fully quantified proteins per plex in each global proteome dataset. c-e) The total number of fully quantified phosphosites (c) , acetylsites (d) , and ubiquitylsites (e) per plex in each dataset. f) Distributions of coefficients of variation (CVs) calculated from metabolomics features identified in pooled samples and analyzed periodically throughout liquid chromatography-mass spectrometry runs. CVs were aggregated and plotted separately for named and unnamed metabolites. g) Transcription start site (TSS) enrichment (top) and fraction of reads in peaks (FRiP, bottom) across ATAC-seq samples per tissue. h) Distributions of RNA integrity numbers (RIN, top) and median 5′ to 3′ bias (bottom) across samples in each tissue in the RNA-Seq data. i) Percent methylation of CpG, CHG and CHH sites in the RRBS data. For boxplots in (h,i) : center line represents median; box bounds represent 25th and 75th percentiles; whiskers represent minimum and maximum excluding outliers; filled dots represent outliers. j) Number of wells across multiplexed immunoassays with fewer than 20 beads. Measurements from these 182 wells were excluded from downstream analysis. k) 2D density plot of targeted analytes’ mean fluorescence intensity (MFI) versus corresponding CHEX4 MFI from the same well for each multiplexed immunoassay measurement, where CHEX4 is a measure of non-specific binding.

Extended Data Fig. 3 Permutation tests.

a-b) Permutation tests of groups within males (a) and females (b) . For each sex, the original group labels were shuffled to minimize the number of animal pairs that remain in the same group. Only the group labels were shuffled and all other covariates remained as in the original data. For each permuted dataset, the differential abundance pipeline was rerun and the number of transcripts that were selected at 5% FDR adjustment were re-counted. c-d) Permutation tests of sex within groups. For each group and each sex, half of the animals were selected randomly and their sex was swapped. Only the sex labels were shuffled and all other covariates remained as in the original data. For each permutation the differential analysis pipeline was rerun and the timewise summary statistics were extracted. A gene was considered sexually dimorphic if for at least one time point the z-score (absolute) difference between males and females was greater than 3. c) Counts of sexually dimorphic genes among the IHW-selected genes of the original data. d) Counts of sexually dimorphic genes among the 5% FDR selected genes within each permuted dataset. Each boxplot in (a-d) represents the differential abundance analysis results over 100 permutations of the transcriptomics data in a specific tissue. Center line represents median; box bounds represent 25th and 75th percentiles; whiskers represent minimum and maximum excluding outliers; open circles represent outliers. Added points represent the results of the true data labels, and their shape corresponds to the empirical p-value ( ● : p > 0.05; ×: 0.01 < p < 0.05; *: p ≤ 0.01).

Extended Data Fig. 4 Correlations between proteins and transcripts throughout endurance training.

a) Number of tissues in which each gene, including features mapped to genes from all omes, is training-regulated. Only differential features from the subset of tissues with deep molecular profiling (lung, gastrocnemius, subcutaneous white adipose, kidney, liver, and heart) and the subset of omes that were profiled in all six of these tissues (DNA methylation, chromatin accessibility, transcriptomics, global proteomics, phosphoproteomics, multiplexed immunoassays) were considered. Numbers above each bar indicate the number of genes that are differential in exactly the number of tissues indicated on the x-axis. b) Pathways significantly enriched by tissue-specific training-regulated genes represented in Fig. 2a (q-value < 0.1). KEGG and Reactome pathways were queried, and redundant pathways were removed (i.e., those with an overlap of 80% or greater with an existing pathway). c) Heatmaps showing the Pearson correlation between the TRNSCRPT and PROT timewise summary statistics (z- and t-scores, respectively) (top, gene-level) and pathway-level enrichment results (Gene Set Enrichment Analysis normalized enrichment scores) (bottom, pathway-level). d) Scatter plots of pathway GSEA NES of the TRNSCRPT and PROT datasets in the seven tissues for which these data were acquired. Pathways showing high discordance or agreement across TRNSCRPT and PROT and with functional relevance or general interest were highlighted.

Extended Data Fig. 5 Heat shock response.

a) Scatter plots of the protein t-scores (PROT) versus the transcript z-scores (TRNSCRPT) by gene at 8 weeks of training (8 W) relative to sedentary controls. Data are shown for the seven tissues for which both proteomics and transcriptomics was acquired. Red points indicate genes associated with the heat shock response, and the labeled points indicate those with a large differential response at the protein level. b-c) Line plots showing protein b) and transcript (c) log 2 fold-changes relative to the untrained controls for a subset of heat shock proteins with increased abundance during exercise training. Each line represents a protein in a single tissue.

Extended Data Fig. 6 Regulatory signaling pathways modulated by endurance training.

a) Heatmap of differences in TF motif enrichment in training-regulated genes across tissues. Each value reflects the average difference in motif enrichment for shared transcription factors. Tissues are clustered with complete linkage hierarchical clustering. b) (left) Filtered PTM-SEA results for the liver showing kinases and signaling pathways with increased activity. (right) Heatmap showing t-scores for phosphosites within the HGF signaling pathway. c) Hypothetical model of HGF signaling effects during exercise training. Phosphorylation of STAT3 and PXN is known to modulate cell growth and cell migration, respectively. Error bars=SEM. d) Filtered PTM-SEA results for the heart showing selected kinases with significant enrichments in at least one time point. Heatmap shows the NES as color and enrichment p-value as dot size. Kinases are grouped by kinase family and sorted by hierarchical clustering. e) (top) Log 2 fold-change of GJA1 and CDH2 protein abundance in the heart. No significant response to exercise training was observed for these proteins (F-test; q-value > 0.05). (bottom) Log 2 fold-changes for selected Src kinase phosphosite targets, GJA1 pY265 and CDH2 pY820, in the heart. These phosphosites show a significant response to exercise training (F-test, 5% FDR). Error bars=SEM. f) Gene Set Enrichment Analysis (GSEA) results from the heart global proteome dataset using the matrisome gene set database. Heatmap shows NES as color and enrichment p-value as dot size. Rows are clustered using hierarchical clustering. g) Log 2 fold-change for basement membrane proteins in heart. Proteins showing a significant response to exercise training are highlighted in orange (F-test; 5% FDR). Error bars=SEM. h) Log 2 protein fold-change of NTN1 protein abundance in heart. A significant response to exercise training was observed for these proteins (F-test; 5% FDR). Error bars=SEM.

Extended Data Fig. 7 Graphical representation of differential results.

a) Number of training-regulated features assigned to groups of graphical states across tissues and time. Red points indicate features that are up-regulated in at least one sex (e.g., only in males: F0_M1; only in females: F1_M0; in both sexes: F1_M1), and blue points indicate features down-regulated in at least one sex (only in males: F0_M-1; only in females: F-1_M0; in both sexes: F-1_M-1). Green points indicate features that are up-regulated in males and down-regulated in females or vice versa (F-1_M1 and F1_M-1, respectively). Point size is proportional to the number of features. Point opacity is proportional to the within-tissue fraction of features represented by that point. Features can be represented in multiple points. The number of omes profiled in each tissue is provided in parentheses next to the tissue abbreviation. b) A schematic example of the graphical representation of the differential analysis results. Top: the z-scores of four features. A positive score corresponds to up-regulation (red), and a negative score corresponds to down regulation (blue). Bottom: the assignment of features to node sets and full path sets (edge sets are not shown for conciseness but can be easily inferred from the full paths). Node labels follow the [time]_F[x]_M[y] format where [time] shows the animal sacrifice week and can take one of (1w, 2w, 4w, or 8w), and [x] and [y] are one of (−1,0,1), corresponding to down-regulation, no effect, and up-regulation, respectively. c) Graphical representation of the feature sets. Columns are training time points, and rows are the differential abundance states. Node and edge sizes are proportional to the number of features that are assigned to each set.

Extended Data Fig. 8 Key pathway enrichments per tissue.

Key pathway enrichments for features that are up-regulated in both sexes at 8 weeks of training in each tissue. For display purposes, enrichment q-values were floored to 1e-10 (Enrichment FDR (−log10) = 10). Bars are colored by the number of omes for which the pathway was significantly enriched (q-value < 0.01) (lighter gray: 1 ome; darker gray: 2 omes; black: 3 omes). Pathways were selected from Supplementary Table 10 .

Extended Data Fig. 9 Associations with signatures of human health and complex traits.

a) Jaccard coefficients between gene sets identified by different omes in 8-week gastrocnemius up-regulated features (“X” marks overlap p > 0.05). b) Network connectivity p-values (Pathways, Biogrid, and string) among the gastrocnemius week-8 multi-omic genes and with the single-omic genes. c) Proportion of features from each ome represented in the gastrocnemius response clusters, identified by the network clustering analysis. d-g) Overlap between our rat vastus lateralis differential expression results and the meta-analysis of human long-term exercise studies by Amar et al. d-e) Spearman correlation (d) and its significance (e) between the meta-analysis fold-changes and the log 2 fold-changes foreach sex and time point. f) GSEA results. Genes were ranked by meta-analysis (−log 10 p-value*log 2 fold-change) and the rat training-differential, sex-consistent gene sets were tested for enrichment at the bottom of the ranking (negative scores) or the top (positive scores). g) Overlap between the rat gene sets from (f) and the high-heterogeneity human meta-analysis genes (I 2  > 75%). h) -log 10 overlap p-values (Fisher’s exact test), comparing rat female gastrocnemius and vastus lateralis week-8 differential transcripts from this study (p < 0.01) and the differential genes from the rat female soleus data of Bye et al. (p < 0.01). HCR: high capacity runners, LCR: low capacity runners. i) A comparison of rat gastrocnemius differential proteins from this study (p < 0.01) and the human endurance training proteomics results of Hostrup et al. (p < 0.01) using Fisher’s exact test. Left: -log 10 overlap p-values. Right: -log 10 sex concordance p-values. j) Statistics of the overlapping proteins from ( i ), week-8 female comparison (y: rat z-scores, x: human t-scores). k) DOSE disease enrichment results of the white adipose, kidney, and liver gene sets. DOSE was applied only on diseases that are relevant for each tissue. The network shows the results for the sex-consistent down-regulated features at week-8.

Extended Data Fig. 10 Characterization of the extent of sex difference in the endurance training response.

The extent of sex differences in the training response were characterized in two ways: first, by correlating log 2 fold-changes between males and females for each training-differential feature; second, by calculating the difference between the area under the log 2 fold-change curve for each training-differential feature, including a (0,0) point (Δ AUC , males - females). The first approach characterizes differences in direction of effect while the second approach characterizes differences in magnitude. Left plot for each tissue: density line plots of correlations from the first approach. Densities or correlations corresponding to features in each ome are plotted separately, with a label that provides the ome and the number of differential features represented. Right plot for each tissue: 2D density plot of Δ AUC against the correlation between the male and female log 2 fold-changes for each training-differential feature used to simultaneously evaluate sex differences in the direction and magnitude of the training response. Points at the top-center of these 2D density plots represent features with high similarity between males and females in terms of both direction and magnitude; features on the right and left sides of the plots represent features with greater magnitudes of response in males and females, respectively.

Extended Data Fig. 11 Sex differences in the endurance training response.

a) Heatmap of the training response of immunoassay analytes across tissues. Gray indicates no data. Bars indicate the number of training-regulated analytes in each tissue (top) and the number of tissues in which the analyte is training-regulated (right, 5% FDR). b) Training-differential cytokines across tissues. 5, 24, and 9 cytokines were annotated as anti-, pro-, and pro/anti- inflammatory, respectively. Bars indicate the number of annotated cytokines in each category that are differential (5% FDR). c) Counts of early vs. (1- or 2-week) vs. late (4- or 8-week) differential cytokines, according to states assigned by the graphical analysis, including all tissues. Cytokines with both early and late responses in the same tissue were excluded. d) Line plots of standardized abundances of training-differential features that follow the largest graphical path in the adrenal gland (i.e., 1w_F-1_M1 − >2w_F-1_M0 − >4w_F-1_M0 − >8w_F-1_M0 according to our graphical analysis notation). The black line represents the average value across all features. The closer a colored line is to this average, the darker it is (distance calculated using sum of squares). e) Line plots of transcript-level log 2 fold-changes corresponding to six transcription factors (TFs) whose motifs are significantly enriched by transcripts in (d) . TF motif enrichment q-values are provided in the legend (error bars = SEM). f) Male versus female NES from PTM-SEA in the lung. Anticorrelated points corresponding to PRKACA NES are in dark red. g) Line plots of standardized abundances of training-differential phosphosites that follow the largest graphical edges of phosphosites in the lung (1w_F1_M-1 − >2w_F1_M-1 − >4w_F0_M-1). h) Top ten kinases with the greatest over-representation of substrates (proteins) corresponding to training-differential phosphosites in (g) . MeanRank scores by library are shown, as reported by KEA3. i) Line plots showing phosphosite-level log 2 fold-changes of PRKACA phosphosite substrates identified in the lung as differential with disparate sex responses (error bars = SEM).

Extended Data Fig. 12 Assessment of immune responses to endurance training.

a) Heatmap of the number and percent of KEGG and Reactome immune pathways significantly enriched by training-regulated features at 8 weeks. b) Line plots of standardized abundances of training-differential proteins in white adipose tissue up-regulated only in males at 8 weeks. Black line shows average across all features. c) Boxplots of the sample-level Pearson correlation between markers of immune cell types, lymphatic tissue, or cell proliferation and the average value of features in (b) at the protein level. Center line represents median; box bounds represent 25th and 75th percentiles; whiskers represent minimum and maximum excluding outliers; filled dots represent outliers. A pink point indicates that the marker is also one of the differential features plotted in (b) . # indicates when the distribution of Pearson correlations for a set of at least two markers is significantly different from 0 (two-sided one-sample t-test, 5% BY FDR). When only one marker is used to define a category on the y-axis, the gene name is provided in parentheses. d) Trajectories of mean absolute signal of various immune cell types in BAT or WAT-SC following deconvolution of bulk RNA-Seq with CIBERSORTx (error bars = SEM). e) Immune cell type enrichment analysis results of training-differentially expressed transcripts. Points represent significant enrichments (5% FDR, one-sided Mann-Whitney U test). f) Line plots showing the log 2 fold-changes for Cxcr3 and Il1a transcripts in the small intestine (error bars = SEM).

Extended Data Fig. 13 Metabolic effects of endurance training.

a) Significant enrichments for relevant categories of KEGG metabolism pathways from features that are up- or down- regulated in both sexes at 8 weeks (8w_F1_M1 and 8w_F-1_M-1 nodes, respectively). Triangles point in the direction of the response (up or down). Points are colored by ome. b) Log 2 fold-change of metabolites regulated across many tissues (F-Test, 5% FDR, error bars=SEM). c) Log 2 fold-change of training-regulated metabolites: 1-methylhistidine in the kidney, cortisol in the kidney, and 1-methylnicotinamide in the liver (F-Test, 5% FDR, error bars = SEM). d) Volcano plots showing abundance changes (log 2 fold-changes; logFC) and significance (-log 10 nominal p-values) for acyl-carnitines. Features are colored based on the carnitine chain length. e) Protein abundance changes in the glycolysis and gluconeogenesis pathway in the heart tissue after 8 weeks of training. Line plots show the log 2 fold-changes over the training time course (error bars = SEM). Red and blue boxes indicate a statistically significant (F-test, 5% FDR) increase and decrease in abundance, respectively, for both males and females at 8 weeks.

Extended Data Fig. 14 Mitochondria and peroxisome adaptations to endurance training.

a) Boxplots showing the percent of mitochondrial genome reads across samples in each tissue that map to the mitochondrial genome (% MT reads). b) Comparison of % MT reads between untrained controls and animals trained for 8 weeks. Plot shows tissues with a statistically significant change after 8 weeks in at least one sex (red asterisk, two-sided Dunnett’s test, 10% FDR). For boxplots in (b,c) : center line represents median; box bounds represent 25th and 75th percentiles; whiskers represent minimum and maximum excluding outliers; filled dots represent outliers. c) Boxplots showing the percent of mitochondrial genome reads across tissue, sex, and time points. Center line represents median; box bounds represent 25th and 75th percentiles; whiskers represent minimum and maximum excluding outliers; open circles represent outliers. Red asterisks indicate a significant change throughout the training time course (F-test, 5% FDR). Center line represents median; box bounds represent 25th and 75th percentiles; whiskers represent minimum and maximum excluding outliers; blue dots represent outliers. d) GSEA using the MitoCarta MitoPathways gene set database and transcriptome (TRNSCRPT) or phosphoproteome (PHOSPHO) differential analysis results. NES are shown for significant pathways (10% FDR) for all tissues, sexes, and time points within the heatmap. Mitochondria pathways (rows) are grouped using the parental group in the MitoPathways hierarchy. e) Protein abundance and protein acetylation level changes in the peroxisome KEGG pathway in the liver tissue after 8 weeks of training. Red boxes indicate an increase in abundance for both males and females, while red circles indicate an increase in at least one acetylsite within the protein (8w_F1_M1 cluster).

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MoTrPAC Study Group., Lead Analysts. & MoTrPAC Study Group. Temporal dynamics of the multi-omic response to endurance exercise training. Nature 629 , 174–183 (2024). https://doi.org/10.1038/s41586-023-06877-w

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