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Mouse Study Finds Exercise Reshapes Organs Well Beyond the Legs
In A Nutshell
- Eight weeks of running altered gene activity in nearly half of detected genes, in at least one of 22 mouse tissues.
- Muscle changed most, but the lungs, kidneys, and heart responded too.
- Females showed broader changes than males, and some organs responded more at rest.
- A 51-gene signature often flagged exercise in outside rodent and human muscle data.
A hard run leaves the legs burning, so muscle gets the credit. A new mouse study in the journal Cell shows that muscle is not the only winner. After eight weeks of voluntary running, nearly half of all the genes researchers could detect had changed their activity in at least one of 22 tissues. Those included the lungs, kidneys, heart, and a brain region called the hypothalamus.
Regular exercise lowers the risk of dying from any cause, yet scientists still know little about what it does inside most of the body. Studies of people can sample little more than blood and a few muscles, according to the paper. Researchers at the Salk Institute for Biological Studies in La Jolla, California, turned to mice, whose organs can all be sampled one by one.
Together, the results form a detailed reference map, or atlas, of the exercised body. Earlier atlases exist, the authors note, but this one captures the trained state during everyday activity across many tissues. Salk says the differences between sexes and times of day, described below, are a first step toward more personalized exercise plans.
Exercise Changed Gene Activity in Lungs, Kidneys, and the Heart
Young mice of both sexes, 10 weeks old, were randomly split into two groups. One group lived with a running wheel to use whenever the mice pleased; the other had none. The wheel users ran in short bursts, mostly at night, a pattern the paper describes as natural and stress-free, unlike forced treadmill running. Both sexes ran at similar speeds and distances.
After eight weeks, the team collected 22 tissues plus blood plasma from some mice at rest and others during their active period. Researchers then checked which genes had been turned up or down in every tissue. They also measured proteins in four leg muscles and metabolites, the small molecules left behind by the body’s chemical reactions, in eight tissues and plasma. Because leg muscles responded most, three of them got a closer look, one cell nucleus at a time. For each, researchers tracked gene activity and DNA methylation, chemical tags that act like dimmer switches for genes. According to the paper’s figure legends, each comparison involved roughly six to ten mice of each sex per group.
Thigh and calf muscles changed the most, with more than 4,000 genes each shifting activity. The lungs, kidneys, heart, diaphragm, liver, and hypothalamus all showed moderate responses, while the pituitary gland, adrenal gland, and groin-area fat changed least. No single gene changed in all 22 tissues, and many responses were specific to individual tissues.
Exercise Reshaped Muscle, Favoring Fibers Built to Resist Fatigue
Muscles shifted away from fast-twitch fibers, built for short bursts of power, toward fatigue-resistant fibers, better suited to long, steady effort. Based on molecular markers, the share of fast-twitch fibers in a female hamstring muscle fell by 22 to 35 percentage points, depending on the measure. Mitochondria, the cell’s energy generators, ramped up in several leg muscles, though not in the soleus, a calf muscle that already relied on oxygen-burning fibers.
Looking at individual cells showed that the number of altered DNA tags varied widely by cell type, with fatigue-resistant muscle fibers topping the list. Salk says this is the first single-cell methylation study of muscle after exercise.
Co-first author Manoj Hariharan, PhD, a former senior staff scientist at Salk, said single-cell studies matter because “there are so many cell type-specific changes that get lost in bulk sequencing.” Bulk sequencing measures a whole tissue at once.
Responses to Exercise Differed by Sex and Time of Day
Sex made a clear difference in gene response. In females, about 1,990 genes changed across at least five tissues, nearly twice the 1,042 in males. In brown fat, a heat-producing tissue, males showed no gene response while females showed 754 changed genes. The pattern reversed in the hypothalamus, where females had none and males had 231.
Timing mattered for certain organs too. Most skeletal muscles and the heart changed more during active hours, while the hypothalamus, kidney, and lung responded more strongly at rest. In the hypothalamus, genes involved in sleep and wake regulation became more active during the rest period, which the authors say points to possible ways exercise could affect sleep. Whether the hour of a workout matters for people is untested, but the mouse data raise the possibility that different organs respond more strongly at different times.
A 51-Gene Signature Often Flagged Exercise in Outside Muscle Data
From the gene data, the team also built a 51-gene signature, a kind of fingerprint meant to tell exercised muscle from sedentary muscle. Tested on 26 outside datasets from rodents and humans, it generalized across species, sex, and age, according to the authors, though accuracy varied by dataset. They say it could help study muscle disuse.
Muscle may get the credit for exercise, yet this map shows organs far from the legs changing too. For now, it captures eight weeks of running in young, healthy mice, and whether the internal organs of people respond in the same ways remains open.
Disclaimer: This article summarizes research conducted in mice and is intended for general informational purposes only. It is not medical advice. Readers should consult a doctor or other qualified health professional before changing an exercise routine or making health decisions.
Paper Notes
Limitations
All work was done in young, healthy mice eating standard chow freely, so results may not carry over to humans, older animals, disease, or other diets. The mice were studied after eight weeks of running, with a three-day comparison in only four tissues, so the study does not show how long the changes last. Running mice were housed alone while sedentary mice lived in groups, a choice meant to avoid isolating the sedentary animals, though the authors acknowledge the housing difference may explain some molecular differences. Female mice were not tracked by reproductive cycle and ran about 16% farther than males, a difference that was not statistically significant but may have contributed to some sex differences. Four mice that stopped running or ran very little were excluded, and groups were small. Each measurement method has blind spots: gene activity does not always predict protein levels, single-nucleus RNA sequencing captures only RNA inside the nucleus, the methylation analysis focused on gene bodies rather than other regulatory regions, and metabolite measurements are not fully quantitative, with many detected molecules unidentified. The study maps patterns and does not test whether any single gene change causes a health benefit, so the link to sleep is a proposed idea. The 51-gene signature was tested on previously published muscle datasets, and its accuracy varied from one dataset to the next, as shown in the paper’s Figure 7. Statements about personalized exercise come from the Salk press release, and the idea that workout timing could matter for people is speculation, not a test in people.
Funding and Disclosures
Support came from the Wu Tsai Human Performance Alliance and the Joe and Clara Tsai Foundation. The Salk Institute’s sequencing core is funded by an NIH-NCI Cancer Center Support Grant (P30 014195), the Chapman Foundation, and the Helmsley Charitable Trust. A National Institutes of Health shared instrumentation grant (S10 OD026929) paid for the sequencer used at UC San Diego. Additional funding included Japanese Ministry of Education, Culture, Sports, Science, and Technology grants to Hikari Yoshitane (24H02299 and 24H02302), a Veterans Administration Research Career Scientist Award to Hemal H. Patel (BX005229), a National Human Genome Research Institute grant (HG010634) supporting the Ecker lab, and computing time through the National Science Foundation-supported ACCESS program. Joseph R. Ecker is an investigator of the Howard Hughes Medical Institute. The authors declare no competing interests. They also report using ChatGPT or Grammarly to improve sentence construction and titles, and say they reviewed the content and take full responsibility for the published article.
Publication Details
Authors: Geraldine Maier, Manoj Hariharan, Ramesh K. Ramasamy, and colleagues, including Susan M. Keach, Joseph R. Ecker, and Satchidananda Panda. Maier, Hariharan, and Ramasamy contributed equally, and Ecker is the lead contact. The authors are affiliated with the Salk Institute for Biological Studies, University of California San Diego, Tokyo Metropolitan Institute of Medical Science, the University of Tokyo, the University of Tsukuba, and the Veterans Affairs San Diego Healthcare System. Correspondence: [email protected], [email protected], and [email protected]. | Journal: Cell (Cell Press, Elsevier), volume 190, pages 1 to 27, January 7, 2027. Received July 9, 2025; revised April 13, 2026; accepted September 21, 2026. Published online October 15, 2026, according to Salk. | Paper title: Multi-omics atlas of chronic exercise | DOI: https://doi.org/10.1016/j.cell.2026.09.044 | Data: Processed data are deposited at Mendeley Data (DOI: 10.17632/pnh3ndbgrd.1), and sequencing data are available through NCBI under BioProject PRJNA1279216.
