Exercise is good for us—but why?
Salk Institute researchers introduce a molecular atlas of exercise-associated changes in mice, defining the healthy, exercised-trained state, which could help improve performance and prevent injury
Salk Institute
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Manoj Hariharan (left), Geraldine Maier (center), and Ramesh Ramasamy (right) debuted a molecular atlas of exercise-associated changes in mice, defining the healthy, exercised-trained state, which could help improve performance and prevent injury.
view moreCredit: Salk Institute
LA JOLLA (October 15, 2026)—To understand what goes wrong in the body, scientists must first know what right looks like. Salk Institute researchers are building a scientific reference, piece by piece, for what makes a body healthy. Their latest effort maps how exercise reshapes the body at the molecular level, examining responses across organs, cell types, sexes, and circadian phases in mice.
The result is a first-of-its-kind molecular atlas spanning 22 tissues and integrating bulk RNA sequencing, metabolomics, proteomics, single-nucleus RNA sequencing, and DNA methylation profiling. The researchers uncovered distinct responses to exercise that vary by tissue, cell type, sex, and circadian categories. By defining a healthy baseline, the atlas gives scientists a starting point to explore how tissues adapt to exercise, work toward more personalized exercise strategies, and identify new molecules and pathways for further investigation.
The study was published in Cell on October 15, 2026, and was funded by both federal research grants and private philanthropy.
What do we know about exercise?
It’s no surprise that exercise is good for you—we hear it all the time. Exercise can make us resilient against disease and dysfunction, speed up recovery from illness, and reduce mortality overall. In fact, studies have linked exercise to more than 30 percent lower all-cause, cardiovascular, and cancer mortalities.
Despite knowing all the good that exercise can do, scientists have had a hard time deciphering why. This question has been difficult to answer, in part because studies in humans are limited to blood and a few muscles. As a result, mouse models have become a popular tool for determining the molecular signatures of exercise.
The Salk research team compared young male and female mice that either spent eight weeks running voluntarily on a wheel or were sedentary. They collected 22 tissue samples, during both active and resting time of the day.
“Exercise doesn’t just change our muscles, it changes many of our organs and cells at different levels—some short-term, some long-term,” says co-first and co-corresponding author Geraldine Maier, PhD, a staff scientist at Salk. “Our experimental setup allows us to capture that detail across tissues, and sexes, and in muscle, down to the individual cell types.”
How do you build an exercise atlas?
After collecting various tissues from sedentary and running mice, the researchers started with bulk RNA sequencing on all 22 tissues. Bulk RNA sequencing reveals which genes are active in each tissue. Then, they conducted metabolomics on eight tissues and plasma, which catalogs the small molecules that cells use and produce by cellular metabolism. Next was proteomics, which measures the protein levels in a certain tissue—in this case, the researchers looked at four specific leg muscles (a hamstring muscle, two calf muscles, and quadriceps).
After discovering that leg muscles had the biggest responses to exercise at the whole-tissue level, they used single-cell RNA and DNA methylation in three leg muscles. Rather than generalizing over the whole tissue, single-cell inquiry provides specific detail that differentiates neighboring cells by their precise identities and activities.
The Salk study is the first to conduct single-cell methylation work on muscle after exercise. Methylation is a type of epigenetic change that regulates the expression of genes. Compared to differences in protein or RNA expression, exercise-induced changes in DNA methylation are more permanent. Methylation can lead to lasting regulatory changes that alter cell type and whole-tissue behavior.
In addition to creating the atlas, the researchers used the transcriptomic dataset to develop a 51-gene exercise signature that distinguishes exercise-trained from sedentary muscle in both mice and humans. This signature could help to identify biomarkers and study muscle disuse and dysfunction.
How does exercise change living systems, on a molecular scale?
The atlas first revealed that exercise induced widespread, tissue-specific cellular remodeling—with most transcriptional changes occurring in skeletal muscle. Exercise changed the activity of nearly half the genes in at least one tissue, yet no single gene’s activity was changed in all 22 tissues. And in muscle, exercise altered methylation in specific cell types but not others. These findings especially demonstrate the power of single-cell-level analyses, as these details would have been missed in bulk sequencing.
When looking at differences across circadian phases, the team noted that most tissues changed more during the active phase, excluding the hypothalamus, kidney, and lung. When looking at sex-based differences, females had broader transcriptional responses and distinct gene expression patterns compared to males. There was also a strong sex-specific epigenetic response to training.
“Our atlas provides a comprehensive resource for understanding the systemic molecular adaptations to endurance exercise,” says co-first author Ramesh Ramasamy, PhD, a former computational biologist at Salk. “Now that we have all this data, researchers can begin developing strategies that harness exercise—either alone or in combination with other interventions—to ensure we all live long, healthy lives.”
What can an exercise atlas be used for?
The atlas is a starting point toward creating exercise routines tailored to individuals, since responses differ by sex and time of day. It also provides the data needed for more targeted research within specific tissues and cell types, which could potentially point to new biomarkers or strategies for improving performance, recovery, and muscle health.
“Now that we have the data,” adds Maier, “labs can identify one gene or metabolic pathway they find interesting then dissect that mechanism. Our atlas gives the field a shared foundation to build on.”
“Exercise impacts the whole body, not just your muscles, so an atlas like ours that looks more holistically at many tissues is key to understanding the true impact of exercise,” says co-first author Manoj Hariharan, PhD, a former senior staff scientist at Salk. “That’s also why single-cell studies are so important—there are so many cell type-specific changes that get lost in bulk sequencing. I hope our work highlights that and encourages more single-cell atlases, and especially multi-omic single-cell atlases, moving forward.”
Further research will need to explore how “sticky” exercise-induced changes are. How long do you have to exercise to see lasting change? How long do those changes last? Do cells remember exercising after months? Years?
An atlas marks the beginning of an endeavor that can go on for decades. With new data come new questions and new discoveries, each bringing us closer to understanding human health and how we can protect it.
Other information and funding
The work was supported by the Wu Tsai Human Performance Alliance; Joe and Clara Tsai Foundation; National Institutes of Health (S10 OD026929, P30 014195, HG010634); Chapman Foundation; Helmsley Charitable Trust; Ministry of Education, Culture, Sports, Science and Technology in Japan; Veterans Administration; National Science Foundation (2138259, 2138286, 2138307, 2137603, 2138296); and Howard Hughes Medical Institute.
This press release was written by Isabella Davis.
Journal: Cell
Paper title: Multi-omics atlas of chronic exercise
DOI: 10.1016/j.cell.2026.09.044
About the Salk Institute for Biological Studies
The Salk Institute is an independent, nonprofit research institute founded in 1960 by Jonas Salk, developer of the first safe and effective polio vaccine. The Institute’s mission is to drive foundational, collaborative, risk-taking research that addresses society’s most pressing challenges, including cancer, Alzheimer’s disease, and crop resilience. This foundational science underpins all translational efforts, generating insights that enable new medicines and innovations worldwide. Learn more at www.salk.edu.
Journal
Cell
Article Title
Multi-Omics Atlas of Chronic Exercise
