Countless studies link regular exercise to lower mortality, improved resilience against disease, and faster recovery from illness. Yet scientists are still working to decipher the precise molecular mechanisms behind these benefits and how physical activity affects the body as a whole.
Human studies often rely on blood samples and small muscle biopsies, leaving many organs and cell types difficult to study directly.
To address this gap, an interdisciplinary team developed a molecular atlas of exercise-associated changes across 22 tissues in mice. Published in Cell on October 15, 2026, the study provides a detailed reference for understanding how the body adapts to endurance exercise.
Inside the Multi-Omics Toolkit: 22 Tissues and Single-Nucleus Resolution
The Salk Institute for Biological Studies project involved more than two dozen researchers, led by co-first authors Geraldine Maier, Manoj Hariharan, and Ramesh K. Ramasamy. The team compared young male and female mice that ran voluntarily on wheels for eight weeks with sedentary mice. Samples were collected during both active and inactive phases of the day.
The researchers combined several molecular techniques to examine different aspects of exercise adaptation. Bulk RNA sequencing across all 22 tissues measured patterns of gene expression. Metabolomics across eight tissues and plasma cataloged small molecules involved in cellular metabolism. Proteomics measured protein abundance in four leg muscles: the quadriceps, a hamstring muscle, and two calf muscles.
The results showed that skeletal muscle had the largest transcriptomic changes at the whole-tissue level. The researchers then used single-nucleus RNA sequencing and DNA methylation profiling in three leg muscles to investigate how individual cell types responded.
As Maier explained in the Salk Institute's news release, "Exercise doesn't just change our muscles, it changes many of our organs and cells at different levels—some short-term, some long-term." The team's experimental approach allowed researchers to examine these responses across tissues, sexes, and individual muscle cell types.
These methods revealed substantial biological complexity. Exercise altered the expression of nearly half the genes examined in at least one tissue, yet no single gene changed its expression across all 22 tissues. The researchers also identified exercise-associated DNA methylation changes in specific muscle cell types that bulk-tissue analyses would have missed.
DNA methylation is an epigenetic process that can influence gene regulation without changing the underlying DNA sequence. These changes may help explain how training affects cells over time, although further research is needed to establish how long exercise-induced methylation patterns persist after training stops.
Sex Differences and Circadian Rhythms in Training Adaptations
The atlas also revealed that exercise responses vary with biological sex and circadian phase. Most tissues showed greater transcriptional changes during the mice's active phase, with the hypothalamus, kidney, and lung as exceptions.
Female mice displayed broader transcriptional responses and distinct patterns of gene expression compared with males. The researchers also found pronounced sex differences in exercise-associated epigenetic remodeling.
These findings suggest that the molecular effects of exercise depend on more than the type or duration of physical activity. Biological sex, tissue identity, and the body's circadian rhythms all help shape the response. However, the results do not establish that women and men need different exercise programs or that a particular workout time is universally better.
Translating Animal Research Into Human Health and Performance
Although the study was conducted in mice, one finding provides a direct bridge to human research. Using the transcriptomic dataset, the team developed a 51-gene exercise signature that distinguishes exercise-trained muscles from sedentary ones in both humans and mice.
This cross-species signature could help researchers investigate biomarkers of athletic training, muscle disuse, and dysfunction. It also provides a starting point for exploring molecular pathways that might eventually inform strategies to improve muscle health, recovery, and resilience.
The distinction between a promising research tool and an established clinical application is critical. The atlas doesn't provide a validated method for prescribing personalized workouts, preventing injuries, or boosting peak performance. Instead, it offers a detailed foundation and road map for testing those possibilities in future studies.
Ultimately, this atlas is a starting point for understanding how endurance exercise triggers systemic molecular adaptations. More research is needed to determine which molecular changes keep our bodies healthy, how long they persist, and whether the findings can reliably guide human exercise interventions.
As Ramasamy concludes in the news release, "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."