Multi-omics reveals molecular signatures of moderate intensity exercise and identifies candidate exercise mimetics in mice.

Exercise is known to promote systemic health and prevent various chronic diseases. However, the molecular mechanisms underlying its beneficial effects remain incompletely understood. Although the health benefits of exercise have been widely studied, most research has treated exercise as a general intervention, without clearly standardizing its intensity. This study focused on a physiologically and molecularly defined moderate intensity, which may uniquely capture the core health-promoting mechanisms of exercise. To characterize the molecularly defined moderate intensity exercise, integrative multi-omics analyses-including transcriptomics, epigenomics, and phosphoproteomics-were performed using skeletal muscle tissue. These analyses revealed that this specifically defined exercise consistently modulated shared molecular pathways across both exercise modalities, especially insulin signaling, FoxO signaling, and circadian rhythm regulation. To explore the translational relevance of the identified molecular signatures, Connectivity Map analysis was used to search for compounds with similar transcriptional profiles. As a secondary outcome, apigenin and doxazosin were found to mimic exercise-associated molecular responses partially. These compounds exerted distinct physiological effects in vivo, including enhanced mitochondrial function and endurance and muscle hypertrophy with musculoskeletal protection. In conclusion, this study primarily elucidates the systemic molecular basis of physiologically and molecularly defined moderate-intensity exercise. The identification of candidate exercise mimetics serves as a potential application of these findings.