Exercise-associated microbial metabolites prevent skeletal muscle atrophy in adult female mice
- Benjamin I. Burke
- Taylor R. Valentino
- Ahmed Ismaeel
- Salim S. El-Amouri
- Jensen Goh
- Logan N. Scott
- Bonnie J. Walton
- Jai K. Joshi
- Cecily R. Wood
- Abigail Burrows-Franco
- John B. May
- Lance A. Johnson
- Michael D. Flythe
- Yuan Wen
- John J. McCarthy
2026-07-10
We previously reported that skeletal muscle adaptation to regular exercise requires a healthy gut microbiome, contributing to growing evidence that some exercise benefits are mediated by microbiome-derived metabolites. Here, to identify such exercise-associated microbial metabolites, we transfer cecal contents from exercise-trained female donor mice into exercise-naïve female recipient mice undergoing unilateral hindlimb immobilization. Recipients of cecal material from exercise-trained donors exhibit less muscle atrophy compared with those receiving transfers from sedentary donors. Untargeted metabolomics reveal metabolites enriched in cecal content, serum, and muscle of recipients from exercise-trained donors, consistent with microbial origin. Oral administration of two such metabolites (pipecolic acid and succinate) attenuates muscle atrophy and preserves muscle function in exercise-naïve mice, potentially by enhancing cellular energy status and translational capacity. These findings further define the gut microbiome-skeletal muscle axis and provide evidence that exercise-associated microbial metabolites serve as a novel class of exercise mimetics for treating conditions responsive to physical activity.