Exercise-associated microbial metabolites prevent skeletal muscle atrophy in adult female mice

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.