Exercise-Associated Microbial Metabolites Prevent Skeletal Muscle Atrophy in Adult Mice

ABSTRACT: 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 donor mice into exercise-naïve 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.

INSTRUMENT(S):

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Muscle, Muscle Cell

SUBMITTER: Yuan Wen  

LAB HEAD: John Joseph McCarthy

PROVIDER: PXD077599 | Pride | 2026-05-27

REPOSITORIES: Pride