On Tuesday, September 29, 2026, Benjamin Burke successfully defended his dissertation and earned his doctoral degree in physiology. Congratulations, Dr. Burke!
Microbial-Derived Exerkines: A Novel Class of Exercise Mimetics—Illustrated in Skeletal Muscle Atrophy
The gut microbiome is a complex ecosystem of microorganisms that exerts widespread effects on host physiology. Exercise
adaptation is increasingly recognized to be regulated, in part, by this microbiome. 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. In the present work, we identified such exercise-associated microbial metabolites,
termed microbial-derived exerkines (MDEs), by transferring cecal contents from exercise-trained donor mice into exercise-naïve
recipient mice undergoing unilateral hindlimb immobilization. Recipients of cecal transfers from exercise-trained donors exhibited
less muscle atrophy than those receiving transfers from sedentary donors. Untargeted metabolomics revealed metabolites enriched in
the cecal contents, serum, and muscle of recipients from exercise-trained donors, consistent with microbial origin. Oral administration
of two such metabolites, pipecolic acid and succinate (PAS), attenuated muscle atrophy and preserved muscle function in exercisenaïve
immobilized mice. Given the heightened susceptibility of aged muscle to disuse atrophy, we also administered PAS to aged
mice undergoing unilateral hindlimb immobilization, observing sex-specific effects on muscle function. Moreover, in diet-induced
obese mice, PAS attenuated losses in muscle mass, muscle stem cell abundance, and muscle function when co-administered with
semaglutide, a glucagon-like peptide-1 receptor agonist known to decrease lean mass and muscle strength. Finally, we demonstrated
that PAS enhances exercise adaptation and performance during a 7-week progressive weighted wheel-running exercise protocol in
adult mice. Together, these findings establish MDEs as a novel class of exercise mimetics for treating conditions responsive to
physical activity.