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Author ORCID Identifier
Date Available
10-20-2027
Year of Publication
2026
Document Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
College
Medicine
Department/School/Program
Physiology
Faculty
John J. McCarthy
Faculty
A. Catalina Vélez-Ortega
Abstract
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 exercise-naïve 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.
Digital Object Identifier (DOI)
https://doi.org/10.13023/etd.2026.453
Archival?
Archival
Funding Information
This work was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (R21AG071888 to JJM, 2021-2022; R01AR084282 to JJM, 2025-2026) and the National Institute on Aging (F31AG087618 to BIB, 2024-2026).
Recommended Citation
Burke, Benjamin I., "MICROBIAL-DERIVED EXERKINES: A NOVEL CLASS OF EXERCISE MIMETICS—ILLUSTRATED IN SKELETAL MUSCLE ATROPHY" (2026). University of Kentucky Doctoral Dissertations. 888.
https://uknowledge.uky.edu/gradschool_diss/888
