Using the gut microbiome to treat disuse atrophy in aging.

PROJECT SUMMARY/ABSTRACT
The age-related loss of skeletal muscle mass and function has considerable effects on autonomy, quality of
life, and disease prognosis. These negative outcomes can be exacerbated by diseases or treatments that
induce immobilization. Older adults are especially susceptible to immobilization-induced losses in muscle size
and function, experiencing larger decrements and impaired rehabilitation in these measures compared to their
young counterparts. Recent findings from our lab have shown how gut microbiome interventions can reduce
the level of atrophy induced via immobilization, supporting an emerging body of literature linking the gut
microbiome to the regulation of muscle mass and function. However, little research has sought to exploit the
gut microbiome to maintain muscle mass during periods of immobilization in older adults, a population
especially susceptible to the negative health effects of disuse. The proposed project will explore the effects
of gut microbiome interventions on skeletal muscle size and function during immobilization and
recovery in aged mice. Our preliminary data suggest that the transfer of cecal contents from exercise-trained
mice to mice undergoing hindlimb immobilization is sufficient to attenuate muscle atrophy. Through
metabolomic analyses, we identified candidate metabolites potentially responsible for the positive effects of the
gut microbiome on muscle atrophy. In subsequent experiments, I found promising evidence that the
administration of these candidate metabolites reduces muscle atrophy during hindlimb immobilization.
However, these findings were in young mice and must be confirmed in aged mice. Based on our preliminary
findings, I hypothesize aged mice receiving cecal transfers from exercise-trained mice or candidate
metabolites will have reduced muscle atrophy, preserved muscle function, and enhanced recovery. To
test this hypothesis, I will transfer the cecal contents from young, exercise-trained or sedentary mice into aged
mice during periods of immobilization and recovery (Aim 1). I will conduct another set of experiments in which
candidate metabolites responsible for the retention of muscle mass will be administered to aged mice during
periods of immobilization and recovery (Aim 2). Collectively, these experiments will allow me to determine the
effectiveness of the gut microbiome in 1) attenuating muscle loss, 2) preserving muscle function, and 3)
enhancing muscle recovery during/following immobilization. This proposed research not only elucidates
mechanisms whereby the gut microbiome regulates aging skeletal muscle, but also has the potential
for extensive clinical impact, potentially implicating pharmaceutical targets relevant to treating muscle
atrophy in an aged population. Through this award, I will receive excellent training in immunohistochemistry,
fluorescent microscopy, western blot analysis, muscle function measurement, microbiology, mass
spectrometry, and bioinformatics, as well as oral and written communication skills.

Grant Number: 5F31AG087618-02
NIH Institute/Center: NIH
Principal Investigator: Benjamin Burke