Using the gut microbiome to treat skeletal muscle atrophy - SUMMARY When skeletal muscle is not used on a regular basis it becomes smaller as a result of myofiber atrophy; not surprisingly, this muscle atrophy is accompanied by a loss of strength. Disuse atrophy is most often caused by disease, surgery, injury or aging. Although there is a good understanding of the molecular mechanisms underlying atrophy, and how they can differ given the cause, the development of an effective treatment remains an ongoing challenge. Resistance exercise is currently the most effective treatment to help reduce the level of atrophy and regain strength; however, many individuals are unable to perform exercise at a sufficient intensity to promote muscle growth. Thus, there is a critical need to develop a new therapeutic approach to work as an adjunct to resistance exercise or as a stand-alone treatment. Research over the last couple of decades has provided a deeper understanding of how the gut microbiome impacts human health and disease throughs its pervasive interactions with cells of the body via microbial-derived metabolites. Studies investigating hibernating squirrels and germ-free mice have established a gut microbiome-skeletal muscle axis involved in regulating skeletal muscle mass and function. We reported the disruption of the mouse gut microbiome by antibiotic treatment blunted skeletal muscle hypertrophy in response to exercise training. We have now acquired preliminary data showing cecal microbial transplant from exercised-trained mice to mice undergoing unilateral hind limb immobilization, significantly reduced the magnitude of muscle atrophy. Metagenomic and metabolomic analyses have identified promising candidate bacterial species and microbial- derived metabolites, respectively, that we hypothesize mediate the observed reduction in muscle atrophy. To test this hypothesis, we will first determine if cecal microbial transplant from exercise-trained mice also attenuates muscle atrophy in male mice and fast-twitch muscles. We will also determine if mTORC1 activation is the mechanism underlying the reduced muscle atrophy. We will next investigate if the administration of a probiotic composed of candidate bacterial species, identified by metagenomics, is able to mimic the effect of cecal microbial transplant by reducing muscle atrophy. A final aim will test if the administration of a post-biotic (a microbial-derived metabolite identified by metabolomics) is capable of attenuating disuse atrophy. Regular exercise is known to change the composition and function of the gut microbiome. Our preliminary data provides compelling evidence that the gut microbiome of exercise-trained mice is able to significantly reduce the magnitude of muscle atrophy following disuse. The proposed studies will determine if a probiotic and/or post-biotic are capable of ameliorating muscle atrophy and preserving muscle function thereby providing a novel therapeutic strategy to treat muscle atrophy.
