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Recent evidence suggests that the gut microbiome could play a role in skeletal muscle plasticity, providing novel treatments for muscle wasting diseases and/or performance enhancements. I first sought to determine if the gut microbiome is necessary for skeletal muscle adaptation to exercise. Forty-two, four-month old, female C57Bl/6J underwent nine weeks of weighted wheel running or remained in cage with a locked wheel, without or without the administration of antibiotics (treated). In response to wheel running, I found that antibiotic depletion of the microbiome led to a blunted hypertrophic response in the soleus muscle as measured by normalized muscle wet weight and mean and fiber-type specific cross-sectional area (CSA). The plantaris muscle of mice who ran with antibiotic-induced dysbiosis showed a blunted glycolytic to oxidative fiber-type shift, decreased myonuclear accretion and satellite cell abundance compared to non-treated runners. These results are the first to demonstrate that an intact microbiome is necessary for skeletal muscle adaption to exercise. I next tested if the gut microbiome mitigates skeletal muscle atrophy induced by hind limb immobilization. Eighteen, four-month old, female C57Bl/6J mice were divided into two groups (n=9/group), that received cecal microbial transfers from either exercise-trained or sedentary donors. After four weeks of cecal transplants, the recipient mice underwent 10-days of single leg hind-limb immobilization. Immunohistochemistry analysis revealed that the recipients of the exercise-trained donors experienced significantly less skeletal muscle atrophy of the soleus muscle, as measures by mean fiber and fiber-type specific CSA. The transfer of microbiome from exercise-trained donors also led to a preservation of Type-2A fibers in the immobilized soleus muscle. These results demonstrated that the transfer of a microbiome from an exercise-trained host into recipients mitigated skeletal muscle atrophy, in addition to the persevering Type-2A fibers abundance during atrophy To better understand how the gut microbiome acts to modulate skeletal muscle mass and fiber-type composition, metagenomic sequencing was performed on donor and recipient of exercise-trained and sedentary cecal content. Sequencing data revealed significant differences in the microbiome between the two recipient groups. Further microbial functional comparisons were made and distinguished significant associations in fucose degradation and histidine metabolism in the recipients who received microbiome from exercised-trained donors. To further interrogate the metagenomic sequencing, microbial sequence features were analyzed with MelonnPan to determine predictive metabolites associated with each recipient group. Lipids and bile acids metabolites were significantly associated with the recipients of the exercise-trained donors. There was a trend for imidazole propionate to be associated with the recipients of the exercise-trained donors. The metagenomic analysis indicated the microbiome from an exercise-trained host was associated with metabolic pathways that generate short chain fatty acids (fucose degradation) and the histidine-derived metabolite imidazole propionate. The results from this dissertation provide evidence of crosstalk between skeletal muscle and the gut microbiome, providing for the first-time data that demonstrates the gut microbiome influences both anabolic and catabolic signaling in skeletal muscle. Although a direct mechanism for the skeletal muscle-gut microbiome interaction was not found, the metabolites propionate and imidazole propionate were identified as possible candidate for future studies. A general conclusion from the two studies described in this dissertation provides new evidence for the regulation of skeletal muscle mass and fiber-type composition. Future work will need to focus on the identification of the gut microbial-derived metabolites promote anabolic pathways in skeletal muscle. Additional studies should also determine if the attenuation in atrophy induced by hind limb immobilization is conserved in other models of atrophy as observed with skeletal muscle wasting diseases and space exploration.