Acetate and combinations of short-chain fatty acids increase oxidative phenotype and contribute to muscle fiber type shift in myotubes.

Introduction: Intestinal microbial fermentation produces short-chain fatty acids (SCFAs) that signal from the large intestine to skeletal muscle. Skeletal muscle exhibits phenotypic plasticity, with fiber-type composition shifting between oxidative (slow-twitch) and glycolytic (fast-twitch) states in response to metabolic and environmental cues. While SCFAs have been implicated in modulating metabolism, their role in skeletal muscle fiber-type regulation remains poorly defined. This study aimed to investigate whether acetate and SCFA mixtures (acetate, propionate, and butyrate) can promote a shift towards an oxidative skeletal fiber type in skeletal muscle cells. Methods: Cultured C2C12 myotubes were exposed to SCFAs, and fiber type-specific gene and protein expression was assessed. Exposure: Exposure to ≥0.5 mM of the SCFA mixture for 8 h increased Conclusion: This study shows that both acetate and SCFA combinations shift muscle myotubes towards oxidative fiber phenotype, with the mixture demonstrating a more pronounced effect at lower concentrations. This supports a role for gut-derived metabolites in muscle adaptation and demonstrates that SCFAs promote a shift toward an oxidative fiber type.