Dynamic changes in butyrate levels regulate satellite cell homeostasis by preventing spontaneous activation during aging.

The gut microbiota plays a pivotal role in systemic metabolic processes and in particular functions, such as developing and preserving the skeletal muscle system. However, the interplay between gut microbiota/metabolites and the regulation of satellite cell (SC) homeostasis, particularly during aging, remains elusive. We propose that gut microbiota and its metabolites modulate SC physiology and homeostasis throughout skeletal muscle development, regeneration, and aging process. Our investigation reveals that microbial dysbiosis manipulated by either antibiotic treatment or fecal microbiota transplantation from aged to adult mice, leads to the activation of SCs or a significant reduction in the total number. Furthermore, employing multi-omics (e.g., RNA-seq, 16S rRNA gene sequencing, and metabolomics) and bioinformatic analysis, we demonstrate that the reduced butyrate levels, alongside the gut microbial dysbiosis, could be the primary factor contributing to the reduction in the number of SCs and subsequent impairments during skeletal muscle aging. Meanwhile, butyrate supplementation can mitigate the antibiotics-induced SC activation irrespective of gut microbiota, potentially by inhibiting the proliferation and differentiation of SCs/myoblasts. The butyrate effect is likely facilitated through the monocarboxylate transporter 1 (Mct1), a lactate transporter enriched on membranes of SCs and myoblasts. As a result, butyrate could serve as an alternative strategy to enhance SC homeostasis and function during skeletal muscle aging. Our findings shed light on the potential application of microbial metabolites in maintaining SC homeostasis and preventing skeletal muscle aging.