Baf60c in skeletal muscle regulates adipose tissue thermogenesis via Musclin-mediated endocrine signaling

Skeletal muscle plays a key role in metabolic homeostasis. Brg1/Brm-associated factor (Baf) 60c, a subunit of the mating type switching/sucrose non-fermenting (SWI/SNF) chromatin remodeling complexes, was previously identified to be robustly involved in glycolytic muscle function and systemic metabolic balance. However, whether Baf60c regulates the secreted factors and couples the skeletal muscle function to systemic metabolism remains unclear. Here, we uncover that Baf60c regulates the expression of a series of secreted factors, among which Musclin, a recently identified negative regulator of beige adipocyte thermogenesis, was top-ranked in the upregulated factors in <i>Baf60c</i>-deficient muscle. Mechanistically, Baf60c physically interacts with the transcription factor myocyte enhancer factor 2c (Mef2c) and modulates the chromatin accessibility at the proximal promoter regions upstream of the <i>Musclin</i> gene transcription start site (TSS), therefore negatively regulating <i>Musclin</i> gene expression in the skeletal muscle. Further <i>in vivo</i> metabolic assays demonstrate that muscle-specific <i>Baf60c</i> ablation inhibits thermogenesis and elevates blood glucose. Conversely, muscle-specific overexpression of <i>Baf60c</i> increases thermogenesis and energy expenditure and improves systemic glucose metabolism. Together, this work uncovers Baf60c/Mef2c-mediated chromatin remodeling signaling in myocytes that control adipose tissue thermogenesis and systemic metabolism through Musclin-mediated muscle-fat crosstalk.