Figure 2.

Metabolic regulation by BAF60c in skeletal muscle. BAF60c drives glycolytic muscle metabolism through Deptor-mediated AKT activation. Mechanistically, BAF60c forms a transcriptional complex with Six4 and recruits the SWI/SNF complex to the proximal Deptor promoter to induce Deptor gene expression. This pathway is important for muscle glucose metabolism and whole body glucose homeostasis in both physiological and diabetic states. In severe diabetic condition, expression of BAF60c and Deptor is downregulated due to activation of ERK pathway by meta-inflammation. Rescue of this pathway by either treatment with an ERK inhibitor or transgenic expression of BAF60c in skeletal muscle ameliorates insulin resistance and improves whole body glucose homeostasis in HFD-induced or genetically obese mice. Under physiological condition, BAF60c acts as a glucose sensor in skeletal muscle. Glucose triggers K_ATP channel-dependent Ca²⁺ response, which elicits the phosphorylation and nuclear exclusion of HDAC5 downstream of CaMKII activation, resulting in BAF60c and Deptor induction and insulin-independent AKT activation. This glucose sensing pathway works in concert with insulin signaling pathway to maintain postprandial glucose homeostasis