Skeletal muscle is a major site of postprandial glucose disposal. Impaired muscle glucose metabolism contributes to insulin resistance and glucose intolerance in type 2 diabetes. Whether glucose directly engages nutrient signaling pathways in skeletal myocytes to maintain homeostasis under physiological and metabolic stress conditions remains largely unexplored. Skeletal myofibers are remarkably heterogeneous in their metabolic properties, ranging from highly oxidative to highly glycolytic types. We recently demonstrated that Baf60c, a subunit of the SWI/SNF chromatin-remodeling complex, is enriched in glycolytic muscles and regulates a program of gene expression that promotes glycolytic metabolism. Muscle-specific transgenic activation of this pathway improved whole body glucose metabolism in obesity. Despite its strong effects on myocyte metabolism, the physiological signals that engage this pathway and the mechanisms through which Baf60c regulates muscle and systemic glucose metabolism remain to be established. A body of preliminary data has been obtained to support our hypothesis that Baf60c is a key target of myocyte nutrient sensing that controls muscle and systemic glucose metabolism. In this proposal, we will first assess the role of Baf60c in skeletal muscle nutrient signaling and glycolytic metabolism and whole body glucose homeostasis. We will dissect the molecular events that lead to the activation of the Baf60c/Deptor pathway. Finally, we will investigate the significance of a muscle-derived secreted factor in the regulation of systemic glucose metabolism. Successful completion of this project will provide novel insights into the physiological and mechanistic basis of glycolytic muscle metabolism and its role in glucose homeostasis.
Metabolic syndrome is linked to increased risk for type 2 diabetes, cardiovascular disease, and non-alcoholic steatohepatitis, and has become a serious public health challenge for the US and the rest of the world. While it has been recognized that insulin resistance is an early pathogenic event in disease progression, the mechanisms that regulate tissue and systemic insulin sensitivity remain poorly understood. We propose to use state-of-the-art molecular, genetic, and metabolic tools to establish the significance of this new pathway in muscle function, dissect novel regulatory components, and assess the cause and effect relationship between muscle metabolism and insulin resistance.
|Wang, Ruo-Ran; Pan, Ran; Zhang, Wenjing et al. (2018) The SWI/SNF chromatin-remodeling factors BAF60a, b, and c in nutrient signaling and metabolic control. Protein Cell 9:207-215|
|Meng, Zhuo-Xian; Tao, Weiwei; Sun, Jingxia et al. (2018) Uncoupling Exercise Bioenergetics From Systemic Metabolic Homeostasis by Conditional Inactivation of Baf60 in Skeletal Muscle. Diabetes 67:85-97|
|Meng, Zhuo-Xian; Gong, Jianke; Chen, Zhimin et al. (2017) Glucose Sensing by Skeletal Myocytes Couples Nutrient Signaling to Systemic Homeostasis. Mol Cell 66:332-344.e4|