Glucose sensing by skeletal myocytes

骨骼肌是餐后葡萄糖处理的主要部位。受损肌肉 糖代谢参与2型胰岛素抵抗和糖耐量减低 糖尿病。葡萄糖是否直接参与骨骼中的营养信号通路 心肌细胞在生理和代谢应激条件下维持内环境平衡 在很大程度上仍未被探索。骨骼肌纤维具有显著的异质性。 代谢特性，从高度氧化到高度糖酵解类型。我们最近 证明了SWI/SNF染色质重塑复合体的一个亚单位BAF60c是 富含糖酵解肌肉，调节一个基因表达程序， 促进糖酵解代谢。这一途径的肌肉特异性转基因激活 改善肥胖患者的全身葡萄糖代谢。尽管它对 肌细胞代谢，参与这一途径的生理信号和 BAF60c调节肌肉和全身糖代谢的机制 仍有待确定。已经获得了大量的初步数据来支持我们的 假设BAF60c是控制肌肉的心肌细胞营养传感的关键靶点 和全身性葡萄糖代谢。在这项提案中，我们将首先评估BAF60c的作用 骨骼肌营养信号转导与糖酵解代谢和全身葡萄糖 动态平衡。我们将剖析导致细胞活化的分子事件 BAF60c/Deptor通路。最后，我们将调查肌肉衍生的意义 调节全身糖代谢的分泌因子。成功完成 这一项目的研究将为我们提供新的见解，让我们了解 糖酵解肌肉代谢及其在葡萄糖稳态中的作用。

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.