Glucose sensing by skeletal myocytes

骨骼肌细胞的葡萄糖传感

• 批准号: 9902419
• 负责人: Jiandie D Lin
• 金额: $ 39万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9902419
• 关键词: Binding; Biological Assay; Blood Glucose; Brain; Calcium Signaling; Cardiovascular Diseases; Cells; Chromatin Remodeling Factor; Data; Disease Progression; Endocrine; Event; Exclusion; Gene Expression; Genes; Glucose; Glucose Intolerance; HDAC5 gene; Hepatic; Histone Deacetylase; Homeostasis; Hormones; Human; Impairment; Insulin; Insulin Resistance; Knockout Mice; Lead; Link; Liver; Mediating; Metabolic; Metabolic stress; Metabolic syndrome; Metabolism; Molecular; Molecular Genetics; Mus; Muscle; Muscle Cells; Muscle Fibers; Muscle function; Non-Insulin-Dependent Diabetes Mellitus; Nuclear; Nutrient; Obesity; Pancreas; Pathogenicity; Pathway interactions; Pharmacology; Phosphorylation; Physiological; Property; Proto-Oncogene Proteins c-akt; Public Health; Regulation; Repression; Rest; Risk; Role; Signal Pathway; Signal Transduction; Site; Skeletal Muscle; Testing; Tissues; Transgenic Organisms; adenoviral-mediated; base; blood glucose regulation; conditional knockout; design; detection of nutrient; glucose disposal; glucose metabolism; hepatic gluconeogenesis; improved; insight; insulin sensitivity; muscle metabolism; nonalcoholic steatohepatitis; novel; overexpression; preservation; programs; response; skeletal; tool

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.

骨骼肌是餐后葡萄糖代谢的主要场所。受损的肌肉 葡萄糖代谢导致2型糖尿病患者胰岛素抵抗和葡萄糖耐受不良 糖尿病葡萄糖是否直接参与骨骼肌中的营养信号通路 肌细胞在生理和代谢应激条件下维持稳态 大部分尚未开发。骨骼肌肌纤维在它们的 代谢特性，从高度氧化型到高度糖酵解型。我们最近 证明Baf 60 c，SWI/SNF染色质重塑复合物的亚基， 富含糖酵解肌肉，并调节基因表达程序， 促进糖酵解代谢。肌肉特异性转基因激活该途径 改善肥胖症患者的全身葡萄糖代谢。尽管它的强大影响， 肌细胞代谢，参与这一途径的生理信号， Baf 60 c调节肌肉和全身葡萄糖代谢的机制 有待确定。已经获得了大量的初步数据来支持我们的研究。 假设Baf 60 c是控制肌肉的肌细胞营养感测的关键靶标 和全身葡萄糖代谢。在本提案中，我们将首先评估Baf 60 c的作用 在骨骼肌营养信号和糖酵解代谢和全身葡萄糖 体内平衡我们将剖析导致细胞激活的分子事件， Baf 60 c/Deptor途径。最后，我们将研究肌肉衍生的 分泌因子调节全身葡萄糖代谢。成功完成 该项目的研究将为人类的生理和机械基础提供新的见解。 糖酵解肌肉代谢及其在葡萄糖稳态中的作用。