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Glucose sensing by skeletal myocytes

骨骼肌细胞的葡萄糖传感

基本信息

批准号：
10133053
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
项目类别：
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/10133053
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 Stress 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

项目摘要

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处理的主要场所。肌肉受损葡萄糖代谢导致 2 型胰岛素抵抗和葡萄糖不耐受糖尿病。葡萄糖是否直接参与骨骼中的营养信号传导途径肌细胞在生理和代谢应激条件下维持稳态很大程度上仍未被探索。骨骼肌纤维在其结构上具有显着的异质性代谢特性，范围从高氧化型到高糖酵解型。我们最近证明 Baf60c（SWI/SNF 染色质重塑复合物的一个亚基）富含糖酵解肌并调节基因表达程序促进糖酵解代谢。该途径的肌肉特异性转基因激活改善肥胖症的全身葡萄糖代谢。尽管它对肌细胞代谢，参与该途径的生理信号以及 Baf60c 调节肌肉和全身葡萄糖代谢的机制仍有待建立。已获得大量初步数据来支持我们的研究假设 Baf60c 是控制肌肉的肌细胞营养感应的关键目标和全身葡萄糖代谢。在这个提案中，我们将首先评估Baf60c的作用骨骼肌营养信号传导、糖酵解代谢和全身葡萄糖体内平衡。我们将剖析导致激活的分子事件 Baf60c/Deptor 途径。最后，我们将研究肌肉衍生的意义调节全身葡萄糖代谢的分泌因子。顺利完成该项目将为了解糖酵解肌肉代谢及其在葡萄糖稳态中的作用。