运动与热量限制对骨骼肌线粒体质量的调控机制研究- - PGC-1a与核受体辅抑制因子的相互作用

项目名称： 运动与热量限制对骨骼肌线粒体质量的调控机制研究- - PGC-1a与核受体辅抑制因子的相互作用

项目编号： No.31300977

项目类型： 青年科学基金项目

立项/批准年度： 2014

项目学科： 生物科学

项目作者： 漆正堂

作者单位： 华东师范大学

项目金额： 21万元

中文摘要： 线粒体自噬与线粒体生物发生共同维持线粒体质量的稳态平衡，近来研究表明，细胞自噬（包括线粒体自噬）在维持线粒体功能、骨骼肌质量以及胰岛素敏感性等方面发挥不可或缺的作用。核受体辅激活因子PGC-1α是线粒体生物发生以及胰岛素敏感性的正调控因子，但线粒体自噬的转录调控机制并不清楚。PGC-1α与核受体辅抑制因子NCoRs可能成为线粒体生物发生与线粒体自噬之间的控制节点。本课题拟建立基因超表达细胞模型，检验线粒体自噬与生物发生在其转录调控阶段是否依赖PGC-1α/NCoRs的相互作用；建立运动与热量摄入限制动物模型，探讨PGC-1α与NCoRs是否参与运动、热量摄入限制对胰岛素抵抗的改善。预期成果将进一步阐明线粒体生物发生、细胞自噬、线粒体自噬的上游调控路径，增进对线粒体质量双向调控的认识；还有望提出肥胖和Ⅱ型糖尿病新的病理机制和预防康复机制，即以运动、热量限制激活线粒体自噬，维持线粒体质量。

中文关键词： 线粒体；骨骼肌；自噬；运动；胰岛素抵抗

英文摘要： Mitophagy and mitochondrial biogenesis are both required for mitochondrial quality control (MQC). Recent studies strongly suggested that autophagy (including mitophagy) plays an essential role in preserving mitochondrial function, skeletal muscle mass, and insulin sensitivity. Nuclear coactivator PGC-1α as a positive and master regulator promotes mitochondrial biogenesis and insulin action in skeletal muscle, however, little is known about the transcription control of mitophagy. Herein, we hypothesize that PGC-1α interacts with nuclear corepressors (NCoRs) in balancing mitochondrial biogenesis and mitophagy at transcription level. We will culture C2C12 cell lines with overexpressed PGC-1α/NCoRs, and investigate whether PGC-1α regulates mitophagy and mitochondrial biogenesis by inhibiting NCoRs. In animal test, we will further investigate whether PGC-1α/NCoRs are involved in the improvement of insulin resistance during exercise and calorie restriction (CR). We hope to further elucidate the upstream transcription control of mitochondrial biogenesis and mitophagy, which may contribute to clarifying the underlying mechanisms for MQC. Moreover, these studies may propose a novel perspective or an evidence for the pathology, prevention and therapy of obesity and type 2 diabetes, that exercise and calorie restriction (C

英文关键词： mitochondrial；skeletal muscle；autophagy；exercise；insulin resistance