肌肉线粒体能量代谢的功能异常在肥胖症和II型糖尿病的发生发展中起着至关重要的作用。肌肉线粒体能量代谢基因主要由核受体调控，但其下游的效应分子及分子机制还不清楚。我们曾发现核受体PPARb/ERRg可调控肌肉特异性的miR-499/208b的表达，并对肌纤维的结构转变有影响。本课题的前期研究表明miR-499/208b可以调节肌肉线粒体能量代谢基因的表达。因此，我们提出：miR-499/208b可能是PPARb/ERRg调节肌肉线粒体能量代谢的关键通路。为证实这一假设，本课题将分别从整体水平、细胞水平和线粒体亚细胞水平阐明miRNA在线粒体能量代谢中的作用过程及其功能贡献，提出一个较系统的核受体/miRNA通路对线粒体能量代谢的调节模式。本课题的完成，将为探讨代谢性疾病的防治新途径提供实验依据。

This proposal focuses on unraveling the nuclear receptor/miRNA axis in the control of muscle mitochondria fuel metabolism. Muscle mitochondria malfunction is a critical component underlying the pathogenesis of many metabolic diseases such as obesity and type 2 diabetes. Nuclear receptors have been identified as key regulators of skeletal muscle fuel metabolism, and have been implicated in metabolic diseases.However,the mechanisms have not been yet fully understood. We have previously found that PPARb and ERRg function to activate transcription of miR-208b and miR-499, triggering a cascade of muscle slow-twitch contractile protein gene expression. Our preliminary data indicated that many energy metabolic genes could be regulated by miR-499. These results have led to the hypothesis of this proposal that, miR-499/208b are important downstream targets of PPARb/ERRg, miR-499/208b could mediate the broad control of muscle mitochondria fuel metabolism by PPARb/ERRg. We will delineate the nuclear receptor/miRNA axis and downstream targets involved in the control of mitochondria fuel metabolism in vivo, using muscle-specific transgenes or knockout mice, and in vitro, in primary muscle cell culture. The nuclear receptor/miRNA regulatory pathways unveiled in these studies will greatly enhance our understanding of the mechanisms that control muscle energy metabolism. A longterm goal is to identify novel targets for metabolic modulator therapies aimed at enhancing muscle fitness in a variety of disease states such as obesity and diabetes.