Regulation of glycolytic muscle metabolism

描述（由申请人提供）：代谢综合征已成为一种全球流行病，它显著增加了2型糖尿病、心血管疾病和非酒精性脂肪性肝炎的风险。骨骼肌胰岛素抵抗是该综合征代谢紊乱的标志，与线粒体氧化能力受损以及从氧化型向糖酵解型肌纤维的转变有关。然而，骨骼肌纤维代谢特性与胰岛素敏感性之间的因果关系尚不清楚。虽然PGC-1共激活因子及其转录伙伴正在成为线粒体生物发生和氧化纤维程序的核心调节因子，但我们对控制快速收缩糖酵解肌发育和功能的调节级联的理解非常有限。本研究的总体目标是探索调节糖酵解肌肉形成的新机制，并研究它们在慢性热量过剩期间胰岛素抵抗发病机制中的作用。在初步研究中，我们已经确定了BAF60c， SWI/SNF染色质重塑复合物的一个亚基，与其他转录因子相互作用，作为快速糖酵解肌肉形成的一种新的调节剂。此外，我们已经描绘了这个调控级联的关键分子成分。在这项建议中，我们将首先使用功能获得和功能丧失小鼠模型来确定这一生理作用

DESCRIPTION (provided by applicant): Metabolic syndrome has become a global epidemic that dramatically increases the risk for type 2 diabetes, cardiovascular disease, and non-alcoholic steatohepatitis. Skeletal muscle insulin resistance is a hallmark of the metabolic derangements in this syndrome that has been associated with impaired mitochondrial oxidative capacity and a shift from oxidative to glycolytic myofiber types. However, the cause and effect relationship between the metabolic properties of skeletal myofibers and insulin sensitivity remains unclear. While the PGC-1 coactivators and their transcriptional partners are emerging as core regulators of mitochondrial biogenesis and the oxidative fiber program, our understanding of the regulatory cascade that controls the development and function of fast-twitch glycolytic muscle is remarkably limited. The overall goal of this proposal is to explore novel mechanisms that regulate glycolytic muscle formation and investigate their role in the pathogenesis of insulin resistance during chronic caloric excess. In preliminary studies, we have identified BAF60c, a subunit of the SWI/SNF chromatin- remodeling complexes that interacts with other transcription factors, as a novel regulator of fast glycolytic muscle formation. Further we have delineated key molecular components of this regulatory cascade. In this proposal, we will first use gain- and loss- of-function mouse models to establish the physiological role of this pathway in the regulation of metabolic and contractile specification of fast glycolytic muscle. We will dissect the core molecular components involved, and assess the role of glycolytic muscle in the development of diet-induced insulin resistance. Successful completion of this project will provide novel insights into the mechanistic basis of glycolytic muscle development and plasticity, and shift the current paradigm on interrelationship between muscle fiber types and the pathogenesis of insulin resistance.