Regulation of glycolytic muscle metabolism

描述(申请人提供)：代谢综合征已成为一种全球流行病，极大地增加了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这种综合征代谢紊乱的一个标志，这种代谢紊乱与线粒体氧化能力受损和从氧化型向糖酵解型肌纤维转变有关。然而，骨骼肌纤维的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共激活子及其转录伙伴正在成为线粒体生物发生和氧化纤维计划的核心调节因子，但我们对控制快速抽动糖酵解肌肉发育和功能的调控级联机制的了解非常有限。这项建议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多时胰岛素抵抗发病机制中的作用。在初步研究中，我们发现BAF60c是SWI/SNF染色质重塑复合体的一个亚单位，可以与其他转录因子相互作用，是快速糖酵解肌肉形成的新调节因子。此外，我们还描绘了这一调节级联反应的关键分子成分。在这项建议中，我们将首先使用功能获得和丧失的小鼠模型来确定这一生理作用 快速糖酵解肌肉代谢和收缩规范的调节途径。我们将剖析涉及的核心分子成分，并评估糖酵解肌肉在饮食诱导的胰岛素抵抗发展中的作用。该项目的成功完成将为糖酵解肌肉发育和可塑性的机制基础提供新的见解，并改变目前关于肌肉纤维类型与胰岛素抵抗发病机制之间相互关系的范式。 公共卫生相关性：代谢综合征与2型糖尿病、心血管疾病和非酒精性脂肪性肝炎的风险增加有关，已成为美国和世界其他地区面临的严重公共卫生挑战。虽然人们已经认识到胰岛素抵抗是疾病进展过程中的一种早期致病事件，但调节组织和全身胰岛素敏感性的机制仍然知之甚少。我们建议使用最先进的分子、遗传和代谢工具来确定这一新途径在肌肉功能中的重要性，剖析新的调节成分，并评估肌肉代谢和胰岛素抵抗之间的因果关系。

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. PUBLIC HEALTH RELEVANCE: Metabolic syndrome is linked to increased risk for type 2 diabetes, cardiovascular disease, and non-alcoholic steatohepatitis, and has become a serious public health challenge for the US and the rest of the world. While it has been recognized that insulin resistance is an early pathogenic event in disease progression, the mechanisms that regulate tissue and systemic insulin sensitivity remain poorly understood. We propose to use state-of-the-art molecular, genetic, and metabolic tools to establish the significance of this new pathway in muscle function, dissect novel regulatory components, and assess the cause and effect relationship between muscle metabolism and insulin resistance.