Regulation of glycolytic muscle metabolism

糖酵解肌肉代谢的调节

• 批准号: 8460494
• 负责人: Jiandie D Lin
• 金额: $ 33.76万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-20 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8460494
• 关键词: Biochemical; Biogenesis; Cardiovascular Diseases; Cell Respiration; Cells; Characteristics; Chromatin Remodeling Factor; Chronic; Data; Development; Diet; Disease Progression; Elderly; Energy Metabolism; Epidemic; Event; Fiber; Gene Expression; Genes; Glucose Intolerance; Goals; Insulin Resistance; Link; Mediating; Metabolic; Metabolic syndrome; Metabolism; Mitochondria; Molecular; Molecular Genetics; Mus; Muscle; Muscle Development; Muscle Fibers; Muscle function; Non-Insulin-Dependent Diabetes Mellitus; Nutrient; Pathogenesis; Pathway interactions; Phenotype; Physiological; Play; Property; Proto-Oncogene Proteins c-akt; Public Health; RNA Interference; Regulation; Rest; Risk; Role; Skeletal Muscle; Specific qualifier value; Syndrome; Testing; Tissues; Transgenic Mice; Transgenic Organisms; base; design; improved; in vivo; insight; insulin sensitivity; loss of function; metabolomics; mouse model; muscle metabolism; nonalcoholic steatohepatitis; novel; programs; skeletal; tool; transcription factor

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.

描述（由申请人提供）：代谢综合征已成为一种全球流行病，可显着增加患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危险的标志，与线粒体氧化能力受损有关，并且从氧化型糖酵解肌纤维类型的转变有关。但是，骨骼肌纤维的代谢特性与胰岛素敏感性之间的原因和作用关系尚不清楚。尽管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剂，但我们对控制快速触发糖酵解肌肉的发育和功能的调节级联反应的理解非常有限。该提案的总体目标是探索调节糖酵解肌肉形成的新型机制，并研究它们在慢性热量过量过程中胰岛素抵抗发病机理中的作用。在初步研究中，我们确定了BAF60C，这是与其他转录因子相互作用的SWI/SNF染色质重塑复合物的亚基，是快速糖酵解肌肉形成的新调节剂。此外，我们描绘了该调节级联的关键分子成分。在此提案中，我们将首先使用增益和损失的鼠标模型来确定此的生理作用 快速糖酵解肌肉的代谢和收缩规范调节的途径。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械基础提供新的见解，并改变肌肉纤维类型之间相互关系的当前范式和胰岛素抵抗的发病机理。