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Mechanisms regulating myostatin-induced insulin resistance in skeletal muscle

骨骼肌肌生长抑制素诱导的胰岛素抵抗的调节机制

基本信息

批准号：
8689648
负责人：
Leslie Consitt
金额：
$ 37.13万
依托单位：
OHIO UNIVERSITY ATHENS
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-07-15 至 2019-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8689648
关键词：
Affect Cardiovascular Diseases Cell Culture Techniques Data Defect Development Diabetes Mellitus Future GLUT4 gene Glucose Goals Health Health Professional Human IRS1 gene Individual Insulin Insulin Resistance Knowledge Laboratories Lead Link MADH3 gene Mediating Medical Research Metabolic Diseases Mission Mitogen-Activated Protein Kinases Mus Muscle Cells Muscle Fibers Non-Insulin-Dependent Diabetes Mellitus Obesity Organ Pathway interactions Phosphorylation Population Precipitating Factors Prevention Proteins Public Health Quality of life Research Research Personnel Role Serine Signal Transduction Skeletal Muscle Therapeutic Intervention Tissues United States Work base cytokine design effective therapy expectation glucose uptake human MADH3 protein improved insight insulin receptor substrate 1 protein insulin signaling myostatin novel programs public health relevance receptor therapeutic target treatment strategy

项目摘要

DESCRIPTION (provided by applicant): Skeletal muscle insulin resistance is a precipitating factor in the development of obesity, type 2 diabetes, and cardiovascular disease. The cellular mechanisms that are responsible for skeletal muscle insulin resistance remain unknown. The long term objective of this research is to understand the role that myostatin signaling may have in the development of skeletal muscle insulin resistance. The central hypothesis of this project is that myostatin-induced SMAD3 phosphorylation increases IRS-1 serine phosphorylation, resulting in insulin resistance in human skeletal muscle cells. This hypothesis has been formulated on the basis of preliminary data produced in the applicant's laboratory. Using primary skeletal muscle cells from lean and severely obese individuals, the Specific Aims of this project are to: 1) determine if myostatin impairs proximal insulin signaling in human skeletal muscle cells; 2) determine the myostatin post-receptor pathway(s) responsible for insulin resistance; and 3) determine whether myostatin signaling is responsible for impaired insulin action in primary human skeletal muscle cells derived from obese, insulin resistant individuals. It is anticipated these studies will reveal new insights regarding the cellular mechanisms that contribute to insulin resistance in skeletal muscle, and provide the framework for targeted and efficient treatment strategies in the near future.

描述（由申请人提供）：骨骼肌胰岛素抵抗是肥胖、2型糖尿病和心血管疾病发展的促发因素。骨骼肌胰岛素抵抗的细胞机制尚不清楚。本研究的长期目标是了解肌肉生长抑制素信号转导在骨骼肌胰岛素抵抗发展中的作用。这个项目的核心假设是肌生长抑制素诱导的SMAD 3磷酸化增加IRS-1丝氨酸磷酸化，导致人骨骼肌细胞的胰岛素抵抗。这一假设是根据申请人实验室提供的初步数据提出的。本课题的具体目的是：1）确定肌生成抑制素是否损害人骨骼肌细胞近端胰岛素信号传导; 2）确定肌生成抑制素受体后通路（一个或多个）负责胰岛素抵抗;和3）确定肌生长抑制素信号传导是否是来源于肥胖的原代人骨骼肌细胞中受损的胰岛素作用的原因，胰岛素抵抗个体。预计这些研究将揭示有关导致骨骼肌胰岛素抵抗的细胞机制的新见解，并在不久的将来为靶向和有效的治疗策略提供框架。