Mechanisms regulating myostatin-induced insulin resistance in skeletal muscle

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一个诱因。骨骼肌胰岛素抵抗的细胞机制仍不清楚。这项研究的长期目标是了解肌肉抑制素信号在骨骼肌胰岛素抵抗发生中的作用。这个项目的中心假设是 肌肉生长抑素诱导的Smad3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。利用瘦肉和严重肥胖个体的原代骨骼肌细胞，该项目的具体目标是：1)确定Myostatin是否损害人类骨骼肌细胞近端的胰岛素信号转导；2)确定导致胰岛素抵抗的Myostatin受体后通路(S)；以及3)确定Myostatin信号是否与肥胖、胰岛素抵抗个体来源的原代人类骨骼肌细胞的胰岛素作用受损有关。预计这些研究将揭示导致骨骼肌胰岛素抵抗的细胞机制的新见解，并在不久的将来为有针对性的有效治疗策略提供框架。

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.