应激诱导蛋白Sesns通过其抗氧化和mTORC1抑制作用维持细胞代谢稳态，但目前对Sesns各亚型与mTORC1之间的调节机制尚不明确。我们前期发现有氧运动显著增加骨骼肌Sesn2和Sesn3表达、Sesn2和Sesn3对肌管细胞糖摄取产生不同影响，且二者结合具增益效应。本项目以此为基础，以Sesn2/3-AMPK-mTORC1和Sesn2/3-GATOR2-mTORC1通路与胰岛素信号活性关系为主线，从运动增加骨骼肌糖摄取视角出发，研究Sesn2/3在运动增加骨骼肌胰岛素敏感性的作用机制。研究采用相关基因敲除小鼠和离体细胞培养模型，通过构建Sesn2/3及点突变表达质粒，从功能增益和缺失两方面入手，对Sesn2/3调控骨骼肌糖代谢机制开展深入研究，以揭示运动增加骨骼肌胰岛素敏感性的机制。本研究将为完善运动改善胰岛素抵抗机制提供理论依据。

Sestrins, the stress-inducible protein family, function as an antioxidant and inhibitor of mTOR complex 1 (mTORC1) to maintain cellular energy homeostasis. However, the regulatory relationship between Sestrin subtype and mTORC1 is still elusive. In our previous studies, we have shown that aerobic exercise increased Sesn2 and Sesn3 expression in the skeletal muscle of mice, and the effect of Sesn2 and Sesn3 on glucose uptake is different in C2C12 myotube, moreover, the combined effect of Sesn2 and Sesn3 on glucose uptake is more significant. Based on our previous findings, this project will be focus on the relationship of Sesn2/3-AMPK/mTORC1 as well as Sesn2/3-GATOR2-mTORC1 signaling pathway and skeletal muscle insulin sensitivity. Starting with exercise elevates cellular glucose uptake, we will study the mechanism of Sesn2/3 in exercise increasing skeletal muscle insulin sensitivity. We will elucidates the biological mechanisms of Sesn2/3 in the process of aerobic exercise ameliorating insulin resistance by using both AMPK, Sens2, Sesn3, and Sesn2+3 transgenic mice and in vitro cell culture models with gain of function and loss of function studies. Our study will provide intervention-based evidence to better understand the mechanism of Sestrins in exercise improving insulin resistance. Together, these studies promise to elucidate a major new pathway controlling exercise ameliorating skeletal muscle insulin resistance.