有氧运动调控骨骼肌HDAC4/HDAC5降解及改善胰岛素抵抗机制的研究

HDAC4 and HDAC5 are members of Class II histone deacetylases, which play important roles in inhibiting skeletal muscle glucose and lipid metabolism-related gene expression and reducing the ratio of oxidative type I fiber. Increased expression of HDAC4 and HDAC5 is strongly associated with decreased insulin sensitivity and the progression of metabolic diseases. In our previous project we found that regular aerobic exercise increased skeletal muscle HDAC4 and HDAC5 protein degradation in the skeletal muscle of insulin resistant mice. We further found that ubiquitin-proteasome system may played an important role in the promotion of HDAC4 and HDAC5 protein degradation under the interference of aerobic exercise by using gene array and co-immunoprecipitation assay. However, the mechanism of how exercise regulates HDAC4 and 5 degradation is far from clear. To illustrate the mechanism of aerobic exercise reguates the degradation of HDAC4 and HDAC5 protein in skeletal muscle, we will use both animal model and cell culture experiments to investigate the underlined regulatory cascades. Our results will provide the theoretical basis for the mechanism of aerobic exercise increasing the expression of skeletal muscle glucose and lipid metabolism-related gene and ameliorating insulin resistance and related metabolic diseases.

HDAC4和HDAC5作为2型组蛋白去乙酰化酶具有抑制骨骼肌细胞代谢相关基因表达、调节氧化型（I型）肌纤维比例的作用，其表达的增加是导致机体组织胰岛素抵抗、引发2型糖尿病的重要原因。在我们承担的青年基金研究中发现6周有氧运动干预可增加胰岛素抵抗小鼠骨骼肌细胞HDAC4和HDAC5蛋白降解，通过基因芯片筛选及免疫共沉淀结果分析发现泛素蛋白酶体系统可能是运动增加骨骼肌HDAC4和HDAC5蛋白降解的重要原因。为进一步揭示有氧运动调控骨骼肌HDAC4/HDAC5降解的作用机制，本课题研究将采用动物实验与离体细胞培养实验相结合的方式，深入研究有氧运动对胰岛素抵抗小鼠和离体培养骨骼肌细胞HDAC4和HDAC5的降解机制，分析其降解对骨骼肌组织胰岛素敏感性的影响，以期为揭示有氧运动调节骨骼肌细胞代谢相关基因表达、改善机体胰岛素抵抗、防治代谢疾病提供理论依据。

近年来研究发现II型组蛋白去乙酰化酶HDAC4和HDAC5具有抑制骨骼肌细胞代谢相关基因表达的作用，其表达增加是导致机体组织胰岛素抵抗、引发2型糖尿病的重要原因。有氧运动能够增加胰岛素抵抗小鼠骨骼肌中HDAC4和HDAC5的降解从而改善机体能量代谢、缓解骨骼肌胰岛素抵抗，但是运动降解HDAC4/5的机制还不完全明确。本研究采用高脂饮食诱导的胰岛素抵抗小鼠模型来探究泛素-蛋白酶体系统在有氧运动降解HDAC4/5及改善机体糖、脂代谢重的作用，并结合C2C12肌管细胞培养等试验方法，深入探究MuRF1、泛素-蛋白酶体通路与HDAC4/5降解之间的关系。此外，采用AMPKα2-/-小鼠及有氧运动干预，探究了AMPK在泛素-蛋白酶体通路中的调控作用。本研究还发现miR-206在有氧运动降解HDAC4过程中起到了重要的作用。为了进一步探究II型HDAC对骨骼肌有氧运动能力及骨骼肌蛋白乙酰化的影响，我们采用乙酰化组学方法研究II型HDAC与有氧运动对骨骼肌代谢相关蛋白的影响，初步研究了代谢酶乙酰化在有氧运动改善机体胰岛素抵抗中的潜在作用。