长期、小剂量二甲双胍干预对中年和老年小鼠骨骼肌纤维线粒体和内质网稳态的影响及其机制研究

一定数量和功能正常的线粒体在维持骨骼肌纤维结构和功能完整性中起核心作用，线粒体和内质网又藉线粒体相关膜相互影响。骨骼肌纤维线粒体功能障碍可致细胞氧化应激反应增强、肌纤维丢失、收缩力量下降和神经-肌接头（NMJ）退变。氧化应激又可诱导内质网应激（ERs），ERs则可通过促进胞吞作用而加速NMJ处乙酰胆碱受体的降解，从而降低NMJ的稳定性。研究表明，衰老会损害线粒体和内质网的正常功能。二甲双胍通过激活AMPK而促进线粒体生物合成、降低细胞活性氧水平及抑制ERs，通过抑制mTORC1而促进自噬，提示其对线粒体和内质网稳态具有积极作用。本研究拟通过观测和评估长期、小剂量二甲双胍干预对中年和老年小鼠骨骼肌纤维线粒体和内质网稳态的作用，结合其对线粒体呼吸作用、骨骼肌运动能力及骨骼肌纤维脱神经支配的影响，综合评估该干预措施延缓骨骼肌减少症发生的有效性、可行性和安全性，以期为该干预措施的实际应用奠定基础。

The definite content and normal function of mitochondria play a core role in maintaining the structural and functional integrity of skeletal muscle fiber, and mitochondria interact with endoplasmic reticulum (ER) via mitochondria-associated membrane (MAM). The dyfunction of mitochondria induces elevated oxidative stress, loss of muscle fiber, reduced muscle contractile force and degeneration of neuromuscular junction (NMJ). The oxidative stress also results in the endoplasmic reticulum stress (ERs) which enhances the degradation of acetylcholine receptor at NMJ via augmented endocytosis and impairs the stability of NMJ. It is proved that aging impinges on mitochondria and ER. Metformin animates the biosynthesis of mitochondria, decreases the level of ROS, inhibits ERs through activating AMPK and accelerates autophagy by suppressing mTORC1, which implies that metformin exerts the positive effects on the homeostasis of mitochondria and ER. The project is aimed at the influence of treatment with long-term and low-dosage metformin on the homeostasis of mitochondria and ER in the skeletal muscle fibers in middle-aged and senescent mice. The validity, feasibility and safety of the treatment in retarding the development of sarcopenia are integratively observed and evaluated by investigating its action on the respiration of isolated mitochondria, motor cooperation of skeletal muscle and denervation of muscle fiber. The purpose of the trial is to pave the way for the application of the treatment in practice in human body.