运动干预通过miR-34a-Sirt1-FoxO信号轴调控细胞自噬改善衰老性肌萎缩的作用机制

衰老性肌萎缩有害于老年人健康生活，运动有益于其预防与治疗。研究证实运动诱导的细胞自噬在其预防与治疗中有关键作用，但其精准靶向分子调控还未明晰。本项目拟以成年小鼠为对照，老年小鼠实施运动干预以评估肌萎缩干预效果，组织染色以观察肌组织或超微组织结构变化，RT-PCR或Western blot测定肌萎缩、细胞自噬与凋亡调控相关的miR-34a与蛋白表达，探明运动干预调控miR-34a介导的细胞自噬对衰老性肌萎缩的防治的精准靶向分子机制；同时，拟采用骨骼肌特异性miR-34a过表达或基因敲除，骨骼肌特异性自噬基因Atg7敲除小鼠从正反两方面论证运动调控的miR-34a-Sirt1-FoxO信号轴介导的细胞自噬在衰老性肌萎缩中的关键作用。明晰精准分子靶点将会为衰老性肌萎缩无创伤性精准诊断、运动干预策略制订与效果评估、衍生性精准干预策略开发提供参考；为未来精准主动健康策略应对老龄化提供科学的指导。

Sarcopenia is harmful to the health and life of the elderly people, but exercise is beneficial to its prevention and treatment. Previous studies have comfirmed that exercise-induced autophagy plays a critical role in the prevention and treatment of sarcopenia; however, its precise and targeted molecular regulation is still unclear. In this project, young adult mice will be used as the controls, aged mice will be subjected to exercise intervention to evaluate intervention effect through muscular atrophy rates; skeletal muscle staining will be used to observe the changes in morphology or ultrastructure of skeletal muscle; RT-PCR and western blot will be applied to evaluate the expression of miR-34a and proteins associated with the regulation of atrophy, autophagy and apoptosis, which will be beneficial to uncover precise and targeted molecular mechanisms for regulating the prevention and treatment of sarcopenia by miR-34a-mediated autophagy upon exercise intervention. Meanwhile, the mice with skeletal muscle specific overexpression or knockout of miR-34a and the mice with skeletal muscle specific knockout of gene Atg7 associated with autophagy will be used to further clarify miR-34a-Sirt1-FoxO signal axis for regulating the functional status of autophagy to modulate the prevention and treatment of sarcopenia during exercise intervention. The exploration and clarification of these precise molecular targets will provide the references for precise and noninvasive prediction and diagnosis of sarcopenia, optimal strategies of exercise intervention, evaluation and monitoring of exercise intervention, and development of derivative precise intervention strategies, as well as scientific guidance for scientific exercise fitness or active healthcare strategies in the future.