运动干预对衰老性肌萎缩的预防与康复: 细胞自噬功能状态的关键作用与调节机制研究

Sarcopenia is associated with the loss of muscle mass and strength as well as the decline in physical functions, which results in the significant impact on the health and life activities of elderly people. It is well known that exercise is benefit to the prevention and treatment of sarcopenia; however, its mechanisms are still unclear. Based on the characteristics of relatively reduced autophagy and accelerated apoptosis during the development of sarcopenia, we would like to use aged rats (20 mouths old) as the experimental subjects. Following exercise training in different modes, the muscle atrophy rate of the aged rats will be determined; the size of muscle fiber cells will be evaluated after HE staining; the damage of mitochondria and endoplasmic reticulum (ER) and the number of autophagosomes will be analyzed by transmission electron microscope. The proteins and genes associated with autophagy, apoptosis, energy metabolism, muscle atrophy or mitochondrial quality control will be subjected to Western blot, real-time polymerase chain reaction (RT-PCR) or RNA-Seq analysis, which will benefit for the exploration of the correlation between sarcopenia and autophagy functional status, the optimization of exercise intervention mode, and the confirmation of our hypothesis that exercise-induced autophagy can inhibit the development of sarcopenia, as well as the clarfication of signal pathway network or optimal targets of exercise intervention for the prevention, rehabilitation and treatments of sarcopenia. Meanwhile, we would like to apply aged rats subjected to pharmacologic inhibition of autophagy via chloroquine (CQ) or musle specifically autophagy-deficient (Atg7-/-) mice as the experimental subjects to explore the determinant role of autophagy functional status in the prevention, rehabilitation and treatments of sarcopenia in the presence of optimal exercise intervention. In contrast, the autophagy deficiency could result in the enhanced loss of muscle mass. This study will demonstrate that functional status of autophagy is a determinant role in modulating muscle homeostasis, improving mitochondrial quality control, and preventing and treating sarcopenia. All of these findings will be helpful to provide a theoretical guidance for reasonable exercise and scientific fitness training to reduce unnecessary injuries and accomplish the prevention and treatments of sarcopenia or some other diseases.

衰老性肌萎缩严重危害着老年人健康与生活, 运动干预有益于其预防与治疗, 但作用机制还不明确。本研究基于衰老性肌萎缩可能由于相对细胞自噬低下与凋亡旺盛的特点, 以老年大鼠为研究对象，运动干预后对肌纤维或肌萎缩率的测定, 肌细胞内线粒体与自噬溶酶体的电镜观察, 自噬、能量代谢、肌萎缩或线粒体质量控制相关蛋白或基因的免疫印迹、RT-PCR或RNA-Seq分析，将致力于探讨衰老性肌萎缩与自噬功能状态的相关性，确立其预防或治疗的优化运动干预，初步探明运动诱导自噬激活的信号通路或运动干预的靶点。以药源性自噬抑制大鼠或肌肉特异性Atg7缺陷小鼠为对象进行优化运动干预，阐明了运动诱导的自噬激活对衰老性肌萎缩预防、康复与治疗的关键作用。本研究首次提出了运动诱导的自噬在调节肌肉代谢稳态平衡, 提高线粒体质量, 预防与治疗肌萎缩中的决定性作用, 为科学运动健身, 减少不必要的损伤和疾病防治提供了新的理论指导。

衰老性肌萎缩严重危害着老年人健康与生活,运动干预有益于其预防与治疗, 但作用机制还不明确。该项目通过自然衰老大鼠与青年大鼠对比进行衰老性骨骼肌萎缩模型的建立，测定了其骨骼肌细胞自噬功能状态，证实了骨骼肌细胞自噬功能低下与过度细胞凋亡是衰老性肌萎缩的重要因素；相应地，运动干预诱导的细胞激活逆转了衰老性肌萎缩，并且，筛选出抗组运动干预是大鼠衰老性肌萎缩治疗的优化干预策略。同时，通过对细胞自噬药源性氯喹抑制的小鼠进行终生的优化运动干预与细胞自噬基因（Beclin1）骨骼肌特异性敲除小鼠进行优化运动干预，进一步从正反两方面论证了运动诱导的细胞自噬对衰老性肌萎缩的预防与治疗的关键作用。并且，RNA-seq与microRNA的扫描分析也发现了一系列新的调控基因与microRNA, 这些microRNA调控的分子信号轴对靶为其未来精准的诊断、靶向干预策略制订、干预效果监控评估等方面研究洞开一个新的领域。