择时运动促衰老卫星细胞成肌分化中线粒体对生物钟基因调控机制研究

“Exercise is a good lifestyle. However, what time is the best time to exercise, why? ” Based on our previous works, in this proposal, we will investigate the role of circadian clock in regulation of scheduled exercise on myogenic differentiation in aged satellite cells. In this proposal, the key scientific problem is that exercise and aging may presupposes the style of reactive oxygen species (ROS) during satellite cells myogenic differentiation in vitro (pulse .vs. continuous). And matching between exercises induced ROS generation rhythms and circadian rhythms is the basis for scheduled exercise. We will study this problem from three directions. 1) To explore the best exercise time period for intervent myogenic differentiation in aged satellite cells. 2) To verify the reality that mitochondrial OMA1 and OPA1 is the checkpoint for different style of ROS, which may be induced by exercise and aging; 3) To explore the machanism involved in regulation between mitochondria and circadian clock, in another word, different level of mitochondrial ATP production may reversibly modulate circadian BMAL1 expression and its functions.

“运动好！一天中什么时候运动最好？为什么？”在我们前期课题基础上，本项目从生物钟这一全新视角探讨不同昼夜时段运动（择时运动）对衰老卫星细胞体外成肌分化的效应及机制差异。本项目核心科学问题为“运动和衰老可预设卫星细胞离体分化时线粒体ROS产生模式（脉冲.vs.连续），让运动源性ROS脉冲节律匹配生物钟节律是择时运动的生物学基础”。本项目从三个方面研究这个命题：1）探寻运动干预衰老卫星细胞成肌分化最佳时间段；2）验证线粒体OMA1-OPA1是不同ROS生成模式的“检查站”；3）探讨线粒体逆向调控生物钟机制，即通过ATP输出双向调控生物钟基因BMAL1表达及其对成肌分化各要素的整合。

本项目以“运动和衰老可预设卫星细胞离体分化时线粒体ROS产生模式（脉冲.vs.连续），让运动源性ROS脉冲节律匹配生物钟节律是择时运动的生物学基础”为核心科学问题，分别通过in vivo和in vitro实验，系统探讨线粒体稳态、氧化还原信号和生物钟的相互关系。主要发现：1）首次证明在干预衰老骨骼肌卫星细胞成肌分化角度，下午运动训练效果优于上午训练；2）首次证明氧化应激导致线粒体稳态和生物钟基因生物节律异常，振幅下降和时相前移是最大特征；3）首次证明PGC-1β-OMA1-OPA1是调控骨骼肌卫星细胞成肌分化中生物节律的关键通路；4）首次证明不同水平ROS可通过AMPK-mTOR- PGC-1β通路双向调控骨骼肌卫星细胞成肌分化中生物节律及线粒体稳态重构。