FoxO1转录因子在抗阻训练影响低氧诱导骨骼肌萎缩中的作用与分子调控机制

Skeletal muscle atrophy induced by hypoxia is an important factor in determining the benefits of altitude training in athletes and also in the loss of muscle strength during acclimatization in the general population. The mechanisms that cause this are still unknown. Our previous study was supported by the National Natural Science Fund Project (project number: 31470057) and used muscle biopsy, whole genome mRNA expression spectrum scanning, and bioinformatics. The study showed that a group of genes and signal transduction pathways are associated with skeletal muscle atrophy during resistance training in a hypoxic environment (altitude of 3700 m). FoxO1 (Forkhead box protein O1) appears to play a key role in the regulation of muscle mass. The FoxO1 protein is potentially involved in the molecular mechanism regarding the effect of resistance training on muscle structure, it also appears to have an effect on the gene expression in resisting skeletal muscle atrophy during hypoxia. In vivo and in vitro experiments of the skeletal muscle will be conducted with gene knockout, RNA interference, RT-PCR, and Western blot. The present study will be to investigate the molecular mechanism of skeletal muscle atrophy in FoxO1 transcription during hypoxic resistance training simulated at altitude (4500m) in male rats.

高原低氧诱导的骨骼肌萎缩是影响运动员高原训练效果及普通人高原习服过程中肌肉力量下降的重要原因，其发生机制至今不明。本研究团队在国家自然科学基金的资助下（项目编号：31470059），通过人体肌肉活检实验，利用全基因组mRNA表达谱扫描、生物信息学等技术发现了一批可能与海拔3700m进行抗阻训练影响骨骼肌萎缩相关的差异表达基因和信号转导通路。其中，FoxO1可能起着关键的调控作用，可以作为抗阻训练影响低氧诱导骨骼肌萎缩的研究对象。因此，本项目拟通过雄性大鼠在体实验和离体骨骼肌细胞实验，利用基因敲除、RNA干扰、RT-PCR、western blot等技术，探讨海拔4500m人工低氧环境下进行抗阻训练影响大鼠骨骼肌萎缩中FoxO1转录因子的作用与分子调控机制。

探究高原适应过程中骨骼肌萎缩的发生机制，有助于探寻有效的训练方法及研发抗骨骼肌萎缩营养品，保持高原习服过程中的工作和运动能力。本项目通过建立动物模型，探讨FoxO1转录因子在抗阻训练影响低氧诱导的骨骼肌萎缩中的作用与分子机制。分别从Akt-FoxO1-MuRF1/Atrogin-1通路在低氧诱导骨骼肌萎缩及抗阻训练减缓肌萎缩中的调控机制，乙酰化FoxO1介导自噬途径在抗阻训练缓解低氧诱导肌萎缩中的调控机制以及抗阻训练改善低氧下骨骼肌萎缩的miRNA调节作用机制三个层面进行研究。发现了Akt调控FoxO1的Ser256位点发生磷酸化，细胞核FoxO1和细胞质Ac-FoxO1参与介导的自噬溶酶体途径以及miR-499-5p、miR-203a-3p对肌细胞生物过程的调控，可能是抗阻训练减缓低氧诱导骨骼肌萎缩的机制。