Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing 400044, China.
Department of Hematology, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, China.
Theranostics. 2020 May 16;10(14):6448-6466. doi: 10.7150/thno.43577. eCollection 2020.
: The exhaustion of muscle satellite cells (SCs) is correlated with muscle diseases, including sarcopenia and Duchenne muscular dystrophy. Exercise benefits skeletal muscle homeostasis and promotes proliferation of SCs. Elucidating the molecular mechanism underlying the muscle function-improving effect of exercise has important implications in regenerative medicine. : Herein, we investigated the effect of 4-week treadmill training on skeletal muscle and SCs in mice. Hematoxylin and eosin (HE) staining was utilized to detect the morphometry of skeletal muscles. Flow cytometry and immunofluorescence were conducted to analyze the abundance and cell cycle of SCs. RNA sequencing was performed to elucidate the transcriptional regulatory network of SCs. The ChIP-PCR assay was used to detect enrichment of H3K27ac at the promoters of Akt. : We observed that exercise resulted in muscle hypertrophy and improved muscle regeneration in mice. Unexpectedly, exercise promoted cell cycling but suppressed the Akt-mTOR pathway in SCs. Proliferative SCs in "exercised mice" required suppressed mTOR activity to limit mitochondrial metabolism, maintaining the "limited activation status" of SCs against exhaustion. Mechanistically, exercise upregulated the expression of Igfbp7, thereby impeding the phosphorylation of Akt and resulting in inhibited mTOR activity and limited mitochondrial metabolism. The limited mitochondrial metabolism resulted in hypoacetylation of histone 3 and reduced enrichment of H3K27ac at promoters of Akt, decreasing the transcription of Akt. Moreover, repeatedly injured mice showed a preserved SC pool and improved muscle regeneration by the suppression of Akt-mTOR signaling. : The findings of our study show that exercise protects proliferative SCs against exhaustion via the Igfbp7-Akt-mTOR axis. These findings establish a link between mechanical signaling, mitochondrial metabolism, epigenetic modification, and stem cell fate decisions; thus, present potential therapeutic targets for muscle diseases correlated with SC exhaustion.
肌肉卫星细胞（SCs）的耗竭与肌肉疾病有关，包括肌肉减少症和杜氏肌营养不良症。运动有益于骨骼肌肉的内稳态，并促进 SC 的增殖。阐明运动改善肌肉功能的分子机制在再生医学中具有重要意义。
在此，我们研究了 4 周跑步机训练对小鼠骨骼肌和 SC 的影响。苏木精和伊红（HE）染色用于检测骨骼肌的形态计量学。流式细胞术和免疫荧光用于分析 SC 的丰度和细胞周期。RNA 测序用于阐明 SC 的转录调控网络。ChIP-PCR 检测用于检测 Akt 启动子处 H3K27ac 的富集。
我们观察到运动导致肌肉肥大，并改善了小鼠的肌肉再生。出乎意料的是，运动促进了 SC 的细胞周期，但抑制了 Akt-mTOR 通路。“运动小鼠”中的增殖性 SC 需要抑制 mTOR 活性来限制线粒体代谢，维持 SC 对耗竭的“有限激活状态”。在机制上，运动上调了 Igfbp7 的表达，从而阻止 Akt 的磷酸化，导致 mTOR 活性受到抑制和线粒体代谢受到限制。有限的线粒体代谢导致组蛋白 3 的低乙酰化和 Akt 启动子处 H3K27ac 的富集减少，从而降低 Akt 的转录。此外，反复受伤的小鼠通过抑制 Akt-mTOR 信号显示出保留的 SC 池，并改善了肌肉再生。
我们的研究结果表明，运动通过 Igfbp7-Akt-mTOR 轴保护增殖性 SC 免受耗竭。这些发现将机械信号、线粒体代谢、表观遗传修饰和干细胞命运决定联系起来；因此，为与 SC 耗竭相关的肌肉疾病提供了潜在的治疗靶点。
