Exercise protects proliferative muscle satellite cells against exhaustion via the Igfbp7-Akt-mTOR axis
Exercise protects proliferative muscle satellite cells against exhaustion via the Igfbp7-Akt-mTOR axis
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运动通过 Igfbp7-Akt-mTOR 轴保护增殖性肌肉卫星细胞免遭疲劳
DOI：
10.7150/thno.43577
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发表时间：
2020-01-01
期刊：
影响因子：
12.4
通讯作者：
Song, Guanbin
中科院分区：
文献类型：
--
作者：
Chen, Zhe;Li, Lei;Song, Guanbin
背景和目的：肌肉卫星细胞的耗竭与肌肉疾病有关，包括肌营养不良症和杜氏肌营养不良症。运动有利于骨骼肌内环境平衡，促进干细胞增殖。阐明运动改善肌肉功能的分子机制对再生医学具有重要意义。方法：观察为期4周的跑台训练对小鼠骨骼肌和干细胞的影响。苏木精-伊红(HE)染色检测骨骼肌形态计量学。用流式细胞仪和免疫荧光技术分析细胞的丰度和细胞周期。RNA测序以阐明SCs的转录调控网络。用芯片-聚合酶链式反应检测H3K27ac在Akt启动子上的浓缩情况。结果：我们观察到运动导致小鼠肌肉肥大和促进肌肉再生。出乎意料的是，运动促进了干细胞中的细胞周期，但抑制了Akt-mTOR通路。在“锻炼的小鼠”中，增殖的干细胞需要抑制mTOR活性来限制线粒体新陈代谢，从而维持干细胞的“有限激活状态”以对抗疲惫。机制上，运动上调IGFBP7的表达，从而阻碍Akt的磷酸化，导致mTOR活性受抑，线粒体代谢受限。有限的线粒体代谢导致组蛋白3的低乙酰化和H3K27ac在Akt启动子上的浓缩减少，从而降低Akt的转录。此外，反复损伤的小鼠表现出保存的SC池，并通过抑制Akt-mTOR信号促进肌肉再生。结论：我们的研究结果表明，运动通过IGFBP7-Akt-mTor轴保护增殖的SCs免受衰竭。这些发现建立了机械信号、线粒体代谢、表观遗传修饰和干细胞命运决定之间的联系；因此，为SC耗竭相关的肌肉疾病提供了潜在的治疗靶点。
Background and Purpose: 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. Methods: 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. Results: 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. Conclusions: 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.