Myogenin is an essential regulator of adult myofibre growth and muscle stem cell homeostasis
Myogenin is an essential regulator of adult myofibre growth and muscle stem cell homeostasis
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DOI：
10.1101/2020.08.10.244590
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发表时间：
2020-08
期刊：
影响因子：
7.7
通讯作者：
M. Ganassi;S. Badodi;Kees Wanders;P. Zammit;S. Hughes
中科院分区：
文献类型：
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作者：
M. Ganassi;S. Badodi;Kees Wanders;P. Zammit;S. Hughes
骨骼肌纤维的生长和维持依赖于驻留的肌肉干细胞(MuSCs)的协调激活和恢复静止。转录因子肌肉生成素(Myog)在发育过程中调节心肌细胞的融合，但其在成体肌肉发生中的作用尚不清楚。与老鼠相比，Myog−/−斑马鱼是有活力的，但肌肉营养不良。通过分离带有相关MUSCs的成人肌纤维，我们发现MYOG−/−肌纤维严重减少了核数量，但增加了肌核域的大小。融合基因的表达减少，PAX7上调，MUSCs的数量增加了五倍，并且错位分布在肌纤维的整个长度上，而不是像野生型那样定位在肌纤维末端。Myog的缺失使mTORC1信号失控，导致MuSCs处于警觉状态，表现出早熟激活和细胞周期进入体外更快的速度，伴随着Myod的上调。因此，除了控制肌细胞融合，Myog还影响MUSC：生态位关系，展示了在整个生命过程中对肌肉动态平衡的多层次贡献。
Growth and maintenance of skeletal muscle fibres depend on coordinated activation and return to quiescence of resident muscle stem-cells (MuSCs). The transcription factor Myogenin (Myog) regulates myocyte fusion during development, but its role in adult myogenesis remains unclear. In contrast to mice, myog−/− zebrafish are viable, but have hypotrophic muscles. By isolating adult myofibres with associated MuSCs we found that myog−/− myofibres have severely reduced nuclear number, but increased myonuclear domain size. Expression of fusogenic genes is decreased, pax7 upregulated, MuSCs are fivefold more numerous and mis-positioned throughout the length of myog−/− myofibers instead of localising at myofibre ends as in wild-type. Loss of Myog dysregulates mTORC1 signalling, resulting in an ‘alerted’ state of MuSCs, which display precocious activation and faster cell cycle entry ex vivo, concomitant with myod upregulation. Thus, beyond controlling myocyte fusion, Myog influences the MuSC:niche relationship, demonstrating a multi-level contribution to muscle homeostasis throughout life.