Stage-specific effects of Notch activation during skeletal myogenesis
Stage-specific effects of Notch activation during skeletal myogenesis
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DOI：
10.7554/elife.17355
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发表时间：
2016-09-19
期刊：
影响因子：
7.7
通讯作者：
Kuang, Shihuan
中科院分区：
文献类型：
--
作者：
Bi, Pengpeng;Yue, Feng;Kuang, Shihuan
骨骼肌发生涉及肌源性干细胞（卫星细胞）的顺序激活、增殖、自我更新/分化和融合。已知Notch信号传导对于卫星细胞的维持是必不可少的，但其在晚期肌发生（即分化后肌细胞和融合后肌管）中的功能尚不清楚。使用阶段特异性Cre等位基因，我们揭示了Notchl在单核肌细胞和多核肌管中的不同作用。具体地，组成性Notchl激活将肌细胞去分化为Pax 7静止卫星细胞，导致肌肉生长和再生的严重缺陷以及出生后致死。相比之下，肌管特异性Notchl激活改善了老化和营养不良肌肉的再生和运动性能。在机制上，肌管中的Notchl活化上调Notch配体的表达，其调节相邻卫星细胞中的Notch信号传导以增强其再生能力。这些结果突出了肌发生期间Notch激活的背景依赖性作用，并证明Notchl活性改善了肌管作为干细胞小生境的功能。
Skeletal myogenesis involves sequential activation, proliferation, self-renewal/differentiation and fusion of myogenic stem cells (satellite cells). Notch signaling is known to be essential for the maintenance of satellite cells, but its function in late-stage myogenesis, i.e. post differentiation myocytes and post-fusion myotubes, is unknown. Using stage-specific Cre alleles, we uncovered distinct roles of Notchl in mononucleated myocytes and multinucleated myotubes. Specifically, constitutive Notchl activation dedifferentiates myocytes into Pax7 quiescent satellite cells, leading to severe defects in muscle growth and regeneration, and postnatal lethality. By contrast, myotube-specific Notchl activation improves the regeneration and exercise performance of aged and dystrophic muscles. Mechanistically, Notchl activation in myotubes upregulates the expression of Notch ligands, which modulate Notch signaling in the adjacent satellite cells to enhance their regenerative capacity. These results highlight context-dependent effects of Notch activation during myogenesis, and demonstrate that Notchl activity improves myotube's function as a stem cell niche.