Sustained expression of HeyL is critical for the proliferation of muscle stem cells in overloaded muscle
Sustained expression of HeyL is critical for the proliferation of muscle stem cells in overloaded muscle
复制标题
DOI：
10.7554/elife.48284
复制
发表时间：
2019-09-23
期刊：
影响因子：
7.7
通讯作者：
Fukada, So-ichiro
中科院分区：
文献类型：
--
作者：
Fukuda, Sumiaki;Kaneshige, Akihiro;Fukada, So-ichiro
在过载和再生肌肉中，新肌核的产生取决于肌肉卫星细胞（MuSC）。由于这两种环境中的MuSC行为尚未单独考虑，因此过载肌肉中的MuSC行为仍未得到研究。在这里，我们发现，与再生肌肉中的MuSC不同，过载肌肉中的大多数MuSC在MyoD表达不存在的情况下增殖。从机制上讲，过载肌肉中的MuSC维持Notch效应基因Heyl的表达，以抑制MyoD表达，这允许在肌纤维上和基底层下有效的MuSC增殖。尽管Heyl敲除小鼠在损伤模型中没有显示出损伤，但在肥大模型中，由于MyoD表达增加和增殖减少，它们的肌肉含有较少的新MuSC衍生的肌核，这最终导致钝化肥大。我们的研究结果表明，持续的HeyL表达是关键的MuSC增殖，特别是在超载的肌肉，从而表明，在超载和再生肌肉的MuSC增殖机制不同。
In overloaded and regenerating muscle, the generation of new myonuclei depends on muscle satellite cells (MuSCs). Because MuSC behaviors in these two environments have not been considered separately, MuSC behaviors in overloaded muscle remain unexamined. Here, we show that most MuSCs in overloaded muscle, unlike MuSCs in regenerating muscle, proliferate in the absence of MyoD expression. Mechanistically, MuSCs in overloaded muscle sustain the expression of Heyl, a Notch effector gene, to suppress MyoD expression, which allows effective MuSC proliferation on myofibers and beneath the basal lamina. Although Heyl-knockout mice show no impairment in an injury model, in a hypertrophy model, their muscles harbor fewer new MuSC-derived myonuclei due to increased MyoD expression and diminished proliferation, which ultimately causes blunted hypertrophy. Our results show that sustained HeyL expression is critical for MuSC proliferation specifically in overloaded muscle, and thus indicate that the MuSC-proliferation mechanism differs in overloaded and regenerating muscle.