TY - JOUR TI - Sustained expression of HeyL is critical for the proliferation of muscle stem cells in overloaded muscle AU - Fukuda, Sumiaki AU - Kaneshige, Akihiro AU - Kaji, Takayuki AU - Noguchi, Yu-taro AU - Takemoto, Yusei AU - Zhang, Lidan AU - Tsujikawa, Kazutake AU - Kokubo, Hiroki AU - Uezumi, Akiyoshi AU - Maehara, Kazumitsu AU - Harada, Akihito AU - Ohkawa, Yasuyuki AU - Fukada, So-ichiro A2 - Stainier, Didier Y VL - 8 PY - 2019 DA - 2019/09/23 SP - e48284 C1 - eLife 2019;8:e48284 DO - 10.7554/eLife.48284 UR - https://doi.org/10.7554/eLife.48284 AB - 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. KW - skeletal muscle KW - satellite cells KW - hypertrophy KW - Notch JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -