Sustained expression of HeyL is critical for the proliferation of muscle stem cells in overloaded muscle

Sumiaki Fukuda, Akihiro Kaneshige, Takayuki Kaji, Yu Taro Noguchi, Yusei Takemoto, Lidan Zhang, Kazutake Tsujikawa, Hiroki Kokubo, Akiyoshi Uezumi, Kazumitsu Maehara, Akihito Harada, Yasuyuki Ohkawa, So Ichiro Fukada

Research output: Contribution to journalArticlepeer-review

25 Citations (Scopus)


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 MuSCderived 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 MuSCproliferation mechanism differs in overloaded and regenerating muscle.

Original languageEnglish
Article numbere48284
Publication statusPublished - Sep 2019

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)


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