Sustained expression of HeyL is critical for the proliferation of muscle stem cells in overloaded muscle
- Osaka University, Japan
- Hiroshima University, Japan
- Tokyo Metropolitan Institute of Gerontology, Japan
- Kyushu University, Japan
Abstract
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.
Data availability
All data generated or analyzed in this study are included in the manuscript and supporting files.
Article and author information
Author details
Funding
Ministry of Education, Culture, Sports, Science, and Technology (Grant-in-Aid for Scientific Research (B))
- So-ichiro Fukada
Naito Foundation
- So-ichiro Fukada
Nakatomi Foundation
- So-ichiro Fukada
Ichiro Kanehara Foundation for the Promotion of Medical Sciences and Medical Care
- So-ichiro Fukada
NCNP (Intramural Research Grant for Neurological and Psychiatric Disorders)
- So-ichiro Fukada
Japan Agency for Medical Research and Development (18am0101084j)
- Kazutake Tsujikawa
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All procedures used for experimental animals were approved by the Experimental Animal Care and Use Committee of Osaka University (approval number: 25-9-3, 30-15).
Reviewing Editor
- Didier Y Stainier, Max Planck Institute for Heart and Lung Research, Germany
Publication history
- Received: May 8, 2019
- Accepted: September 19, 2019
- Accepted Manuscript published: September 23, 2019 (version 1)
- Version of Record published: September 30, 2019 (version 2)
Copyright
© 2019, Fukuda et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Sustained expression of HeyL is critical for the proliferation of muscle stem cells in overloaded muscle
eLife 8:e48284.
https://doi.org/10.7554/eLife.48284
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