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

  1. Sumiaki Fukuda
  2. Akihiro Kaneshige
  3. Takayuki Kaji
  4. Yu-taro Noguchi
  5. Yusei Takemoto
  6. Lidan Zhang
  7. Kazutake Tsujikawa
  8. Hiroki Kokubo
  9. Akiyoshi Uezumi
  10. Kazumitsu Maehara
  11. Akihito Harada
  12. Yasuyuki Ohkawa
  13. So-ichiro Fukada  Is a corresponding author
  1. Osaka University, Japan
  2. Hiroshima University, Japan
  3. Tokyo Metropolitan Institute of Gerontology, Japan
  4. 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

  1. Sumiaki Fukuda

    Project for Muscle Stem Cell Biology, Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Japan
    Competing interests
    The authors declare that no competing interests exist.
  2. Akihiro Kaneshige

    Project for Muscle Stem Cell Biology, Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Japan
    Competing interests
    The authors declare that no competing interests exist.
  3. Takayuki Kaji

    Project for Muscle Stem Cell Biology, Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Japan
    Competing interests
    The authors declare that no competing interests exist.
  4. Yu-taro Noguchi

    Project for Muscle Stem Cell Biology, Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Japan
    Competing interests
    The authors declare that no competing interests exist.
  5. Yusei Takemoto

    Project for Muscle Stem Cell Biology, Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Japan
    Competing interests
    The authors declare that no competing interests exist.
  6. Lidan Zhang

    Project for Muscle Stem Cell Biology, Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Japan
    Competing interests
    The authors declare that no competing interests exist.
  7. Kazutake Tsujikawa

    Laboratory of Molecular and Cellular Physiology, Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Japan
    Competing interests
    The authors declare that no competing interests exist.
  8. Hiroki Kokubo

    Department of Cardiovascular Physiology and Medicine, Hiroshima University, Hiroshima, Japan
    Competing interests
    The authors declare that no competing interests exist.
  9. Akiyoshi Uezumi

    Muscle Aging and Regenerative Medicine, Research Team for Geriatric Medicine, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan
    Competing interests
    The authors declare that no competing interests exist.
  10. Kazumitsu Maehara

    Division of Transcriptomics, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan
    Competing interests
    The authors declare that no competing interests exist.
  11. Akihito Harada

    Division of Transcriptomics, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan
    Competing interests
    The authors declare that no competing interests exist.
  12. Yasuyuki Ohkawa

    Division of Transcriptomics, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan
    Competing interests
    The authors declare that no competing interests exist.
  13. So-ichiro Fukada

    Project for Muscle Stem Cell Biology, Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Japan
    For correspondence
    fukada@phs.osaka-u.ac.jp
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4051-5108

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

  1. Didier Y Stainier, Max Planck Institute for Heart and Lung Research, Germany

Publication history

  1. Received: May 8, 2019
  2. Accepted: September 19, 2019
  3. Accepted Manuscript published: September 23, 2019 (version 1)
  4. 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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  1. Sumiaki Fukuda
  2. Akihiro Kaneshige
  3. Takayuki Kaji
  4. Yu-taro Noguchi
  5. Yusei Takemoto
  6. Lidan Zhang
  7. Kazutake Tsujikawa
  8. Hiroki Kokubo
  9. Akiyoshi Uezumi
  10. Kazumitsu Maehara
  11. Akihito Harada
  12. Yasuyuki Ohkawa
  13. So-ichiro Fukada
(2019)
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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