Myogenin is an essential regulator of adult myofibre growth and muscle stem cell homeostasis

  1. Massimo Ganassi  Is a corresponding author
  2. Sara Badodi
  3. Kees Wanders
  4. Peter S Zammit
  5. Simon M Hughes  Is a corresponding author
  1. King's College London, United Kingdom
  2. Queen Mary University of London, United Kingdom
  3. Kings College London, United Kingdom

Abstract

Growth and maintenance of skeletal muscle fibres depend on coordinated activation and return to quiescence of resident muscle stem cells (MuSCs). The transcription factor Myogenin (Myog) regulates myocyte fusion during development, but its role in adult myogenesis remains unclear. In contrast to mice, myog-/- zebrafish are viable, but have hypotrophic muscles. By isolating adult myofibres with associated MuSCs we found that myog-/- myofibres have severely reduced nuclear number, but increased myonuclear domain size. Expression of fusogenic genes is decreased, Pax7 upregulated, MuSCs are fivefold more numerous and mis-positioned throughout the length of myog-/- myofibres instead of localising at myofibre ends as in wild-type. Loss of Myog dysregulates mTORC1 signalling, resulting in an 'alerted' state of MuSCs, which display precocious activation and faster cell cycle entry ex vivo, concomitant with myod upregulation. Thus, beyond controlling myocyte fusion, Myog influences the MuSC:niche relationship, demonstrating a multi-level contribution to muscle homeostasis throughout life.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files.

Article and author information

Author details

  1. Massimo Ganassi

    Randall Centre for Cell and Molecular Biophysics, King's College London, London, United Kingdom
    For correspondence
    massimo.ganassi@kcl.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
  2. Sara Badodi

    Blizard Institute, Queen Mary University of London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  3. Kees Wanders

    Randall Centre for Cell and Molecular Biophysics, King's College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3209-9853
  4. Peter S Zammit

    Randall Centre for Cell and Molecular Biophysics, Kings College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9562-3072
  5. Simon M Hughes

    Randall Centre for Cell and Molecular Biophysics, King's College London, London, United Kingdom
    For correspondence
    simon.hughes@kcl.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8227-9225

Funding

Medical Research Council (G1001029)

  • Simon M Hughes

Medical Research Council (MR/N021231/1)

  • Simon M Hughes

Medical Research Council (MR/P023215/1)

  • Peter S Zammit

Medical Research Council (MR/S002472/1)

  • Peter S Zammit

Muscular Dystrophy UK (RA3/3052)

  • Peter S Zammit

Association Francaise contre les Myopathies (AFM17865)

  • Peter S Zammit

FSH Society (FSHS-82013-06)

  • Peter S Zammit

FSH Society (FSHS-82017-05)

  • Peter S Zammit

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 experiments were performed on zebrafish derived from F2 or later filial generation, in accordance with licence held under the UK Animals (Scientific Procedures) Act 1986 and later modifications and conforming to all relevant guidelines and regulations.

Reviewing Editor

  1. Andrea Munsterberg, University of East Anglia, United Kingdom

Publication history

  1. Received: June 26, 2020
  2. Accepted: September 30, 2020
  3. Accepted Manuscript published: October 1, 2020 (version 1)
  4. Version of Record published: October 30, 2020 (version 2)

Copyright

© 2020, Ganassi 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. Massimo Ganassi
  2. Sara Badodi
  3. Kees Wanders
  4. Peter S Zammit
  5. Simon M Hughes
(2020)
Myogenin is an essential regulator of adult myofibre growth and muscle stem cell homeostasis
eLife 9:e60445.
https://doi.org/10.7554/eLife.60445
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