Myogenin is an essential regulator of adult myofibre growth and muscle stem cell homeostasis
- King's College London, United Kingdom
- Queen Mary University of London, United Kingdom
- 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
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.
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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