Lack of Tgfbr1 and Acvr1b synergistically stimulates myofibre hypertrophy and accelerates muscle regeneration

  1. Michèle MG Hillege
  2. Andi Shi
  3. Ricardo A Galli
  4. Gang Wu
  5. Philippe Bertolino
  6. Willem MH Hoogaars
  7. Richard T Jaspers  Is a corresponding author
  1. Vrije Universiteit Amsterdam, Netherlands
  2. Université de Lyon, UMR INSERM U1052, CNRS 5286, France

Abstract

In skeletal muscle, transforming growth factor-β (TGF-β) family growth factors, TGF-β1 and myostatin, are involved in atrophy and muscle wasting disorders. Simultaneous interference with their signalling pathways may improve muscle function, however little is known about their individual and combined receptor signalling. Here we show that inhibition of TGF-β signalling by simultaneous muscle-specific knockout of TGF-β type I receptors Tgfbr1 and Acvr1b in mice, induces substantial hypertrophy, while such effect does not occur by single receptor knockout. Hypertrophy is induced by increased phosphorylation of Akt and p70S6K and reduced E3 ligases expression, while myonuclear number remains unaltered. Combined knockout of both TGF-β type I receptors increases the number of satellite cells, macrophages and improves regeneration post cardiotoxin-induced injury by stimulating myogenic differentiation. Extra cellular matrix gene expression is exclusively elevated in muscle with combined receptor knockout. Tgfbr1 and Acvr1b are synergistically involved in regulation of myofibre size, regeneration and collagen deposition.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting file; Source Data files have been provided for Figures 1 to 5.

The following data sets were generated

Article and author information

Author details

  1. Michèle MG Hillege

    Department of Human Movement, Vrije Universiteit Amsterdam, Amsterdam, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7857-8994
  2. Andi Shi

    Department of Human Movement, Vrije Universiteit Amsterdam, Amsterdam, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  3. Ricardo A Galli

    Department of Human Movement, Vrije Universiteit Amsterdam, Amsterdam, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  4. Gang Wu

    Department of Oral and Maxillofacial Surgery/Pathology, Vrije Universiteit Amsterdam, Amsterdam, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  5. Philippe Bertolino

    Centre de Recherche en Cancérologie de Lyon, Université de Lyon, UMR INSERM U1052, CNRS 5286, Lyon, France
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8064-8269
  6. Willem MH Hoogaars

    Department of Human Movement Sciences, Vrije Universiteit Amsterdam, Amsterdam, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  7. Richard T Jaspers

    Department of Human Movement Sciences, Vrije Universiteit Amsterdam, Amsterdam, Netherlands
    For correspondence
    r.t.jaspers@vu.nl
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6951-0952

Funding

Prinses Beatrix Spierfonds (W.OR14-17)

  • Michèle MG Hillege
  • Willem MH Hoogaars
  • Richard T Jaspers

China Scholarship Council (201808440351))

  • Andi Shi

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 according to the national guidelines approved by the Central Committee for Animal Experiments (CCD) (AVD112002017862) and the Institute of Animal Welfare (IvD) of the Vrije Universiteit Amsterdam.

Reviewing Editor

  1. Christopher L-H Huang, University of Cambridge, United Kingdom

Publication history

  1. Preprint posted: March 6, 2021 (view preprint)
  2. Received: February 4, 2022
  3. Accepted: March 5, 2022
  4. Accepted Manuscript published: March 24, 2022 (version 1)
  5. Version of Record published: April 12, 2022 (version 2)

Copyright

© 2022, Hillege 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. Michèle MG Hillege
  2. Andi Shi
  3. Ricardo A Galli
  4. Gang Wu
  5. Philippe Bertolino
  6. Willem MH Hoogaars
  7. Richard T Jaspers
(2022)
Lack of Tgfbr1 and Acvr1b synergistically stimulates myofibre hypertrophy and accelerates muscle regeneration
eLife 11:e77610.
https://doi.org/10.7554/eLife.77610
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