MACF1 controls skeletal muscle function through the microtubule-dependent localization of extra-synaptic myonuclei and mitochondria biogenesis

  1. Alireza Ghasemizadeh
  2. Emilie Christin
  3. Alexandre Guiraud
  4. Nathalie Couturier
  5. Marie Abitbol
  6. Valerie Risson
  7. Emmanuelle Girard
  8. Krzysztof Jagla
  9. Cedric Soler
  10. lilia Laddada
  11. Colline Sanchez
  12. Francisco-Ignacio Jaque-Fernandez
  13. Vincent Jacquemond
  14. Jean-Luc Thomas
  15. Marine Lanfranchi
  16. Julien Courchet
  17. Julien Gondin
  18. Laurent Schaeffer
  19. Vincent Gache  Is a corresponding author
  1. INMG, France
  2. GReD Laboratory/Clermont-Auvergne University, France
  3. Institut Génétique Reproduction et Développement, France
  4. Centre de Génétique et de Physiologie Moléculaire et Cellulaire, France

Abstract

Skeletal muscles are composed of hundreds of multinucleated muscle fibers (myofibers) whose myonuclei are regularly positioned all along the myofiber's periphery except the few ones clustered underneath the neuromuscular junction (NMJ) at the synaptic zone. This precise myonuclei organization is altered in different types of muscle disease, including centronuclear myopathies (CNMs). However, the molecular machinery regulating myonuclei position and organization in mature myofibers remains largely unknown. Conversely, it is also unclear how peripheral myonuclei positioning is lost in the related muscle diseases. Here, we describe the microtubule-associated protein, MACF1, as an essential and evolutionary conserved regulator of myonuclei positioning and maintenance, in cultured mammalian myotubes, in Drosophila muscle, and in adult mammalian muscle using a conditional muscle-specific knockout mouse model. In vitro, we show that MACF1 controls microtubules dynamics and contributes to microtubule stabilization during myofiber's maturation. In addition, we demonstrate that MACF1 regulates the microtubules density specifically around myonuclei, and, as a consequence, governs myonuclei motion. Our in vivo studies show that MACF1 deficiency is associated with alteration of extra-synaptic myonuclei positioning and microtubules network organization, both preceding NMJ fragmentation. Accordingly, MACF1 deficiency results in reduced muscle excitability and disorganized triads, leaving voltage-activated sarcoplasmic reticulum Ca2+ release and maximal muscle force unchanged. Finally, adult MACF1-KO mice present an improved resistance to fatigue correlated with a strong increase in mitochondria biogenesis.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files. Source data files have been provided for all Figures

Article and author information

Author details

  1. Alireza Ghasemizadeh

    MNCA team, INMG, Lyon, France
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8202-8546
  2. Emilie Christin

    MNCA team, INMG, Lyon, France
    Competing interests
    The authors declare that no competing interests exist.
  3. Alexandre Guiraud

    MNCA team, INMG, Lyon, France
    Competing interests
    The authors declare that no competing interests exist.
  4. Nathalie Couturier

    MNCA team, INMG, Lyon, France
    Competing interests
    The authors declare that no competing interests exist.
  5. Marie Abitbol

    MNCA team, INMG, Lyon, France
    Competing interests
    The authors declare that no competing interests exist.
  6. Valerie Risson

    INSERM U1217,CNRS UMR5310, Université Claude Bernard Lyon I, INMG, LYON, France
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6812-6297
  7. Emmanuelle Girard

    INSERM U1217,CNRS UMR5310, Université Claude Bernard Lyon I, INMG, LYON, France
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6730-9596
  8. Krzysztof Jagla

    GReD Laboratory/Clermont-Auvergne University, Clermont-Ferrandf, France
    Competing interests
    The authors declare that no competing interests exist.
  9. Cedric Soler

    Institut Génétique Reproduction et Développement, Clermont-Ferrand, France
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2312-5370
  10. lilia Laddada

    GReD Laboratory/Clermont-Auvergne University, Clermont-Ferrandf, France
    Competing interests
    The authors declare that no competing interests exist.
  11. Colline Sanchez

    MNCA team, INMG, Lyon, France
    Competing interests
    The authors declare that no competing interests exist.
  12. Francisco-Ignacio Jaque-Fernandez

    INSERM U1217,CNRS UMR5310, Université Claude Bernard Lyon I, INMG, LYON, France
    Competing interests
    The authors declare that no competing interests exist.
  13. Vincent Jacquemond

    Centre de Génétique et de Physiologie Moléculaire et Cellulaire, Lyon, France
    Competing interests
    The authors declare that no competing interests exist.
  14. Jean-Luc Thomas

    MNCA team, INMG, Lyon, France
    Competing interests
    The authors declare that no competing interests exist.
  15. Marine Lanfranchi

    INSERM U1217,CNRS UMR5310, Université Claude Bernard Lyon I, INMG, LYON, France
    Competing interests
    The authors declare that no competing interests exist.
  16. Julien Courchet

    INSERM U1217, CNRS UMR5310, Université Claude Bernard Lyon I, INMG, Lyon, France
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1199-9329
  17. Julien Gondin

    INSERM U1217, CNRS UMR5310, Université Claude Bernard Lyon I, INMG, Lyon, France
    Competing interests
    The authors declare that no competing interests exist.
  18. Laurent Schaeffer

    INSERM U1217,CNRS UMR5310, Université Claude Bernard Lyon I, INMG, LYON, France
    Competing interests
    The authors declare that no competing interests exist.
  19. Vincent Gache

    INSERM U1217,CNRS UMR5310, Université Claude Bernard Lyon I, INMG, Lyon, France
    For correspondence
    vincent.gache@inserm.fr
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2928-791X

Funding

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Mohammed Akaaboune, University of Michigan, United States

Ethics

Animal experimentation: All of the experiments and procedures were conducted in accordance with the guidelines of the local animal ethics committee of the University Claude Bernard - Lyon 1 and in accordance with French and European legislation on animal experimentation and approved by the ethics committee CECCAPP (ref APAFIS#17455-2018091216033835v5) and the French ministry of research.

Version history

  1. Preprint posted: May 15, 2019 (view preprint)
  2. Received: May 18, 2021
  3. Accepted: August 10, 2021
  4. Accepted Manuscript published: August 27, 2021 (version 1)
  5. Version of Record published: October 8, 2021 (version 2)

Copyright

© 2021, Ghasemizadeh 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. Alireza Ghasemizadeh
  2. Emilie Christin
  3. Alexandre Guiraud
  4. Nathalie Couturier
  5. Marie Abitbol
  6. Valerie Risson
  7. Emmanuelle Girard
  8. Krzysztof Jagla
  9. Cedric Soler
  10. lilia Laddada
  11. Colline Sanchez
  12. Francisco-Ignacio Jaque-Fernandez
  13. Vincent Jacquemond
  14. Jean-Luc Thomas
  15. Marine Lanfranchi
  16. Julien Courchet
  17. Julien Gondin
  18. Laurent Schaeffer
  19. Vincent Gache
(2021)
MACF1 controls skeletal muscle function through the microtubule-dependent localization of extra-synaptic myonuclei and mitochondria biogenesis
eLife 10:e70490.
https://doi.org/10.7554/eLife.70490

Share this article

https://doi.org/10.7554/eLife.70490

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