1. Cell Biology
  2. Stem Cells and Regenerative Medicine
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The role of Pitx2 and Pitx3 in muscle stem cells gives new insights into P38α MAP kinase and redox regulation of muscle regeneration

  1. Aurore Lhonore  Is a corresponding author
  2. Pierre-Henri Commère
  3. Elisa Negroni
  4. Giorgia Pallafacchina
  5. Bertrand Friguet
  6. Jacques Drouin
  7. Margaret Buckingham
  8. Didier Montarras  Is a corresponding author
  1. CNRS UMR 3738, Institut Pasteur, France
  2. Institut Pasteur, France
  3. Sorbonne Universités, Université Pierre et Marie Curie Université Paris 06, INSERM UMRS974, France
  4. Italian National Research Council (CNR) Neuroscience Institute, Italy
  5. CNRS UMR 8256, INSERM ERL U1164, France
  6. Institut de Recherches Cliniques de Montréal, France
Research Article
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Cite this article as: eLife 2018;7:e32991 doi: 10.7554/eLife.32991

Abstract

Skeletal muscle regeneration depends on satellite cells. After injury these muscle stem cells exit quiescence, proliferate and differentiate to regenerate damaged fibres. We show that this progression is accompanied by metabolic changes leading to increased production of reactive oxygen species (ROS). Using Pitx2/3 single and double mutant mice that provide genetic models of deregulated redox states, we demonstrate that moderate overproduction of ROS results in premature differentiation of satellite cells while high levels lead to their senescence and regenerative failure. Using the ROS scavenger, N-Acetyl-Cysteine, (NAC) in primary cultures we show that a physiological increase in ROS is required for satellite cells to exit the cell cycle and initiate differentiation through the redox activation of p38a MAP kinase. Subjecting cultured satellite cells to transient inhibition of P38a MAP kinase in conjunction with NAC treatment leads to their rapid expansion, with striking improvement of their regenerative potential in grafting experiments.

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 and supplement figures.

The following previously published data sets were used

Article and author information

Author details

  1. Aurore Lhonore

    Department of Developmental and Stem Cell Biology, CNRS UMR 3738, Institut Pasteur, Paris, France
    For correspondence
    alhonore@hotmail.com
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6371-4455
  2. Pierre-Henri Commère

    Platform of Cytometry, Institut Pasteur, Paris, France
    Competing interests
    No competing interests declared.
  3. Elisa Negroni

    Center for Research in Myology, Sorbonne Universités, Université Pierre et Marie Curie Université Paris 06, INSERM UMRS974, Paris, France
    Competing interests
    No competing interests declared.
  4. Giorgia Pallafacchina

    Italian National Research Council (CNR) Neuroscience Institute, Padova, Italy
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9766-5970
  5. Bertrand Friguet

    Biological Adaptation and Aging-IBPS, CNRS UMR 8256, INSERM ERL U1164, Paris, France
    Competing interests
    No competing interests declared.
  6. Jacques Drouin

    Laboratory of Molecular Genetics, Institut de Recherches Cliniques de Montréal, Montréal, France
    Competing interests
    No competing interests declared.
  7. Margaret Buckingham

    Department of Developmental and Stem Cell Biology, CNRS UMR 3738, Institut Pasteur, Paris, France
    Competing interests
    Margaret Buckingham, Reviewing editor, eLife.
  8. Didier Montarras

    Department of Developmental and Stem Cell Biology, CNRS UMR 3738, CNRS UMR 3738, Institut Pasteur, Paris, France
    For correspondence
    didier.montarras@pasteur.fr
    Competing interests
    No competing interests declared.

Funding

Agence Nationale de la Recherche (REGSAT)

  • Margaret Buckingham

AFM-Téléthon

  • Didier Montarras

AFM-Téléthon (Postdoc Fellowship)

  • Aurore Lhonore

Agence Nationale de la Recherche (ANR-10-LABX-73)

  • Margaret Buckingham

Seventh Framework Programme (OptiStem 223098)

  • Margaret Buckingham

Seventh Framework Programme (Marie Curie IRG 248496)

  • Aurore Lhonore

Fondation pour la Recherche Médicale (Postdoc Fellowship)

  • Aurore Lhonore

Fondation pour la Recherche Médicale (Postdoc Fellowship)

  • Giorgia Pallafacchina

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 animal procedures were approved and conducted in accordance with the Institut Pasteur animal ethics committee (CEEA Institut Pasteur n{degree sign}2013-0017 and APAFIS #2455 2015 1122133311) following the regulations of the Ministry of Agriculture and the European Community guidelines. All surgery were performed under Ketamine /Xylazine anesthesia and and every effort was made to minimize suffering.

Reviewing Editor

  1. Andrew Brack, University of California, San Francisco, United States

Publication history

  1. Received: October 20, 2017
  2. Accepted: August 1, 2018
  3. Accepted Manuscript published: August 14, 2018 (version 1)
  4. Version of Record published: October 16, 2018 (version 2)

Copyright

© 2018, Lhonore 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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