The role of Pitx2 and Pitx3 in muscle stem cells gives new insights into P38α MAP kinase and redox regulation of muscle regeneration

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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

(2010) An adult tissue-specific stem cell in its niche: a gene profiling analysis of in vivo quiescent and activated muscle satellite cells
Publicly available at the NCBI Gene Expression Omnibus (accession no: GSE15155).

http://www.ncbi.nlm.nih.gov/geo

Article and author information

Author details

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.

"This ORCID iD identifies the author of this article:" 0000-0001-6371-4455
Pierre-Henri Commère

Platform of Cytometry, Institut Pasteur, Paris, France

Competing interests
No competing interests declared.
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.
Giorgia Pallafacchina

Italian National Research Council (CNR) Neuroscience Institute, Padova, Italy

Competing interests
No competing interests declared.

"This ORCID iD identifies the author of this article:" 0000-0001-9766-5970
Bertrand Friguet

Biological Adaptation and Aging-IBPS, CNRS UMR 8256, INSERM ERL U1164, Paris, France

Competing interests
No competing interests declared.
Jacques Drouin

Laboratory of Molecular Genetics, Institut de Recherches Cliniques de Montréal, Montréal, France

Competing interests
No competing interests declared.
Margaret Buckingham

Department of Developmental and Stem Cell Biology, CNRS UMR 3738, Institut Pasteur, Paris, France

Competing interests
Margaret Buckingham, Reviewing editor, eLife.
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.

Copyright

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.