The role of Pitx2 and Pitx3 in muscle stem cells gives new insights into P38α MAP kinase and redox regulation of muscle regeneration
- CNRS UMR 3738, Institut Pasteur, France
- Institut Pasteur, France
- Sorbonne Universités, Université Pierre et Marie Curie Université Paris 06, INSERM UMRS974, France
- Italian National Research Council (CNR) Neuroscience Institute, Italy
- CNRS UMR 8256, INSERM ERL U1164, France
- Institut de Recherches Cliniques de Montréal, France
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.
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An adult tissue-specific stem cell in its niche: a gene profiling analysis of in vivo quiescent and activated muscle satellite cellsPublicly available at the NCBI Gene Expression Omnibus (accession no: GSE15155).
Article and author information
Author details
Giorgia Pallafacchina
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
© 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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The role of Pitx2 and Pitx3 in muscle stem cells gives new insights into P38α MAP kinase and redox regulation of muscle regeneration
eLife 7:e32991.
https://doi.org/10.7554/eLife.32991
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