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Elife. 2018 Aug 14;7. pii: e32991. doi: 10.7554/eLife.32991.

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

Author information

1
Department of Developmental and Stem Cell Biology, CNRS, UMR 3738, Institut Pasteur, Paris, France.
2
Biological Adaptation and Aging-IBPS, CNRS UMR 8256, INSERM ERL U1164, Sorbonne Universités, Université Pierre et Marie Curie, Paris, France.
3
Platform of Cytometry, Institut Pasteur, Paris, France.
4
Center for Research in Myology, Sorbonne Universités, Université Pierre et Marie Curie, Paris, France.
5
NeuroscienceInstitute, Department of Biomedical Sciences, Italian National Research Council, Universityof Padova, Padova, Italy.
6
Laboratory of Molecular Genetics, Institut de Recherches Cliniques de Montréal, Montréal, Canada.

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 p38α MAP kinase. Subjecting cultured satellite cells to transient inhibition of P38α MAP kinase in conjunction with NAC treatment leads to their rapid expansion, with striking improvement of their regenerative potential in grafting experiments.

KEYWORDS:

Pitx2/3; cell biology; cell therapy; mouse; muscle stem cell; p38α MAPK; redox state; regeneration; regenerative medicine; stem cells

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