Geriatric muscle stem cells switch reversible quiescence into senescence

Pedro Sousa-Victor, Susana Gutarra, Laura García-Prat, Javier Rodriguez-Ubreva, Laura Ortet, Vanessa Ruiz-Bonilla, Mercè Jardí, Esteban Ballestar, Susana González, Antonio L. Serrano, Eusebio Perdiguero () and Pura Muñoz-Cánoves ()
Additional contact information
Pedro Sousa-Victor: Cell Biology Group, Pompeu Fabra University, CIBER on Neurodegenerative diseases, E-08003 Barcelona, Spain
Susana Gutarra: Cell Biology Group, Pompeu Fabra University, CIBER on Neurodegenerative diseases, E-08003 Barcelona, Spain
Laura García-Prat: Cell Biology Group, Pompeu Fabra University, CIBER on Neurodegenerative diseases, E-08003 Barcelona, Spain
Javier Rodriguez-Ubreva: Chromatin and Disease Group, Cancer Epigenetics and Biology Programme, Bellvitge Biomedical Research Institute, L’Hospitalet de Llobregat, E-08907 Barcelona, Spain
Laura Ortet: Cell Biology Group, Pompeu Fabra University, CIBER on Neurodegenerative diseases, E-08003 Barcelona, Spain
Vanessa Ruiz-Bonilla: Cell Biology Group, Pompeu Fabra University, CIBER on Neurodegenerative diseases, E-08003 Barcelona, Spain
Mercè Jardí: Cell Biology Group, Pompeu Fabra University, CIBER on Neurodegenerative diseases, E-08003 Barcelona, Spain
Esteban Ballestar: Chromatin and Disease Group, Cancer Epigenetics and Biology Programme, Bellvitge Biomedical Research Institute, L’Hospitalet de Llobregat, E-08907 Barcelona, Spain
Susana González: Stem Cell Aging Group, Centro Nacional de Investigaciones Cardiovasculares, E-28029 Madrid, Spain
Antonio L. Serrano: Cell Biology Group, Pompeu Fabra University, CIBER on Neurodegenerative diseases, E-08003 Barcelona, Spain
Eusebio Perdiguero: Cell Biology Group, Pompeu Fabra University, CIBER on Neurodegenerative diseases, E-08003 Barcelona, Spain
Pura Muñoz-Cánoves: Cell Biology Group, Pompeu Fabra University, CIBER on Neurodegenerative diseases, E-08003 Barcelona, Spain

Nature, 2014, vol. 506, issue 7488, 316-321

Abstract: Abstract Regeneration of skeletal muscle depends on a population of adult stem cells (satellite cells) that remain quiescent throughout life. Satellite cell regenerative functions decline with ageing. Here we report that geriatric satellite cells are incapable of maintaining their normal quiescent state in muscle homeostatic conditions, and that this irreversibly affects their intrinsic regenerative and self-renewal capacities. In geriatric mice, resting satellite cells lose reversible quiescence by switching to an irreversible pre-senescence state, caused by derepression of p16INK4a (also called Cdkn2a). On injury, these cells fail to activate and expand, undergoing accelerated entry into a full senescence state (geroconversion), even in a youthful environment. p16INK4a silencing in geriatric satellite cells restores quiescence and muscle regenerative functions. Our results demonstrate that maintenance of quiescence in adult life depends on the active repression of senescence pathways. As p16INK4a is dysregulated in human geriatric satellite cells, these findings provide the basis for stem-cell rejuvenation in sarcopenic muscles.

Date: 2014
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DOI: 10.1038/nature13013

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