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Nature. 2014 Feb 20;506(7488):316-21. doi: 10.1038/nature13013. Epub 2014 Feb 12.

Geriatric muscle stem cells switch reversible quiescence into senescence.

Author information

1
1] Cell Biology Group, Department of Experimental and Health Sciences, Pompeu Fabra University, CIBER on Neurodegenerative diseases, E-08003 Barcelona, Spain [2] Buck Institute for Research on Aging, Novato, California 94945, USA.
2
1] Cell Biology Group, Department of Experimental and Health Sciences, Pompeu Fabra University, CIBER on Neurodegenerative diseases, E-08003 Barcelona, Spain [2].
3
Chromatin and Disease Group, Cancer Epigenetics and Biology Programme, Bellvitge Biomedical Research Institute, L'Hospitalet de Llobregat, E-08907 Barcelona, Spain.
4
Cell Biology Group, Department of Experimental and Health Sciences, Pompeu Fabra University, CIBER on Neurodegenerative diseases, E-08003 Barcelona, Spain.
5
Stem Cell Aging Group, Centro Nacional de Investigaciones Cardiovasculares, E-28029 Madrid, Spain.
6
1] Cell Biology Group, Department of Experimental and Health Sciences, Pompeu Fabra University, CIBER on Neurodegenerative diseases, E-08003 Barcelona, Spain [2] Institució Catalana de Recerca i Estudis Avançats, E-08010 Barcelona, Spain.

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 p16(INK4a) (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. p16(INK4a) 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 p16(INK4a) is dysregulated in human geriatric satellite cells, these findings provide the basis for stem-cell rejuvenation in sarcopenic muscles.

PMID:
24522534
DOI:
10.1038/nature13013
[Indexed for MEDLINE]

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