title: Geriatric muscle stem cells switch reversible quiescence into senescence.
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.
authors: 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.
authors: Pedro
authors: P
authors: Sousa-Victor
authors: 1] Cell Biology Group, Department of Experimental and Health Sciences, Pompeu Fabra University, CIBER on Neurodegenerative diseases, E-08003 Barcelona, Spain [2].
authors: Susana
authors: S
authors: Gutarra
authors: 1] Cell Biology Group, Department of Experimental and Health Sciences, Pompeu Fabra University, CIBER on Neurodegenerative diseases, E-08003 Barcelona, Spain [2].
authors: Laura
authors: L
authors: García-Prat
authors: Chromatin and Disease Group, Cancer Epigenetics and Biology Programme, Bellvitge Biomedical Research Institute, L'Hospitalet de Llobregat, E-08907 Barcelona, Spain.
authors: Javier
authors: J
authors: Rodriguez-Ubreva
authors: Cell Biology Group, Department of Experimental and Health Sciences, Pompeu Fabra University, CIBER on Neurodegenerative diseases, E-08003 Barcelona, Spain.
authors: Laura
authors: L
authors: Ortet
authors: Cell Biology Group, Department of Experimental and Health Sciences, Pompeu Fabra University, CIBER on Neurodegenerative diseases, E-08003 Barcelona, Spain.
authors: Vanessa
authors: V
authors: Ruiz-Bonilla
authors: Cell Biology Group, Department of Experimental and Health Sciences, Pompeu Fabra University, CIBER on Neurodegenerative diseases, E-08003 Barcelona, Spain.
authors: Mercè
authors: M
authors: Jardí
authors: Chromatin and Disease Group, Cancer Epigenetics and Biology Programme, Bellvitge Biomedical Research Institute, L'Hospitalet de Llobregat, E-08907 Barcelona, Spain.
authors: Esteban
authors: E
authors: Ballestar
authors: Stem Cell Aging Group, Centro Nacional de Investigaciones Cardiovasculares, E-28029 Madrid, Spain.
authors: Susana
authors: S
authors: González
authors: Cell Biology Group, Department of Experimental and Health Sciences, Pompeu Fabra University, CIBER on Neurodegenerative diseases, E-08003 Barcelona, Spain.
authors: Antonio L
authors: AL
authors: Serrano
authors: Cell Biology Group, Department of Experimental and Health Sciences, Pompeu Fabra University, CIBER on Neurodegenerative diseases, E-08003 Barcelona, Spain.
authors: Eusebio
authors: E
authors: Perdiguero
authors: 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.
authors: Pura
authors: P
authors: Muñoz-Cánoves
mesh_terms: D000328:Adult; D000375:Aging / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D050687:E2F1 Transcription Factor / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011371:Progeria / Q000378:metabolism / Q000473:pathology; D012038:Regeneration; D012060:Rejuvenation; D016160:Retinoblastoma Protein / Q000378:metabolism; D032496:Satellite Cells, Skeletal Muscle / Q000166:cytology* / Q000378:metabolism*; D055815:Young Adult
chemical_list: C417743:Cdkn2a protein, mouse; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050687:E2F1 Transcription Factor; D016160:Retinoblastoma Protein