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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.

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Change history

  • 19 February 2014

    Reference 19 was changed and one reference was updated in the Methods section.

Accessions

Gene Expression Omnibus

Data deposits

Microarray data have been deposited into the NCBI Gene Expression Omnibus under accession number GSE53728.

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Acknowledgements

We are indebted to M. Raya and V. Lukesova for their contributions to this study; J. Martín-Caballero (PRBB Animal Facility), O. Fornas (UPF/CRG FACS Facility) and CRG/UPF Genomic Facility for technical help; A. Consiglio for help in lentivirus obtention; E. Rebollo for advice on imaging; M. van Lohuizen for Bmi1-deficient mice; M. Blasco’s laboratory for help with ageing mice; T. Kawamura and M. Serrano for p16INK4a constructs; A. Sacco, S. Tajbakhsh, B. Gayraud-Morel, D. Montarras, J. Morgan and F. S. Tedesco for advice on cell transplantation; A. Brack and P. Zammit for advice on reserve cells; and Myoage network and tissue bank for support. The authors acknowledge funding from MINECO-Spain (SAF2012-38547, FIS-PS09/01267, FIS-PI13/025, PLE2009-0124), AFM, MDA, E-Rare, Fundació Marató TV3, DuchennePP-NL and EU-FP7 (Myoage, Optistem and Endostem). P.S.-V. and L.G.-P. were supported by predoctoral fellowships from Fundação para a Ciência e a Tecnologia (Portugal) and Programa de Formación de Personal Investigador (Spain), respectively.

Author information

Author notes

    • Pedro Sousa-Victor

    Present address: Buck Institute for Research on Aging, Novato, California 94945, USA.

    • Susana Gutarra
    •  & Laura García-Prat

    These authors contributed equally to this work.

Affiliations

  1. Cell Biology Group, Department of Experimental and Health Sciences, Pompeu Fabra University, CIBER on Neurodegenerative diseases, E-08003 Barcelona, Spain

    • Pedro Sousa-Victor
    • , Susana Gutarra
    • , Laura García-Prat
    • , Laura Ortet
    • , Vanessa Ruiz-Bonilla
    • , Mercè Jardí
    • , Antonio L. Serrano
    • , Eusebio Perdiguero
    •  & Pura Muñoz-Cánoves
  2. Chromatin and Disease Group, Cancer Epigenetics and Biology Programme, Bellvitge Biomedical Research Institute, L’Hospitalet de Llobregat, E-08907 Barcelona, Spain

    • Javier Rodriguez-Ubreva
    •  & Esteban Ballestar
  3. Stem Cell Aging Group, Centro Nacional de Investigaciones Cardiovasculares, E-28029 Madrid, Spain

    • Susana González
  4. Institució Catalana de Recerca i Estudis Avançats, E-08010 Barcelona, Spain

    • Pura Muñoz-Cánoves

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Contributions

P.S.-V. designed and performed experiments, analysed data, interpreted results and wrote the manuscript. S.Gu. and L.G.-P. designed and performed experiments, analysed data and interpreted results. L.O., V.R.-B. and M.J. performed experiments and provided technical support. J.R.-U. and E.B. performed ChIP experiments and edited the manuscript. S.Go. generated transgenic mice and edited the manuscript. A.L.S. and E.P. conceived the project, designed and performed experiments, interpreted results and wrote the manuscript. P.M.-C. conceived the project, designed experiments, interpreted results and wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Eusebio Perdiguero or Pura Muñoz-Cánoves.

Extended data

Supplementary information

Excel files

  1. 1.

    Supplementary Table 1

    Gene list and gene Ontology of Up- and Down-regulated genes in all pairwise comparisons.

  2. 2.

    Supplementary Table 2

    Gene list and gene Ontology of the cluster G1, G2 and G3. Gene set enrichment analysis (GSEA) of Cluster G1.

  3. 3.

    Supplementary Table 4

    qPCR and ChIP primers list.

Word documents

  1. 1.

    Supplementary Table 3

    Senescence geneset with significantly upregulated genes belonging to Cluster G1 indicated.

About this article

Publication history

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DOI

https://doi.org/10.1038/nature13013

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