Geriatric Muscle Stem Cells Switch Reversible Quiescence Into Senescence

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aging / metabolism*
  • Animals
  • Cells, Cultured
  • Cyclin-Dependent Kinase Inhibitor p16 / deficiency
  • Cyclin-Dependent Kinase Inhibitor p16 / genetics
  • Cyclin-Dependent Kinase Inhibitor p16 / metabolism*
  • E2F1 Transcription Factor / metabolism
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Progeria / metabolism
  • Progeria / pathology
  • Regeneration
  • Rejuvenation
  • Retinoblastoma Protein / metabolism
  • Satellite Cells, Skeletal Muscle / cytology*
  • Satellite Cells, Skeletal Muscle / metabolism*
  • Young Adult

Substances

  • Cdkn2a protein, mouse
  • Cyclin-Dependent Kinase Inhibitor p16
  • E2F1 Transcription Factor
  • Retinoblastoma Protein

Associated data

  • GEO/GSE53728