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Age-specific functional epigenetic changes in p21 and p16 in injury-activated satellite cells

Ju Li1, Suhyoun Han, Wendy Cousin

  • 1Department of Bioengineering, University of California-Berkeley, Berkeley, California, USA; California Institute for Quantitative Biosciences (QB3), Berkeley, California, USA.

Stem Cells (Dayton, Ohio)
|December 3, 2014
PubMed

Insights

Aging muscle stem cells lose regenerative ability. Young cells epigenetically silence cyclin-dependent kinase inhibitors (CDKIs) p21 and p16, while old cells show increased pERK signaling that silences p21, enhancing proliferation and aiding muscle repair.

Area of Science:

  • Muscle stem cell biology
  • Aging and regeneration
  • Epigenetics and cell cycle regulation

Background:

  • Muscle regenerative capacity declines with age due to impaired muscle stem cell proliferation.
  • Old muscle stem cells exhibit reduced proliferation in response to tissue damage.

Purpose of the Study:

  • To identify age-specific molecular mechanisms underlying the decline in muscle stem cell proliferation.
  • To investigate the role of cyclin-dependent kinase inhibitors (CDKIs) and signaling pathways in age-related muscle regeneration defects.

Main Methods:

  • Analysis of epigenetic silencing of p21 and p16 gene loci in young versus old muscle stem cells.
  • Investigating the association of phosphorylated ERK (pERK) with CDKI promoters.
  • Assessing the impact of FGF2/pERK signaling on p21 expression and cell proliferation in aged satellite cells.

Main Results:

  • Epigenetic silencing of p21 and p16 is less pronounced in young muscle stem cells compared to old cells.
  • FGF2-induced pERK associates with p21 and p16 promoters specifically in old cells.
  • In old cells, FGF2/pERK signaling epigenetically and transcriptionally silences p21, reducing its protein levels and promoting proliferation.
  • Elevated levels of other CDKIs (p15INK4B, p27KIP1) are observed in aged satellite cells.

Conclusions:

  • Age-specific epigenetic regulation of CDKIs, particularly p21, is a key factor in reduced muscle regeneration.
  • The FGF2/pERK pathway plays a critical role in age-related silencing of p21 in muscle stem cells.
  • Understanding these mechanisms offers potential strategies to combat age-related tissue degeneration and improve muscle repair.
Keywords:
AgingCDK inhibitorChromatinEpigeneticMAPKMuscle stem cellsSignal transductionTissue regenerationpERK

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