Age‐Specific Functional Epigenetic Changes in p21 and p16 in Injury‐Activated Satellite Cells

• Published in: Stem cells (Dayton, Ohio) Vol. 33; no. 3; pp. 951 - 961
• Main Authors: Li, Ju, Han, Suhyoun, Cousin, Wendy, Conboy, Irina M.
• Format: Journal Article
• Language: English
• Published: United States Oxford University Press 01.03.2015
• Subjects: Age; Age Factors; Aging; Animals; CDK inhibitor; Chromatin; Cyclin-Dependent Kinase Inhibitor p16 - genetics; Cyclin-Dependent Kinase Inhibitor p16 - metabolism; Cyclin-Dependent Kinase Inhibitor p21 - genetics; Cyclin-Dependent Kinase Inhibitor p21 - metabolism; Epigenesis, Genetic; Epigenetic; Epigenetics; Guided Tissue Regeneration; Kinases; MAPK; Mice; Mice, Inbred C57BL; Muscle stem cells; Muscle, Skeletal - injuries; Muscle, Skeletal - metabolism; Muscle, Skeletal - pathology; pERK; Satellite Cells, Skeletal Muscle - metabolism; Satellite Cells, Skeletal Muscle - physiology; Satellites; Signal Transduction; Stem cells; Tissue regeneration; Signal transduction; Chromatin; CDK inhibitor; Aging; Epigenetic; MAPK; Tissue regeneration; pERK; Muscle stem cells
• ISSN: 1066-5099; 1549-4918
• DOI: 10.1002/stem.1908

The regenerative capacity of muscle dramatically decreases with age because old muscle stem cells fail to proliferate in response to tissue damage. Here, we uncover key age‐specific differences underlying this proliferative decline: namely, the genetic loci of cyclin/cyclin‐dependent kinase (CDK) inhibitors (CDKIs) p21 and p16 are more epigenetically silenced in young muscle stem cells, as compared to old, both in quiescent cells and those responding to tissue injury. Interestingly, phosphorylated ERK (pERK) induced in these cells by ectopic FGF2 is found in association with p21 and p16 promoters, and moreover, only in the old cells. Importantly, in the old satellite cells, FGF2/pERK silences p21 epigenetically and transcriptionally, which leads to reduced p21 protein levels and enhanced cell proliferation. In agreement with the epigenetic silencing of the loci, young muscle stem cells do not depend as much as old on ectopic FGF/pERK for their myogenic proliferation. In addition, other CDKIs, such asp15INK4B and p27KIP1, become elevated in satellite cells with age, confirming and explaining the profound regenerative defect of old muscle. This work enhances our understanding of tissue aging, promoting strategies for combating age‐imposed tissue degeneration. Stem Cells 2015;33:951–961