title: Age-specific functional epigenetic changes in p21 and p16 in injury-activated satellite cells.
abstract: 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 asp15(INK4B) and p27(KIP1) , 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.
authors.affiliation: Department of Bioengineering, University of California-Berkeley, Berkeley, California, USA; California Institute for Quantitative Biosciences (QB3), Berkeley, California, USA.
authors.forename: Ju
authors.initials: J
authors.lastname: Li
authors.forename: Suhyoun
authors.initials: S
authors.lastname: Han
authors.forename: Wendy
authors.initials: W
authors.lastname: Cousin
authors.forename: Irina M
authors.initials: IM
authors.lastname: Conboy
mesh_terms: D000367:Age Factors; D000818:Animals; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics* / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics* / Q000378:metabolism; D044127:Epigenesis, Genetic; D048091:Guided Tissue Regeneration; D051379:Mice; D008810:Mice, Inbred C57BL; D018482:Muscle, Skeletal / Q000293:injuries* / Q000378:metabolism* / Q000473:pathology; D032496:Satellite Cells, Skeletal Muscle / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16; D050759:Cyclin-Dependent Kinase Inhibitor p21
keywords: Aging; CDK inhibitor; Chromatin; Epigenetic; MAPK; Muscle stem cells; Signal transduction; Tissue regeneration; pERK