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 CDK inhibitors (CDKI) 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 FGF-2 is found in association with p21 and p16 promoters, and moreover, only in the old cells. Importantly, in the old satellite cells FGF-2/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.

Dynamic changes in heparan sulfate during muscle differentiation and ageing regulate myoblast cell fate and FGF2 signalling

“…Moreover, we speculate that the increase in 6-O-sulfation that we observe in aged muscle could have important consequences on the level of activation of resident SCs. It has been reported that FGF2 signalling is increased in aged muscle and leads to SC hyper-activation and consequent exhaustion [31], [33]. Since 6-O-sulfation promotes FGF2 signalling [47], [48], it is reasonable to speculate that the increase in FGF2 signalling observed in aged SCs is, at least in part, due to the increased 6-O-sulfation that we observed in the muscle heparanome.…”

“…The number of quiescent SCs and their regenerative potential are reduced with ageing [31], [33] and accompanied by alterations in MAPK signalling [29], [30], which is strongly affected by the extracellular heparanome [44], [45]. Furthermore, previous studies have shown age-related changes in HS structures in other tissues [34], [35].…”

“…This is due to both intrinsic SC impairment and changes in molecular signalling that occur in the SC niche [29], [30], [31], [32]. Interestingly, HS regulates several signalling events that are reportedly altered in the aged SC niche, such as FGF2 signalling [31], [33]. Moreover, age-related changes in HS have been reported in some human tissues including aorta and cardiac muscle [34], [35].…”

­­­Mechanosensitivity of aged muscle stem cells

“…DNA damage and disturbed signalling cascades might be responsible for the lack of intrinsic regenerative capacity of the aged MuSC . The aged niche conditions of MuSCs are known to cause epigenetic changes in the regulation of gene expression, which strongly determine MuSC fate and function . However, it is also possible that in addition to these changes, or as a result of these changes, aged MuSCs do not perceive mechanical loads appropriately.…”

Changes in Communication between Muscle Stem Cells and their Environment with Aging

“…Consequently, local histones are hypermethylated, stabilizing the nucleosomes, so that DNA in methylated regions is tightly packed preventing binding of transcription factors or RNA polymerases. A recent study shows that histone methylation patterns are different between aged and young satellite cells in mice [117], and that the methylation profile can be modified by the presence of local growth factors such as FGF-2 [118]. The authors associated this histone methylation profile to a slower capacity of aged satellite cells to re-enter the cell cycle for aged satellite cells [117].…”