Elevated H3K27ac in aged skeletal muscle leads to increase in extracellular matrix and fibrogenic conversion of muscle satellite cells

Abstract

Epigenetic alterations occur in various cells and tissues during aging, but it is not known if such alterations are also associated with aging in skeletal muscle. Here, we examined the changes of a panel of histone modifications and found H3K27ac (an active enhancer mark) is markedly increased in aged human skeletal muscle tissues. Further analyses uncovered that the H3K27ac increase and enhancer activation are associated with the up‐regulation of extracellular matrix (ECM) genes; this may result in alteration of the niche environment for skeletal muscle stem cells, also called satellite cells (SCs), which causes decreased myogenic potential and fibrogenic conversion of SCs. In mice, treatment of aging muscles with JQ1, an inhibitor of enhancer activation, inhibited the ECM up‐regulation and fibrogenic conversion of SCs and restored their myogenic differentiation potential. Altogether, our findings not only uncovered a novel aspect of skeletal muscle aging that is associated with enhancer remodeling but also implicated JQ1 as a potential treatment approach for restoring SC function in aging muscle.

Molecular Insights Into Lysyl Oxidases in Cartilage Regeneration and Rejuvenation

“…During the progression of aging-associated degeneration diseases, altered cell fate of adult stem cells, or dysfunction of terminally differentiated mature cells occurs, which may result from the changed ECM niche modified with aging-related proteins and reduced expression of ECM-synthesis-associated proteins (Goupille et al, 1998;Chan et al, 2006;Sakai et al, 2012;Wang et al, 2015;Jeon et al, 2017;Patil et al, 2019), which may be correlated with the LOX family members. Therefore, reverting aging-associated genes in ECM may become an important strategy for joint rejuvenation (Chan et al, 2006;Fuoco et al, 2014;Li et al, 2014;Sun et al, 2011;Wang et al, 2019;Zhou J. et al, 2019). Modulation of expression of LOXs family members through transcriptional regulation of HIF-1 may become promising therapeutic approaches for treating aging-induced cartilage degeneration as potential rejuvenating therapies.…”

Fibrogenesis in LAMA2-Related Muscular Dystrophy Is a Central Tenet of Disease Etiology

“…This protein is typically only expressed in cells of a mesenchymal lineage in adult skeletal muscle (Sinanan et al, 2008;Murray et al, 2017). It is interesting to note that a similar phenomenon has been observed in aged human skeletal muscle where increased TGF-beta signaling and acetylation of the 27th residue of histone H3 (H3K27ac) on ECM genes pushes satellite cells away from myogenic fates and toward fibrogenic fates (Zhou et al, 2019). Taken together, this data demonstrate that satellite cells have the ability to become fibrotic effector cells in response to chronic TGF-beta signaling.…”

Understanding muscle regenerative decline with aging: new approaches to bring back youthfulness to aged stem cells

“…Analysis of histone modifications in whole human skeletal muscle tissues found an age‐associated increase in the active enhancer marker H3K27ac. In mouse models, this enhancer activation is associated with the upregulation of ECM genes during aging, contributing to a decline in myogenic capacity and increased fibrogenic conversion of aged satellite cells .…”