Muscle stem cells (MuSCs) are the resident stem cells in skeletal muscle responsible for adult muscle regeneration. They remain quiescent in G₀ state and enter the cell cycle in response to stimuli such as muscle injury. Aged MuSCs have a decreased regeneration capacity, which can be attributed to two possible causes. The first one is related to the niche in which MuSCs reside, containing mesenchymal stromal cells, immune cells, endothelial cells, and the extracellular matrix. The deficiency in aged MuSCs regeneration capacity has been associated with the extrinsic signals provided by the niche through Notch signaling, Wnt signaling, and others. Another possible reason is that cells change intrinsically with age. The most plausible hypothesis is that the intrinsic change is regu...[ Read more ]

Muscle stem cells (MuSCs) are the resident stem cells in skeletal muscle responsible for adult muscle regeneration. They remain quiescent in G₀ state and enter the cell cycle in response to stimuli such as muscle injury. Aged MuSCs have a decreased regeneration capacity, which can be attributed to two possible causes. The first one is related to the niche in which MuSCs reside, containing mesenchymal stromal cells, immune cells, endothelial cells, and the extracellular matrix. The deficiency in aged MuSCs regeneration capacity has been associated with the extrinsic signals provided by the niche through Notch signaling, Wnt signaling, and others. Another possible reason is that cells change intrinsically with age. The most plausible hypothesis is that the intrinsic change is regulated by epigenetic change, which can be cell-autonomous and/or downstream the signaling pathways. For example, aging is strongly correlated with changes in DNA methylation. However, how histone modifications control aged MuSC function remains unclear. It has been shown that H3K27me3 increases significantly in MuSCs with age, which is related to gene silencing by polycomb repressive complex 2 (PRC2). Our study characterized the pattern of a histone mark on the same residue that is associated with transcriptional activation, H3K27ac, in young and aged MuSC quiescence and activation. We found a globally elevated H3K27ac level in aged quiescent MuSCs despite the minor alteration in the distribution pattern. Since acetylation neutralizes the charge of lysine and weakens the bond between histone and DNA, our result suggests that aged MuSCs have a more open chromatin structure than young MuSCs. Furthermore, the increase of the H3K27ac level observed in some of the genes may contribute to the impaired function with age. Taken together, aged MuSCs may have a weaker control of the gene expression that leads to the declined function.