An Age-Related Epigenetic Change that Degrades Muscle Stem Cell Function

Stem cells support their tissues by generating daughter somatic cells and various forms of pro-regenerative signaling. Unfortunately, this activity declines with age. In the better studied stem cell populations, such as those in muscle tissue, this appears to be more a matter of signaling changes in the local environment than intrinsic damage to the stem cells themselves. The stem cells spend ever more time in a quiescent state, emerging ever more rarely to generate new daughter cells. At the high level, these changes must be a reaction to rising levels of molecular damage and its consequences such as chronic inflammation, but most of the research community is more interesting in finding proximate causes than in tackling root causes. The research here is an example of the type, in which scientists identify a specific epigenetic change that alters the muscle stem cell niche to suppress stem cell activity.

Muscle possesses remarkable regenerative capacity mediated by adult muscle stem cells, also called satellite cells (SCs) that reside in close association with individual myofibers, underneath the fiber's basal lamina. Responding to muscle injury, SCs will be activated and proliferate, differentiate, and fuse to existing damaged fibers or fuse with one another to form myofibers de novo. Meanwhile, a subpopulation of SCs returns to quiescence to replenish the stem cell pool. As we age, the mass, function, and regenerating capacity of muscle gradually decline, affecting mobility, voluntary function, and quality of life. It is thus imperative to investigate mechanisms accounting for the age-related muscle loss and functional decline.

Changes at all levels, including gene expression, histone modification, DNA methylation, and physical changes in muscle stem cell environment, or niche, have been found to be associated with aging. For instance, one of the studies of gene expression in aging muscle revealed that mitochondrial dysfunction is a major age-related phenomenon and highlighted the beneficial effects of maintaining a high physical capacity in the prevention of age-related muscle function decline. In another report, transcriptome-wide analysis demonstrated that the expression of extracellular matrix (ECM) genes is up-regulated during muscle aging. The myofiber basal lamina is comprised of an ECM network that is in direct contact with SCs and ECM plays an essential role in maintaining microenvironment homeostasis and SC function; the increased ECM levels in aging niche thus lead to deregulated behaviors of SCs. Specifically, SCs displayed decreased myogenic potential but increased expression of fibrogenic genes in aged muscle.

Alterations at epigenetic levels are also known to be associated with aging. For example, DNA hypermethylation at gene regions is associated with aging muscle. However, potential alterations of histone marks in aging muscle have not been investigated. For example, H3K27ac enrichment is a hallmark of enhancers. Several studies have shown the deregulation of H3K27ac and enhancers in aging tissues/cell types. In this study, we examined the changes of a panel of histone marks and found H3K27ac is markedly increased during aging in human skeletal muscle tissues. We next identified aging-related enhancer alterations and found them associated with the up-regulation of ECM genes. Furthermore, comparison of transcriptomes in young and aged SCs demonstrated that an age-related fibrogenic conversion of SCs. In mice, treatment of aging muscles with JQ1, an inhibitor of enhancer activation, reverted the ECM up-regulation and fibrogenic conversion of SCs, thus restored myogenic potential of SCs, suggesting that ECM increase in aging muscle is a result of enhancer activation and JQ1 can be a potential treatment approach for restoring SC function in aging muscle.

Link: https://doi.org/10.1111/acel.12996

Comments

Post a comment; thoughtful, considered opinions are valued. Comments incorporating ad hominem attacks, advertising, and other forms of inappropriate behavior are likely to be deleted.

Note that there is a comment feed for those who like to keep up with conversations.