Elevated H3K27ac in aged skeletal muscle tissue drives a fibrogenic conversion of muscle satellite cells

A variety of epigenetic alterations impairs functions of cells and tissues during aging, but it is not known if epigenetic alterations are associated with aging muscle. Here, we examined the changes of a panel of histone marks and found H3K27ac (an active enhancer mark) is markedly increased during aging in human skeletal muscle tissues. Our integrated analysis showed that enhancer activation during muscle aging is associated with the up-regulation of extracelluar matrix (ECM) genes, which may result in stiffness of the niche environment of satellite cells (SCs). An age-related fibrogenic conversion of geriatric SCs was observed through differential gene expression analysis. In mice, treatment of aging muscles with JQ1, an inhibitor of enhancer activation reverted the ECM up-regulation and fibrogenic conversion of SCs, suggesting that ECM increase in aging muscle is indeed a result of enhancer activation. The study here not only uncovered a novel aspect of muscle aging that is associated with enhancer remodeling but also highlighted JQ1 as a potential treatment approach for restoring SC function in aging muscle.多种表观遗传改变（epigenetic alterations）会在衰老过程中损伤细胞与组织的功能，但目前尚不清楚表观遗传改变是否与衰老骨骼肌相关。本研究针对一组组蛋白修饰标记（histone marks）展开检测，发现人类骨骼肌组织在衰老进程中，H3K27ac，一种活性增强子标记（active enhancer mark），的水平显著升高。整合分析结果显示，骨骼肌衰老过程中的增强子激活与细胞外基质（extracellular matrix, ECM）基因的上调表达密切相关，这可能会导致肌卫星细胞（satellite cells, SCs）所处微环境的组织刚度提升。通过差异基因表达分析（differential gene expression analysis），我们观察到衰老肌卫星细胞出现了年龄相关性成纤维样转化。在小鼠模型中，使用增强子激活抑制剂（inhibitor of enhancer activation）JQ1处理衰老肌肉，可逆转细胞外基质基因的上调表达以及肌卫星细胞的成纤维样转化，这表明衰老肌肉中细胞外基质的增加确实由增强子激活所导致。本研究不仅揭示了与增强子重塑（enhancer remodeling）相关的骨骼肌衰老新机制，同时也指出JQ1可作为恢复衰老骨骼肌中肌卫星细胞功能的潜在治疗策略。

搜集汇总

背景与挑战

背景概述

该数据集通过ChIP-Seq技术分析小鼠骨骼肌衰老过程中的H3K27ac变化，发现H3K27ac增加导致增强子激活和细胞外基质基因上调，驱动卫星细胞向纤维化转化。研究还表明，JQ1抑制剂可逆转这一过程，为衰老肌肉功能恢复提供了潜在治疗策略。