Aging provokes both morphological and functional changes in cells, which are accompanied by a fundamental shift in gene expression patterns. One of the characteristic alterations associated with senescence in fibroblast cells is the down-regulation of collagen type I genes. In the present study, we investigated the contribution of myocardin-related transcription factor A, or MRTF-A, in this process. In mouse embryonic fibroblast (MEF) cells and human foreskin fibroblast (HFF) cells, senescence, induced by either progressive passage or treatment with hydrogen peroxide (H2O2), led to augmented lysine acetylation of MRTF-A paralleling down-regulation of collagen type I and SIRT1, a lysine deacetylase. SIRT1 interacted with MRTF-A to promote MRTF-A deacetylation. SIRT1 over-expression or activation by selective agonists enhanced trans-activation of the collagen promoters by MRTF-A. On the contrary, SIRT1 depletion or inhibition by specific antagonists suppressed trans-activation of the collagen promoters by MRTF-A. Likewise, mutation of four lysine residues within MRTF-A rendered it more potent in terms of activating the collagen promoters but unresponsive to SIRT1. Importantly, SIRT1 activation in senescent fibroblasts mitigated repression of collagen type I expression whereas SIRT1 inhibition promoted the loss of collagen type I expression prematurely in young fibroblasts. Mechanistically, SIRT1 enhanced the affinity of MRTF-A for the collagen type I promoters. In conclusion, our data unveil a novel mechanism that underscores aging-associated loss of collagen type I in fibroblasts via SIRT1-mediated post-translational modification of MRTF-A.

中文翻译：

---

SIRT1对MRTF-A的脱乙酰作用阻止了成纤维细胞中衰老诱导的I型胶原的下调。

衰老引起细胞的形态和功能改变，伴随着基因表达模式的根本转变。与成纤维细胞衰老相关的特征性变化之一是I型胶原基因的下调。在本研究中，我们调查了心肌蛋白相关转录因子A或MRTF-A在此过程中的贡献。在小鼠胚胎成纤维细胞（MEF）和人包皮成纤维细胞（HFF）细胞中，通过逐步传代或用过氧化氢（H2O2）处理诱导衰老，导致MRTF-A的赖氨酸乙酰化增强，并同时下调了I型胶原。 SIRT1是赖氨酸脱乙酰基酶。SIRT1与MRTF-A相互作用以促进MRTF-A脱乙酰化。SIRT1的过表达或选择性激动剂的激活增强了MRTF-A对胶原蛋白启动子的反式激活。相反，SIRT1的消耗或特定拮抗剂的抑制抑制了MRTF-A对胶原蛋白启动子的反式激活。同样，MRTF-A中四个赖氨酸残基的突变使其在激活胶原蛋白启动子方面更有效，但对SIRT1无反应。重要的是，衰老的成纤维细胞中SIRT1的激活减轻了I型胶原蛋白表达的抑制，而SIRT1的抑制则促进了年轻成纤维细胞中I型胶原蛋白表达的丧失。从机制上讲，SIRT1增强了MRTF-A对I型胶原启动子的亲和力。结论，