心肌病是一种逐渐进展的心肌疾病，导致收缩功能受损。已知基因毒性癌症治疗是心肌病的强大推动因素，而自发性疾病的原因尚不清楚。为了验证内源性基因毒性应激对心肌病的贡献假说，我们使用Ercc1的floxed等位基因和在肌肉特异性肌酸激酶（Ckmm）启动子控制下表达Cre的小鼠，在条纹肌细胞中特异性地删除了DNA修复基因Ercc1，或相对全身进行了耗竭（Ercc1-/D小鼠）。Ckmm-Cre+/-; Ercc1-/fl小鼠在7个月的时候因心脏疾病突然死亡。作为年轻成年人，Ckmm-Cre+/-; Ercc1-/fl小鼠的心脏结构和功能正常，但到了6个月的时候，出现了明显的室壁扩大、壁厚变薄、间质纤维化和收缩功能障碍迹象，表明患有扩张型心肌病。组织特异性或系统模型中的心脏组织显示出增加的细胞凋亡，Ckmm-Cre+/-; Ercc1-/fl小鼠的心肌对基因毒素过敏，导致凋亡。Ckmm-Cre+/-; Ercc1-/fl和Ercc1-/D小鼠的心脏组织中的p53水平和靶基因表达，包括多种抗氧化剂都有所增加。尽管如此，年长突变小鼠的心脏组织显示出增加的氧化应激迹象。遗传或药物抑制p53可减轻凋亡并改善疾病指标。类似地，过表达线粒体定向的过氧化氢酶可以改善疾病指标。总之，这些数据支持结论：内源性产生的DNA损伤可驱动心脏疾病，并通过慢性激活p53和增加氧化应激，驱动心肌细胞凋亡、扩张型心肌病和猝死。© 2023 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.

Cardiomyopathy is a progressive disease of the myocardium leading to impaired contractility. Genotoxic cancer therapies are known to be potent drivers of cardiomyopathy, whereas causes of spontaneous disease remain unclear. To test the hypothesis that endogenous genotoxic stress contributes to cardiomyopathy, we deleted the DNA repair gene Ercc1 specifically in striated muscle using a floxed allele of Ercc1 and mice expressing Cre under control of the muscle-specific creatinine kinase (Ckmm) promoter or depleted systemically (Ercc1-/D mice). Ckmm-Cre+/- ;Ercc1-/fl mice expired suddenly of heart disease by 7 months of age. As young adults, the hearts of Ckmm-Cre+/- ;Ercc1-/fl mice were structurally and functionally normal, but by 6-months-of-age, there was significant ventricular dilation, wall thinning, interstitial fibrosis, and systolic dysfunction indicative of dilated cardiomyopathy. Cardiac tissue from the tissue-specific or systemic model showed increased apoptosis and cardiac myocytes from Ckmm-Cre+/- ;Ercc1-/fl mice were hypersensitive to genotoxins, resulting in apoptosis. p53 levels and target gene expression, including several antioxidants, were increased in cardiac tissue from Ckmm-Cre+/- ;Ercc1-/fl and Ercc1-/D mice. Despite this, cardiac tissue from older mutant mice showed evidence of increased oxidative stress. Genetic or pharmacologic inhibition of p53 attenuated apoptosis and improved disease markers. Similarly, overexpression of mitochondrial-targeted catalase improved disease markers. Together, these data support the conclusion that DNA damage produced endogenously can drive cardiac disease and does so mechanistically via chronic activation of p53 and increased oxidative stress, driving cardiac myocyte apoptosis, dilated cardiomyopathy, and sudden death.© 2023 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.