Duchenne muscular dystrophy (DMD) is a devastating neuromuscular disease that causes progressive muscle wasting and cardiomyopathy. This X-linked disease results from mutations of the DMD allele on the X-chromosome resulting in the loss of expression of the protein dystrophin. Dystrophin loss causes cellular dysfunction that drives the loss of healthy skeletal muscle and cardiomyocytes. As gene therapy strategies strive toward dystrophin restoration through micro-dystrophin delivery or exon skipping, preclinical models have shown that incomplete restoration in the heart results in heterogeneous dystrophin expression throughout the myocardium. This outcome prompts the question of how much dystrophin restoration is sufficient to rescue the heart from DMD-related pathology. Female DMD carrier hearts can shed light on this question, due to their mosaic cardiac dystrophin expression resulting from random X-inactivation. In this work, a dystrophinopathy carrier mouse model was derived by breeding male or female dystrophin-null mdx mice with a wild type mate. We report that these carrier hearts are significantly susceptible to injury induced by one or multiple high doses of isoproterenol, despite expressing ~57% dystrophin. Importantly, only carrier mice with dystrophic mothers showed mortality after isoproterenol. These findings indicate that dystrophin restoration in approximately half of the heart still allows for marked vulnerability to injury. Additionally, the discovery of divergent stress-induced mortality based on parental origin in mice with equivalent dystrophin expression underscores the need for better understanding of the epigenetic, developmental, and even environmental factors that may modulate vulnerability in the dystrophic heart.

中文翻译：

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在心脏中具有镶嵌肌营养不良蛋白表达的DMD携带者模型揭示了对心肌损伤的复杂脆弱性。

杜兴氏肌营养不良症（DMD）是一种破坏性神经肌肉疾病，可引起进行性肌肉消瘦和心肌病。这种X连锁疾病是X染色体上DMD等位基因的突变导致蛋白质肌营养不良蛋白表达损失的结果。肌营养不良蛋白的丧失引起细胞功能障碍，从而导致健康的骨骼肌和心肌细胞丧失。随着基因治疗策略努力通过微肌营养不良蛋白递送或外显子跳跃来恢复肌营养不良蛋白，临床前模型表明，心脏中不完全恢复会导致整个心肌的异质肌营养不良蛋白表达。这一结果提示了肌营养不良蛋白的恢复量足以从DMD相关病理中拯救心脏的问题。女性DMD携带者的心可以阐明这个问题，由于它们的镶嵌性肌营养不良蛋白表达是由随机X灭活引起的。在这项工作中，通过与野生型伴侣繁殖雄性或雌性肌营养不良蛋白的mdx小鼠，获得了肌营养不良病携带者小鼠模型。我们报告说，尽管表达〜57％肌营养不良蛋白，这些携带者的心脏对一种或多种高剂量异丙肾上腺素诱导的损伤非常敏感。重要的是，只有患有营养不良母亲的携带者小鼠在异丙肾上腺素后表现出死亡率。这些发现表明，肌营养不良蛋白在大约一半的心脏中恢复仍然允许明显的易损性。此外，发现在具有相同肌营养不良蛋白表达的小鼠中，基于亲本来源的不同的应激诱发的死亡率，突显了对更好地了解表观遗传，发育，