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Abstract：
Dystrophin-deficiency causes cardiomyopathies and shortens the life expectancy of Duchenne and Becker muscular dystrophy patients. Restoring Dystrophin expression in the heart by gene transfer is a promising avenue to explore as a therapy. Truncated Dystrophin gene constructs have been engineered and shown to alleviate dystrophic skeletal muscle disease, but their potential in preventing the development of cardiomyopathy is not fully understood. In the present study, we found that either the mechanical or the signaling functions of Dystrophin were able to reduce the dilated heart phenotype of Dystrophin mutants in a Drosophila model. Our data suggest that Dystrophin retains some function in fly cardiomyocytes in the absence of a predicted mechanical link to the cytoskeleton. Interestingly, cardiac-specific manipulation of nitric oxide synthase expression also modulates cardiac function, which can in part be reversed by loss of Dystrophin function, further implying a signaling role of Dystrophin in the heart. These findings suggest that the signaling functions of Dystrophin protein are able to ameliorate the dilated cardiomyopathy, and thus might help to improve heart muscle function in micro-Dystrophin-based gene therapy approaches.
摘要：
肌营养不良蛋白缺乏会导致心肌病并缩短Duchenne和Becker肌营养不良患者的预期寿命。通过基因转移恢复心脏中的肌营养不良蛋白表达是探索作为疗法的有希望的途径。截短的肌营养不良蛋白基因构建体已经被改造并显示出缓解营养不良性骨骼肌疾病，但是它们在预防心肌病发展方面的潜力尚未完全了解。在本研究中,我们发现，在果蝇模型中，肌营养不良蛋白的机械或信号功能能够降低肌营养不良蛋白突变体的扩张心脏表型。我们的数据表明，在没有与细胞骨架的预测机械联系的情况下，肌营养不良蛋白在飞心肌细胞中保留了一些功能。有趣的是,一氧化氮合酶表达的心脏特异性操纵也调节心脏功能，部分可以通过肌营养不良蛋白功能的丧失而逆转，进一步暗示肌营养不良蛋白在心脏中的信号传导作用。这些发现表明，肌营养不良蛋白的信号功能能够改善扩张型心肌病，因此，可能有助于改善基于微肌养蛋白的基因治疗方法中的心肌功能。
