Myosin is vital for body movement and heart contractility. Mutations in MYH7, encoding slow/ß-cardiac myosin heavy chain, are an important cause of hypertrophic and dilated cardiomyopathy, as well as skeletal muscle disease. A dominant missense mutation (R1845W) in MYH7 has been reported in several unrelated cases with myosin storage myopathy. We have developed a Drosophila model for a myosin storage myopathy in order to investigate the dose-dependent mechanisms underlying the pathological roles of R1845W mutation. This study shows that higher expression level of the mutated allele is concomitant with severe impairment of muscle function and progressively disrupted muscle morphology. The impaired muscle morphology associated with the mutant allele was supressed by expression of Abba/Thin, an E3 ubiquitin ligase.This Drosophila model recapitulates pathological features seen in myopathy patients with the R1845W mutation and severe ultrastructural abnormalities including extensive loss of thick filaments with selective A-band loss and preservation of I-band and Z-disks were observed in indirect flight muscles of flies with exclusive expression of mutant myosin. Further, the impaired muscle morphology associated with the mutant allele was supressed by expression of Abba/Thin, an E3 ubiquitin ligase. These findings suggest that modification of ubiquitin proteasome system may be beneficial in myosin storage myopathy by reducing the impact of MYH7 mutation in patients.

中文翻译：

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E3 泛素连接酶的过度表达可抑制肌球蛋白贮积性肌病果蝇模型中肌肉形态的受损。

肌球蛋白对于身体运动和心脏收缩力至关重要。编码慢/β-心肌肌球蛋白重链的MYH7突变是肥厚型和扩张型心肌病以及骨骼肌疾病的重要原因。MYH7中的显性错义突变 (R1845W)在几例与肌球蛋白储存性肌病无关的病例中已有报道。我们开发了肌球蛋白贮积性肌病的果蝇模型，以研究 R1845W 突变病理作用背后的剂量依赖性机制。这项研究表明，突变等位基因的较高表达水平伴随着肌肉功能的严重受损和肌肉形态的逐渐破坏。与突变等位基因相关的受损肌肉形态被 Abba/Thin（一种 E3 泛素连接酶）的表达所抑制。该果蝇模型概括了 R1845W 突变肌病患者的病理特征和严重的超微结构异常，包括选择性 A 粗肌丝的广泛损失在仅表达突变肌球蛋白的果蝇间接飞行肌肉中观察到 I 带和 Z 盘的带丢失和保留。此外，与突变等位基因相关的受损肌肉形态受到 Abba/Thin（一种 E3 泛素连接酶）的表达的抑制。这些发现表明，泛素蛋白酶体系统的修饰可能通过减少患者MYH7突变的影响而有益于肌球蛋白贮积性肌病。