Background A reduction in both dystrophin and neuronal nitric oxide synthase (NOS1) secondary to microRNA-31 (miR-31) upregulation contributes to the atrial electrical remodelling that underpins human and experimental atrial fibrillation (AF). By contrast, patients with Duchenne Muscular Dystrophy (DMD), who lack dystrophin and NOS1 and, at least in the skeletal muscle, have raised miR-31 expression, do not have increase susceptibility to AF in the absence of left ventricular (LV) dysfunction. Here we investigated whether dystrophin-deficiency is also associated with atrial upregulation of miR-31, loss of NOS1 protein, and increased AF susceptibility in young mdx mice. Methods and Results Echocardiography showed normal cardiac structure and function in 12- 13 weeks mdx mice, with no indication by assay of hydroxyproline that atrial fibrosis had developed. Absence of dystrophin in mdx mice was accompanied by an overall reduction in syntrophin and a lower NOS1 protein content in the skeletal muscle and in the left atrial and ventricular myocardium, with the latter occurring alongside reduced Nos1 transcript levels (exons 1-2 by qPCR) and an increase in NOS1-polyubiquitination (assessed using tandem polyubiquitination pulldowns; P<0.05 vs. WT). Neither the upregulation of miR-31 nor the substantial reduction in NOS activity observed in the skeletal muscle was present in the atrial tissue of mdx mice. At difference with the skeletal muscle, the mdx atrial myocardium showed a reduction in the constitutive NOS inhibitor, caveolin-1, coupled with an increase in NOS3 serine1177 phosphorylation, in the absence of differences in the protein content of other NOS isoforms or in the relative expression NOS1 splice variants. In line with these findings, transoesophageal atrial burst pacing revealed no difference in AF susceptibility between mdx mice and their wild type littermates. Conclusions Dystrophin depletion is not associated with atrial miR-31 upregulation, reduced NOS activity or increased AF susceptibility in the mdx mouse. Compared with the skeletal muscle, the milder atrial biochemical phenotype may explain why patients with DMD do not exhibit a higher prevalence of atrial arrhythmias despite a reduction in NOS1 content.

中文翻译：

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为什么杜氏肌营养不良症患者早发性房颤不常见？mdx 鼠标的见解

背景 microRNA-31 (miR-31) 上调继发的肌营养不良蛋白和神经元一氧化氮合酶 (NOS1) 减少有助于心房电重塑，而心房电重塑是人类和实验性心房颤动 (AF) 的基础。相比之下，杜氏肌营养不良症 (DMD) 患者缺乏肌营养不良蛋白和 NOS1，并且至少在骨骼肌中 miR-31 表达升高，在没有左心室 (LV) 功能障碍的情况下，房颤的易感性不会增加。在这里，我们研究了抗肌营养不良蛋白缺乏是否也与年轻 mdx 小鼠心房上调 miR-31、NOS1 蛋白缺失和 AF 易感性增加有关。方法和结果超声心动图显示 12-13 周 mdx 小鼠的心脏结构和功能正常，羟脯氨酸测定未表明心房纤维化已发生。mdx 小鼠中肌营养不良蛋白的缺失伴随着肌营养不良蛋白的整体减少以及骨骼肌、左心房和心室心肌中 NOS1 蛋白含量的降低，后者伴随着 Nos1 转录水平的降低（通过 qPCR 检测，外显子 1-2）以及NOS1-多聚泛素化的增加(使用串联多聚泛素化下拉评估；与WT相比，P＜0.05)。mdx 小鼠的心房组织中既不存在 miR-31 的上调，也不存在骨骼肌中观察到的 NOS 活性的大幅降​​低。与骨骼肌不同，mdx 心房心肌显示组成型 NOS 抑制剂 Caveolin-1 减少，同时 NOS3 丝氨酸 1177 磷酸化增加，而其他 NOS 亚型或相对蛋白含量没有差异。表达 NOS1 剪接变体。与这些发现一致，经食管心房突发起搏显示 mdx 小鼠与其野生型同窝小鼠之间的 AF 易感性没有差异。结论 mdx 小鼠抗肌营养不良蛋白耗竭与心房 miR-31 上调、NOS 活性降低或 AF 易感性增加无关。与骨骼肌相比，较温和的心房生化表型可以解释为什么 DMD 患者尽管 NOS1 含量减少，但房性心律失常的患病率并未升高。