Aberrant expression of the cardiac gap junction protein connexin-43 (Cx43) has been suggested as playing a role in the development of cardiac disease in the mdx mouse model of Duchenne muscular dystrophy (DMD); however, a mechanistic understanding of this association is lacking. Here, we identified a reduction of phosphorylation of Cx43 serines S325/S328/S330 in human and mouse DMD hearts. We hypothesized that hypophosphorylation of Cx43 serine-triplet triggers pathological Cx43 redistribution to the lateral sides of cardiomyocytes (remodeling). Therefore, we generated knockin mdx mice in which the Cx43 serine-triplet was replaced with either phospho-mimicking glutamic acids (mdxS3E) or nonphosphorylatable alanines (mdxS3A). The mdxS3E, but not mdxS3A, mice were resistant to Cx43 remodeling, with a corresponding reduction of Cx43 hemichannel activity. MdxS3E cardiomyocytes displayed improved intracellular Ca²⁺ signaling and a reduction of NADPH oxidase 2 (NOX2)/ROS production. Furthermore, mdxS3E mice were protected against inducible arrhythmias, related lethality, and the development of cardiomyopathy. Inhibition of microtubule polymerization by colchicine reduced both NOX2/ROS and oxidized CaMKII, increased S325/S328/S330 phosphorylation, and prevented Cx43 remodeling in mdx hearts. Together, these results demonstrate a mechanism of dystrophic Cx43 remodeling and suggest that targeting Cx43 may be a therapeutic strategy for preventing heart dysfunction and arrhythmias in DMD patients.

中文翻译：

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预防 connexin-43 重塑可预防杜氏肌营养不良症心肌病。


心脏间隙连接蛋白 connexin-43 (Cx43) 的异常表达被认为在杜氏肌营养不良 (DMD) mdx 小鼠模型中的心脏病发展中发挥作用；然而，缺乏对这种关联的机械理解。在这里，我们发现人和小鼠 DMD 心脏中 Cx43 丝氨酸 S325/S328/S330 的磷酸化减少。我们假设 Cx43 丝氨酸三联体的低磷酸化会触发病理性 Cx43 重新分布到心肌细胞的侧面（重塑）。因此，我们生成了敲入 mdx 小鼠，其中 Cx43 丝氨酸三联体被磷酸模拟谷氨酸 (mdxS3E) 或不可磷酸化丙氨酸 (mdxS3A) 取代。 mdxS3E（而非 mdxS3A）小鼠对 Cx43 重塑具有抵抗力，Cx43 半通道活性相应降低。 MdxS3E 心肌细胞表现出细胞内 Ca ²⁺信号传导改善和 NADPH 氧化酶 2 (NOX2)/ROS 产生减少。此外，mdxS3E 小鼠可以免受诱导性心律失常、相关致死和心肌病的发展。秋水仙碱抑制微管聚合可减少 NOX2/ROS 和氧化的 CaMKII，增加 S325/S328/S330 磷酸化，并防止 mdx 心脏中的 Cx43 重塑。总之，这些结果证明了营养不良性 Cx43 重塑的机制，并表明靶向 Cx43 可能是预防 DMD 患者心功能障碍和心律失常的治疗策略。