Viral myocarditis has been found to be one of the leading causes of sudden death in young adults. However, no effective drugs have been developed to intervene the progression of myocarditis. Accordingly, the present study is carried out to explore the protective role played by melatonin in the setting of viral myocarditis with a focus on Mst1-Hippo pathway, mitochondrial dysfunction and ER stress. Cardiac function was determined via echocardiographic examination. Mitochondrial function and ER stress were detected via ELISA, western blots, and immunofluorescence. Our data demonstrated that virus injection induced cardiac dysfunction as evidenced by reduced contractile function in myocardium. Besides, LDH release assay and western blotting analysis demonstrated that cardiomyocyte death was activated by virus injection. Interestingly, melatonin treatment improved cardiac function and repressed virus-mediated cardiomyocyte apoptosis. At the molecular levels, mitochondrial dysfunction was induced by virus infection, as indicated by mitochondrial membrane potential reduction, mPTP opening rate elevation and caspase-9-related apoptosis activation. Besides, ER stress parameters were also elevated in virus-treated cardiomyocytes. Interestingly, melatonin treatment maintained mitochondrial dysfunction and repressed ER stress. To the end, we found that Mst1 was upregulated by virus infection; this effect was attenuated through supplementation with melatonin. However, Mst1 overexpression reduced the beneficial impact exerted by melatonin on cardiomyocyte viability, mitochondrial function and ER homeostasis. Our study illustrated that melatonin treatment attenuated viral myocarditis via sustaining cardiomyocyte viability, repressing mitochondrial dysfunction and inhibiting ER stress in a manner dependent on Mst1 inhibition.

中文翻译：

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褪黑激素对Mst1的抑制作用通过减轻ER应激和线粒体功能障碍来改善心肌炎。

已发现病毒性心肌炎是年轻人突然死亡的主要原因之一。然而，尚未开发出有效的药物来干预心肌炎的进展。因此，本研究旨在探讨褪黑激素在病毒性心肌炎中的保护作用，重点是Mst1-Hippo途径，线粒体功能障碍和ER应激。通过超声心动图检查确定心脏功能。通过ELISA，蛋白质印迹和免疫荧光检测线粒体功能和内质网应激。我们的数据表明，病毒注射可引起心脏功能障碍，如心肌收缩功能下降所证明。此外，LDH释放测定和蛋白质印迹分析表明，病毒注射可激活心肌细胞死亡。有趣的是 褪黑素治疗可改善心脏功能并抑制病毒介导的心肌细胞凋亡。在分子水平上，病毒感染可引起线粒体功能障碍，如线粒体膜电位降低，mPTP开启率升高和caspase-9相关的细胞凋亡激活所表明。此外，在病毒处理过的心肌细胞中，ER应激参数也升高。有趣的是，褪黑激素治疗可维持线粒体功能障碍并抑制内质网应激。最终，我们发现Mst1被病毒感染上调；通过补充褪黑激素可减弱这种作用。但是，Mst1过表达减少了褪黑激素对心肌细胞活力，线粒体功能和ER稳态的有益影响。