AIM Imbalanced mitochondrial dynamic including suppressed mitochondrial fusion has been observed in diabetic hearts. However, it is still unknown whether mitochondrial fusion promoter is an effective protection to diabetic hearts. This study was designed to explore the efficacy of mitochondrial fusion promoter on diabetic cardiomyopathy (DCM). METHODS Male Sprague-Dawley rats were injected with streptozotocin (STZ, 65 mg/kg/d) intraperitoneally to induce diabetes. Seven weeks after vehicle or STZ injection, control or diabetic rats were treated with the vehicle or a mitochondrial fusion promoter-M1 (2 mg/kg/d) intraperitoneally for 6 weeks. Moreover, M1 was administrated to the primary cardiomyocytes cultured in normal glucose medium (NG, 5.5 mmol/L) or high glucose (HG, 33 mnol/L). RESULTS Administration of M1 significantly promoted mitochondrial fusion and attenuated the reduction in optic atrophy 1 (Opa1) expression in diabetic hearts. Importantly, M1 treatment attenuated oxidative stress, improved mitochondrial function and alleviated DCM in diabetic rats. In HG-treated cardiomyocytes, M1 treatment consistently increased the expression of Opa1, promoted mitochondrial fusion, enhanced mitochondrial respiratory capacity and reduced mitochondria-derived superoxide production, all of which were blunted by Opa1 siRNA knockdown. In addition, selective upregulation of Opa1 alone can also promote mitochondrial fusion, improve mitochondrial function and inhibited mitochondria-derived superoxide production in HG-cultured cardiomyocytes. CONCLUSION Our findings show for the first time that mitochondrial fusion promoter M1 effectively balances mitochondrial dynamics and protects against diabetic cardiomyopathy (DCM) via an Opa1-dependent way, suggesting that promoting mitochondrial fusion might be a potential therapeutic strategy for DCM.

中文翻译：

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线粒体融合启动子以视神经萎缩1依赖性方式恢复线粒体动力学平衡并改善糖尿病性心肌病。

目的在糖尿病心脏中观察到线粒体动力学失衡，包括线粒体融合受到抑制。然而，线粒体融合启动子是否是对糖尿病心脏的有效保护仍是未知的。这项研究旨在探讨线粒体融合启动子对糖尿病性心肌病（DCM）的疗效。方法雄性Sprague-Dawley大鼠腹膜内注射链脲佐菌素（STZ，65 mg / kg / d）以诱发糖尿病。注射媒介物或STZ后7周，腹膜内用媒介物或线粒体融合促进剂M1（2 mg / kg / d）治疗对照组或糖尿病大鼠，持续6周。此外，将M1给予在正常葡萄糖培养基（NG，5.5mmol / L）或高葡萄糖（HG，33 mol / L）中培养的原代心肌细胞。结果在糖尿病心脏中，M1的使用显着促进了线粒体融合并减弱了视神经萎缩1（Opa1）表达的降低。重要的是，M1处理可减轻糖尿病大鼠的氧化应激，改善线粒体功能并减轻DCM。在HG处理过的心肌细胞中，M1处理持续增加Opa1的表达，促进线粒体融合，增强线粒体呼吸能力并降低线粒体衍生的超氧化物的产生，所有这些都因Opa1 siRNA敲低而减弱。此外，单独的Opa1选择性上调还可以促进HG培养的心肌细胞中的线粒体融合，改善线粒体功能并抑制线粒体来源的超氧化物的产生。