Targeting mitochondrial quality control with melatonin has been found promising for attenuating diabetic cardiomyopathy (DCM), although the underlying mechanisms remain largely undefined. Activation of SIRT6 and melatonin membrane receptors exerts cardioprotective effects while little is known about their roles during DCM. Using high‐fat diet‐streptozotocin‐induced diabetic rat model, we found that prolonged diabetes significantly decreased nocturnal circulatory melatonin and heart melatonin levels, reduced the expressions of cardiac melatonin membrane receptors, and decreased myocardial SIRT6 and AMPK‐PGC‐1α‐AKT signaling. 16 weeks of melatonin treatment inhibited the progression of DCM and the following myocardial ischemia‐reperfusion (MI/R) injury by reducing mitochondrial fission, enhancing mitochondrial biogenesis and mitophagy via re‐activating SIRT6 and AMPK‐PGC‐1α‐AKT signaling. After the induction of diabetes, adeno‐associated virus carrying SIRT6‐specific small hairpin RNA or luzindole was delivered to the animals. We showed that SIRT6 knockdown or antagonizing melatonin receptors abolished the protective effects of melatonin against mitochondrial dysfunction as evidenced by aggravated mitochondrial fission and reduced mitochondrial biogenesis and mitophagy. Additionally, SIRT6 shRNA or luzindole inhibited melatonin‐induced AMPK‐PGC‐1α‐AKT activation as well as its cardioprotective actions. Collectively, we demonstrated that long‐term melatonin treatment attenuated the progression of DCM and reduced myocardial vulnerability to MI/R injury through preserving mitochondrial quality control. Melatonin membrane receptor‐mediated SIRT6‐AMPK‐PGC‐1α‐AKT axis played a key role in this process. Targeting SIRT6 with melatonin treatment may be a promising strategy for attenuating DCM and reducing myocardial vulnerability to ischemia‐reperfusion injury in diabetic patients.

中文翻译：

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褪黑激素通过改善线粒体质量控制减轻糖尿病心肌病并降低心肌对缺血再灌注损伤的易感性：SIRT6 的作用

已发现用褪黑激素靶向线粒体质量控制有望减轻糖尿病性心肌病 (DCM)，尽管其潜在机制仍未明确。SIRT6 和褪黑激素膜受体的激活发挥了心脏保护作用，而对它们在 DCM 中的作用知之甚少。使用高脂饮食-链脲佐菌素诱导的糖尿病大鼠模型，我们发现长期糖尿病显着降低夜间循环褪黑激素和心脏褪黑激素水平，降低心脏褪黑激素膜受体的表达，降低心肌 SIRT6 和 AMPK-PGC-1α-AKT 信号. 褪黑激素治疗 16 周通过减少线粒体裂变来抑制 DCM 和随后的心肌缺血再灌注 (MI/R) 损伤的进展，通过重新激活 SIRT6 和 AMPK-PGC-1α-AKT 信号增强线粒体生物发生和线粒体自噬。诱导糖尿病后，携带SIRT6特异性小发夹RNA或luzindole的腺相关病毒被传递给动物。我们表明，SIRT6 敲低或拮抗褪黑激素受体消除了褪黑激素对线粒体功能障碍的保护作用，如线粒体裂变加重和线粒体生物发生和线粒体自噬减少所证明的。此外，SIRT6 shRNA 或卢津多尔抑制褪黑激素诱导的 AMPK-PGC-1α-AKT 激活及其心脏保护作用。总的来说，我们证明长期褪黑激素治疗通过保持线粒体质量控制来减缓 DCM 的进展并降低心肌对 MI/R 损伤的易感性。褪黑激素膜受体介导的 SIRT6-AMPK-PGC-1α-AKT 轴在这一过程中发挥了关键作用。用褪黑激素治疗靶向 SIRT6 可能是减轻糖尿病患者 DCM 和降低心肌易受缺血再灌注损伤的有希望的策略。