Defining the molecular mechanisms underlying cardiac resilience is crucial to find effective approaches to protect the heart. A physiologic level of ROS is produced in the heart by fatty acid oxidation, but stressful events can boost ROS and cause mitochondrial dysfunction and cardiac functional impairment. Melusin is a muscle specific chaperone required for myocardial compensatory remodeling during stress. Here we report that Melusin localizes in mitochondria where it binds the mitochondrial trifunctional protein, a key enzyme in fatty acid oxidation, and decreases it activity. Studying both mice and human induced pluripotent stem cell-derived cardiomyocytes, we found that Melusin reduces lipid oxidation in the myocardium and limits ROS generation in steady state and during pressure overload and doxorubicin treatment, preventing mitochondrial dysfunction. Accordingly, the treatment with the lipid oxidation inhibitor Trimetazidine concomitantly with stressful stimuli limits ROS accumulation and prevents long-term heart dysfunction. These findings disclose a physiologic mechanism of metabolic regulation in the heart and demonstrate that a timely restriction of lipid metabolism represents a potential therapeutic strategy to improve cardiac resilience to stress.

中文翻译：

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代谢调整的内在机制可促进心脏对压力的恢复力。


定义心脏弹性的分子机制对于找到保护心脏的有效方法至关重要。生理水平的 ROS 是通过脂肪酸氧化在心脏中产生的，但压力事件会提高 ROS 并导致线粒体功能障碍和心脏功能障碍。Melusin 是压力期间心肌代偿重塑所需的肌肉特异性伴侣。在这里，我们报道了 Melusin 定位于线粒体中，在那里它结合线粒体三功能蛋白（脂肪酸氧化的关键酶）并降低其活性。通过研究小鼠和人诱导的多能干细胞衍生的心肌细胞，我们发现 Melusin 可减少心肌中的脂质氧化，并限制稳态下以及压力超负荷和阿霉素治疗期间 ROS 的产生，从而防止线粒体功能障碍。因此，脂质氧化抑制剂曲美他嗪治疗与压力刺激同时治疗可限制 ROS 积累并防止长期心功能障碍。这些发现揭示了心脏代谢调节的生理机制，并表明及时限制脂质代谢代表了提高心脏对压力的适应能力的潜在治疗策略。