Methamphetamine-associated cardiomyopathy is the leading cause of death linked with illicit drug use. Here we show that Sigmar1 is a therapeutic target for methamphetamine-associated cardiomyopathy and defined the molecular mechanisms using autopsy samples of human hearts, and a mouse model of “binge and crash” methamphetamine administration. Sigmar1 expression is significantly decreased in the hearts of human methamphetamine users and those of “binge and crash” methamphetamine-treated mice. The hearts of methamphetamine users also show signs of cardiomyopathy, including cellular injury, fibrosis, and enlargement of the heart. In addition, mice expose to “binge and crash” methamphetamine develop cardiac hypertrophy, fibrotic remodeling, and mitochondrial dysfunction leading to contractile dysfunction. Methamphetamine treatment inhibits Sigmar1, resulting in inactivation of the cAMP response element-binding protein (CREB), decreased expression of mitochondrial fission 1 protein (FIS1), and ultimately alteration of mitochondrial dynamics and function. Therefore, Sigmar1 is a viable therapeutic agent for protection against methamphetamine-associated cardiomyopathy.

甲基苯丙胺相关心肌病是与非法药物使用相关的死亡的主要原因。在这里，我们证明 Sigmar1 是甲基苯丙胺相关心肌病的治疗靶点，并使用人类心脏尸检样本和“暴食和崩溃”甲基苯丙胺给药的小鼠模型定义了分子机制。人类甲基苯丙胺使用者和“暴饮暴食”甲基苯丙胺治疗小鼠的心脏中 Sigmar1 表达显着降低。甲基苯丙胺使用者的心脏也会出现心肌病的迹象，包括细胞损伤、纤维化和心脏扩大。此外，暴露于“暴饮暴食”甲基苯丙胺的小鼠会出现心脏肥大、纤维化重塑和线粒体功能障碍，从而导致收缩功能障碍。甲基苯丙胺治疗会抑制 Sigmar1，导致 cAMP 反应元件结合蛋白 (CREB) 失活，线粒体裂变 1 蛋白 (FIS1) 表达减少，并最终改变线粒体动力学和功能。因此，Sigmar1 是一种可行的治疗药物，可预防甲基苯丙胺相关的心肌病。