Myotonic Dystronhy type 1 cells display impaired metabolism and mitochondrial dysfunction that are reversed by metformin
Myotonic Dystronhy type 1 cells display impaired metabolism and mitochondrial dysfunction that are reversed by metformin
复制标题
肌强直性1型细胞表现出代谢受损和线粒体功能障碍，二甲双胍可逆转
DOI：
10.18632/aging.103022
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发表时间：
2020-04-15
期刊：
影响因子：
5.2
通讯作者：
Matheu, Ander
中科院分区：
文献类型：
--
作者：
Garcia-Puga, Mikel;Saenz-Antonanzas, Ander;Matheu, Ander
强直性肌营养不良 1 型（DM1；MIM #160900）是一种常染色体显性遗传疾病，临床特征为进行性肌肉无力和多系统变性。在 DM1 患者中观察到的广泛表型类似于多系统加速衰老过程的表现。然而，这些表型背后的分子机制仍然很大程度上未知。在这项研究中，我们描述了代谢和线粒体对 DM1 患者和健康个体的成纤维细胞和外周血单核细胞 (PBMC) 的影响。我们的结果显示氧化磷酸化系统 (OXPHOS) 活性、耗氧率 (OCR)、ATP 产生、能量代谢和线粒体均下降！ DM1 成纤维细胞的动态变化，以及活性氧 (ROS) 积累的增加。 DM1 患者的 PBMC 也显示线粒体减少！动力学和能量代谢。此外，二甲双胍治疗逆转了代谢和线粒体！ DM1 衍生的成纤维细胞中的缺陷以及其他加速老化表型，例如增殖受损。我们的结果发现细胞代谢和线粒体受损！功能障碍是 DM1 病理生理学的重要驱动因素，因此揭示了二甲双胍在临床前环境中治疗的功效。
Myotonic dystrophy type 1 (DM1; MIM #160900) is an autosomal dominant disorder, clinically characterized by progressive muscular weakness and multisystem degeneration. The broad phenotypes observed in patients with DM1 resemble the appearance of a multisystem accelerated aging process. However, the molecular mechanisms underlying these phenotypes remain largely unknown. In this study, we characterized the impact of metabolism and mitochondria on fibroblasts and peripheral blood mononuclear cells (PBMCs) derived from patients with DM1 and healthy individuals. Our results revealed a decrease in oxidative phosphorylation system (OXPHOS) activity, oxygen consumption rate (OCR), ATP production, energy metabolism, and mitochondria! dynamics in DM1 fibroblasts, as well as increased accumulation of reactive oxygen species (ROS). PBMCs of DM1 patients also displayed reduced mitochondria! dynamics and energy metabolism. Moreover, treatment with metformin reversed the metabolic and mitochondria! defects as well as additional accelerated aging phenotypes, such as impaired proliferation, in DM1-derived fibroblasts. Our results identify impaired cell metabolism and mitochondria! dysfunction as important drivers of DM1 pathophysiology and, therefore, reveal the efficacy of metformin treatment in a pre-clinical setting.