Leiden University Medical Center, 2300RC Leiden, The Netherlands.
Murdoch Childrens Research Institute, The Royal Children's Hospital, Flemington Road, Parkville, Victoria 3052, Australia.
Stem Cell Reports. 2013 Dec 12;1(6):560-74. doi: 10.1016/j.stemcr.2013.11.008. eCollection 2013.
Diminished mitochondrial function is causally related to some heart diseases. Here, we developed a human disease model based on cardiomyocytes from human embryonic stem cells (hESCs), in which an important pathway of mitochondrial gene expression was inactivated. Repression of PGC-1α, which is normally induced during development of cardiomyocytes, decreased mitochondrial content and activity and decreased the capacity for coping with energetic stress. Yet, concurrently, reactive oxygen species (ROS) levels were lowered, and the amplitude of the action potential and the maximum amplitude of the calcium transient were in fact increased. Importantly, in control cardiomyocytes, lowering ROS levels emulated this beneficial effect of PGC-1α knockdown and similarly increased the calcium transient amplitude. Our results suggest that controlling ROS levels may be of key physiological importance for recapitulating mature cardiomyocyte phenotypes, and the combination of bioassays used in this study may have broad application in the analysis of cardiac physiology pertaining to disease.
线粒体功能减弱与一些心脏病有关。在这里，我们基于人胚胎干细胞（hESC）中的心肌细胞开发了一种人类疾病模型，其中一条重要的线粒体基因表达途径被失活。PGC-1α的抑制，在心肌细胞发育过程中通常会被诱导，会降低线粒体的含量和活性，并降低应对能量应激的能力。然而，同时，活性氧（ROS）水平降低，动作电位的幅度和钙瞬变的最大幅度实际上增加。重要的是，在对照心肌细胞中，降低 ROS 水平模拟了 PGC-1α 敲低的这种有益作用，并且同样增加了钙瞬变幅度。我们的研究结果表明，控制 ROS 水平对于再现成熟心肌细胞表型可能具有关键的生理意义，并且本研究中使用的生物测定组合可能具有广泛的应用前景，可用于分析与疾病相关的心脏生理学。
