PGC-1α and Reactive Oxygen Species Regulate Human Embryonic Stem Cell-Derived Cardiomyocyte Function

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. [Display omitted] •PGC-1α regulates a mitochondrial biogenesis program in hESC-derived cardiomyocytes•The PGC-1α program can result in potentially detrimental increased ROS levels•Controlling ROS is essential for maximizing the calcium transient•PGC-1α deficiency is exposed by hypertrophic or beta-adrenergic stress/stimulation Mitochondrial function is critically important for the heart. In this study, Mummery and colleagues identify the gene PGC-1α as a key regulator of mitochondrial function in hESC-derived cardiomyocytes, controlling respiration and ROS production. Investigation of this phenotype exposed a trade-off between energetic capacity and oxidative stress. Controlling this balance may help improve PSC-derived cardiomyocyte function.