Journal article
PGC-1α and reactive oxygen species regulate human embryonic stem cell-derived cardiomyocyte function
MJ Birket, S Casini, G Kosmidis, DA Elliott, AA Gerencser, A Baartscheer, C Schumacher, PG Mastroberardino, AG Elefanty, EG Stanley, CL Mummery
Stem Cell Reports | Published : 2013
Open access
Abstract
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 leve..
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Awarded by Seventh Framework Programme
Funding Acknowledgements
We thank Richard Davis, Stefan Braam, and Dorien Ward for advice and protocols for the spin EB differentiation method, and for discussions about the data. We also thank Arie Verkerk for help with manuscript preparation, and David Hood (York University, Ontario, Canada) for the PGC-1 alpha promoter plasmid. This research was support by grants from the Human Frontiers Research Program (M. B.), European Research Council (ERC 323182 to C. M.), ZonMW Animal Alternatives (114000101 to S. C.), Netherlands Institute of Regenerative Medicine (M. B.), Rembrandt Institute of Cardiovascular Science (C. M. and G. K.), Netherlands Genomics Initiative (NGI/NWO 05040202 to P. M.), and Marie Curie IRG 247918 (to P. M.). The Seahorse Extracellular Flux Analyzer was purchased with the generous contribution of Dorpmans-Wigmans Stichting. C. L. M. is a cofounder and consultant of Pluriomics bv.