title: PGC-1α and reactive oxygen species regulate human embryonic stem cell-derived cardiomyocyte function.
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 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.
authors.affiliation: Leiden University Medical Center, 2300RC Leiden, The Netherlands.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Birket
authors.affiliation: Leiden University Medical Center, 2300RC Leiden, The Netherlands.
authors.forename: Simona
authors.initials: S
authors.lastname: Casini
authors.affiliation: Leiden University Medical Center, 2300RC Leiden, The Netherlands.
authors.forename: Georgios
authors.initials: G
authors.lastname: Kosmidis
authors.affiliation: Murdoch Childrens Research Institute, The Royal Children's Hospital, Flemington Road, Parkville, Victoria 3052, Australia.
authors.forename: David A
authors.initials: DA
authors.lastname: Elliott
authors.affiliation: Buck Institute for Research on Aging, Novato, CA 94945, USA.
authors.forename: Akos A
authors.initials: AA
authors.lastname: Gerencser
authors.affiliation: Amsterdam Medical Center, 1105AZ Amsterdam, The Netherlands.
authors.forename: Antonius
authors.initials: A
authors.lastname: Baartscheer
authors.affiliation: Amsterdam Medical Center, 1105AZ Amsterdam, The Netherlands.
authors.forename: Cees
authors.initials: C
authors.lastname: Schumacher
authors.affiliation: Erasmus Medical Center, 3015GE Rotterdam, The Netherlands.
authors.forename: Pier G
authors.initials: PG
authors.lastname: Mastroberardino
authors.affiliation: Murdoch Childrens Research Institute, The Royal Children's Hospital, Flemington Road, Parkville, Victoria 3052, Australia ; Monash Immunology and Stem Cell Laboratories, Monash University, Wellington Road, Clayton, Victoria 3800, Australia.
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Elefanty
authors.affiliation: Murdoch Childrens Research Institute, The Royal Children's Hospital, Flemington Road, Parkville, Victoria 3052, Australia ; Monash Immunology and Stem Cell Laboratories, Monash University, Wellington Road, Clayton, Victoria 3800, Australia.
authors.forename: Ed G
authors.initials: EG
authors.lastname: Stanley
authors.affiliation: Leiden University Medical Center, 2300RC Leiden, The Netherlands.
authors.forename: Christine L
authors.initials: CL
authors.lastname: Mummery
mesh_terms: D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D002118:Calcium; D002454:Cell Differentiation; D053595:Embryonic Stem Cells / Q000166:cytology* / Q000378:metabolism; D004734:Energy Metabolism; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D006801:Humans; D008928:Mitochondria / Q000378:metabolism / Q000502:physiology; D032383:Myocytes, Cardiac / Q000166:cytology / Q000502:physiology*; D018384:Oxidative Stress / Q000235:genetics; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D017382:Reactive Oxygen Species / Q000378:metabolism*; D012518:Sarcomeres / Q000187:drug effects / Q000648:ultrastructure; D013481:Superoxides / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
chemical_list: D000318:Adrenergic beta-Agonists; C486497:PPARGC1A protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D017382:Reactive Oxygen Species; D014157:Transcription Factors; D013481:Superoxides; D002118:Calcium