PGC-1α and reactive oxygen species regulate human embryonic stem cell-derived cardiomyocyte function

Matthew J Birket, Simona Casini, Georgios Kosmidis, David A Elliott, Akos A Gerencser, Antonius Baartscheer, Cees Schumacher, Pier G Mastroberardino, Andrew G Elefanty, Ed G Stanley, Christine L Mummery

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)560-74
Number of pages15
JournalStem Cell Reports
Volume1
Issue number6
DOIs
Publication statusPublished - 2013

Keywords

  • Adrenergic beta-Agonists/pharmacology
  • Calcium
  • Cell Differentiation
  • Embryonic Stem Cells/cytology
  • Energy Metabolism
  • Gene Expression Regulation
  • Gene Knockdown Techniques
  • Humans
  • Mitochondria/metabolism
  • Myocytes, Cardiac/cytology
  • Oxidative Stress/genetics
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Reactive Oxygen Species/metabolism
  • Sarcomeres/drug effects
  • Superoxides/metabolism
  • Transcription Factors/genetics

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