Abstract
Cardiogenesis within embryos or associated with heart repair requires stem cell differentiation into energetically competent, contracting cardiomyocytes. While it is widely accepted that the coordination of genetic circuits with developmental bioenergetics is critical to phenotype specification, the metabolic mechanisms that drive cardiac transformation are largely unknown. Here, we aim to define the energetic requirements for and the metabolic microenvironment needed to support the cardiac differentiation of embryonic stem cells. We demonstrate that anaerobic glycolytic metabolism, while sufficient for embryonic stem cell homeostasis, must be transformed into the more efficient mitochondrial oxidative metabolism to secure cardiac specification and excitation–contraction coupling. This energetic switch was programmed by rearrangement of the metabolic transcriptome that encodes components of glycolysis, fatty acid oxidation, the Krebs cycle, and the electron transport chain. Modifying the copy number of regulators of mitochondrial fusion and fission resulted in mitochondrial maturation and network expansion, which in turn provided an energetic continuum to supply nascent sarcomeres. Disrupting respiratory chain function prevented mitochondrial organization and compromised the energetic infrastructure, causing deficient sarcomerogenesis and contractile malfunction. Thus, establishment of the mitochondrial system and engagement of oxidative metabolism are prerequisites for the differentiation of stem cells into a functional cardiac phenotype. Mitochondria-dependent energetic circuits are thus critical regulators of de novo cardiogenesis and targets for heart regeneration.
Key Points
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While anaerobic metabolism is sufficient to sustain embryonic stem cell energetics, it must be transformed into mitochondria-mediated oxidative metabolism to secure cardiac specification
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Induction of cardiogenic pathways is linked to restructuring of the metabolic transcriptome and organization of the mitochondrial network
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Maturation and integration of mitochondria with the nascent electromechanical apparatus confer the functional competence required to develop a cardiac phenotype
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Disruption of respiratory chain function and prevention of mitochondrial network organization compromise the developing energetic infrastructure, causing deficient sarcomere formation, improper beating area assembly, and defective contractility
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As mandatory components of genomic reprogramming during cardiac differentiation, energetic circuits are metabolic regulators of cardiogenesis and targets for heart regeneration
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Acknowledgements
This work was supported by the National Institutes of Health (NIH), American Heart Association, Marriott Heart Disease Research Program, Marriott Foundation, Ted Nash Long Life Foundation, Ralph Wilson Medical Research Foundation, Asper Foundation, and the Mayo Clinic Clinician-Investigator Program.
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Chung, S., Dzeja, P., Faustino, R. et al. Mitochondrial oxidative metabolism is required for the cardiac differentiation of stem cells. Nat Rev Cardiol 4 (Suppl 1), S60–S67 (2007). https://doi.org/10.1038/ncpcardio0766
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DOI: https://doi.org/10.1038/ncpcardio0766
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