title: Myocardial VHL-HIF Signaling Controls an Embryonic Metabolic Switch Essential for Cardiac Maturation.
abstract: While gene regulatory networks involved in cardiogenesis have been characterized, the role of bioenergetics remains less studied. Here we show that until midgestation, myocardial metabolism is compartmentalized, with a glycolytic signature restricted to compact myocardium contrasting with increased mitochondrial oxidative activity in the trabeculae. HIF1α regulation mirrors this pattern, with expression predominating in compact myocardium and scarce in trabeculae. By midgestation, the compact myocardium downregulates HIF1α and switches toward oxidative metabolism. Deletion of the E3 ubiquitin ligase Vhl results in HIF1α hyperactivation, blocking the midgestational metabolic shift and impairing cardiac maturation and function. Moreover, the altered glycolytic signature induced by HIF1 trabecular activation precludes regulation of genes essential for establishment of the cardiac conduction system. Our findings reveal VHL-HIF-mediated metabolic compartmentalization in the developing heart and the connection between metabolism and myocardial differentiation. These results highlight the importance of bioenergetics in ventricular myocardium specialization and its potential relevance to congenital heart disease.
authors.affiliation: Myocardial Pathophysiology Program, Centro Nacional de Investigaciones Cardiovasculares (CNIC), 28029 Madrid, Spain.
authors.forename: Ivan
authors.initials: I
authors.lastname: Menendez-Montes
authors.affiliation: Myocardial Pathophysiology Program, Centro Nacional de Investigaciones Cardiovasculares (CNIC), 28029 Madrid, Spain.
authors.forename: Beatriz
authors.initials: B
authors.lastname: Escobar
authors.affiliation: Myocardial Pathophysiology Program, Centro Nacional de Investigaciones Cardiovasculares (CNIC), 28029 Madrid, Spain.
authors.forename: Beatriz
authors.initials: B
authors.lastname: Palacios
authors.affiliation: Myocardial Pathophysiology Program, Centro Nacional de Investigaciones Cardiovasculares (CNIC), 28029 Madrid, Spain.
authors.forename: Manuel Jose
authors.initials: MJ
authors.lastname: Gómez
authors.affiliation: Developmental and Cell Biology Program, CNIC, 28029 Madrid, Spain; CIBER de Enfermedades Respiratorias (CIBERES), Madrid, Spain.
authors.forename: Jose Luis
authors.initials: JL
authors.lastname: Izquierdo-Garcia
authors.affiliation: Myocardial Pathophysiology Program, Centro Nacional de Investigaciones Cardiovasculares (CNIC), 28029 Madrid, Spain.
authors.forename: Lorena
authors.initials: L
authors.lastname: Flores
authors.affiliation: Myocardial Pathophysiology Program, Centro Nacional de Investigaciones Cardiovasculares (CNIC), 28029 Madrid, Spain; Cardiac Imaging Department, Hospital de La Princesa, 28006 Madrid, Spain.
authors.forename: Luis Jesus
authors.initials: LJ
authors.lastname: Jiménez-Borreguero
authors.affiliation: Research Unit, Hospital Santa Cristina, 28009 Madrid, Spain.
authors.forename: Julian
authors.initials: J
authors.lastname: Aragones
authors.affiliation: Developmental and Cell Biology Program, CNIC, 28029 Madrid, Spain; CIBER de Enfermedades Respiratorias (CIBERES), Madrid, Spain; Department of Chemistry and Physics II, Pharmacy School, Universidad Complutense de Madrid, 28040 Madrid, Spain.
authors.forename: Jesus
authors.initials: J
authors.lastname: Ruiz-Cabello
authors.affiliation: Developmental and Cell Biology Program, CNIC, 28029 Madrid, Spain.
authors.forename: Miguel
authors.initials: M
authors.lastname: Torres
authors.affiliation: Myocardial Pathophysiology Program, Centro Nacional de Investigaciones Cardiovasculares (CNIC), 28029 Madrid, Spain. Electronic address: smartinp@cnic.es.
authors.forename: Silvia
authors.initials: S
authors.lastname: Martin-Puig
mesh_terms: D000818:Animals; D002451:Cell Compartmentation; D015536:Down-Regulation / Q000235:genetics; D004734:Energy Metabolism; D005260:Female; D017353:Gene Deletion; D018507:Gene Expression Regulation, Developmental; D006019:Glycolysis; D006329:Heart Conduction System / Q000196:embryology / Q000378:metabolism; D006333:Heart Failure / Q000196:embryology / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D009200:Myocardial Contraction; D009206:Myocardium / Q000378:metabolism*; D038081:Organogenesis; D010084:Oxidation-Reduction; D011247:Pregnancy; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism; D013997:Time Factors; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000378:metabolism*
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D051794:Von Hippel-Lindau Tumor Suppressor Protein; C494469:VHL protein, mouse
keywords: HIF; VHL; cardiac conduction system; cardiac maturation; glycolysis; heart development; hypoxia; metabolic reprogramming; mitochondria; transcriptional repression