Myocardial VHL-HIF Signaling Controls an Embryonic Metabolic Switch Essential for Cardiac Maturation

• DOI: 10.1016/j.devcel.2016.11.012
• Publication Date: 2016-12-19T17:47:41Z
• Authors: Ivan Menendez-Montes; Beatriz Escobar; Beatriz Palacios; Manuel Jose Gómez; Jose Luis Izquier...; Lorena Flores; Luis Jesus Jiméne...; Julian Aragones; Jesus Ruiz-Cabello; Miguel Torres; Silvia Martin-Puig
• Keywords: Heart Failure; 0303 health sciences; Myocardium; Organogenesis; Down-Regulation; Gene Expression Regulation, Developmental; Hypoxia-Inducible Factor 1, alpha Subunit; Myocardial Contraction; Cell Compartmentation; Mitochondria; Mice, Inbred C57BL; 03 medical and health sciences; Heart Conduction System; Pregnancy; Mutation; Animals; Female; Energy Metabolism; Glycolysis; Oxidation-Reduction; Gene Deletion; Signal Transduction

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.