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

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. [Display omitted] •HIF1 promotes an enhanced glycolytic program in the embryonic compact myocardium•Midgestational trabeculae devoid of HIF1α display increased mitochondrial content•HIF1 signaling controls a midgestational switch toward oxidative metabolism•VHL/HIF signaling disruption compromises cardiac function and maturation Menendez-Montes et al. describe how spatiotemporal activation of VHL/HIF signaling within the developing myocardium delineates metabolic compartments with enhanced glycolytic signature in the compact myocardium compared with increased mitochondrial activity in midgestation trabeculae. Sustained HIF1 activation results in ventricular chamber defects, cardiac dysfunction, and altered expression of conduction system genes.