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

SUMMARY While gene regulatory networks involved in cardio- genesis have been characterized, the role of bioener- getics remains less studied. Here we show that until midgestation, myocardial metabolism is compart- mentalized, with a glycolytic signature restricted to compact myocardium contrasting with increased mitochondrial oxidative activity in the trabeculae. HIF1a regulation mirrors this pattern, with expres- sion predominating in compact myocardium and scarce in trabeculae. By midgestation, the compact myocardium downregulates HIF1a and switches toward oxidative metabolism. Deletion of the E3 ubiquitin ligase Vhl results in HIF1a hyperactivation, blocking the midgestational metabolic shift and impairing cardiac maturation and function. More- over, 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 meta- bolism and myocardial differentiation. These results highlight the importance of bioenergetics in ventricu- lar myocardium specialization and its potential rele- vance to congenital heart disease.