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

Publication date: 19 December 2016
Source:Developmental Cell, Volume 39, Issue 6
Author(s): Ivan Menendez-Montes, Beatriz Escobar, Beatriz Palacios, Manuel Jose Gómez, Jose Luis Izquierdo-Garcia, Lorena Flores, Luis Jesus Jiménez-Borreguero, Julian Aragones, Jesus Ruiz-Cabello, Miguel Torres, Silvia Martin-Puig
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.

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Teaser

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.


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