Oxygen-independent, hormonal control of HIF-1α regulates the developmental and regenerative growth of cardiomyocytes.

Here, we present an O2-independent/HIF-1α (Hypoxia inducible factor-1α)-dependent mechanism that regulates developmental and regenerative growth of mammalian cardiomyoblasts. An autocrine feedback mechanism of GH/IGF1/SST (Growth hormone/Insulin-like growth factor 1/Somatostatin) signaling, mediated by GHRH/GHRH-R (Growth hormone-releasing hormone/GHRH-Receptor), is established specifically in NKX2-5 (NK2 Homeobox 5) expressing myocardial cells which affects HIF-1α stability through cAMP (cyclic adenosine monophosphate) or cGMP (cyclic guanosine monophosphate) activity. cAMP-mediated HIF-1α stabilization fuels Warburg metabolism and enhances NKX2-5 expression, limiting the developmental and regenerative growth of cardiomyoblasts. In contrast, cGMP-mediated HIF-1α inhibition (or knock-out of HIF-1α) redirects glycolytically derived citrate toward long-chain saturated fatty acid biosynthesis, leading to enhanced developmental and regenerative growth of cardiomyoblasts. These findings suggest that HIF1α-mediated glycolysis serves as a rate-limiting, O2-independent sensor of cardiomyogenesis and that targeting GHRH/GHRH-R signaling could be a therapeutic strategy for regenerating the mammalian heart post-injury.