Mitochondrial Substrate Utilization Regulates Cardiomyocyte Cell Cycle Progression

Shortly after birth, the mammalian neonatal heart can robustly regenerate following injury, mediated by cardiomyocyte proliferation. The postnatal shift from anaerobic glycolysis to mitochondrial oxidative phosphorylation, particularly towards fatty acid (FA) utilization coincides with cardiomyocyte cell cycle arrest. Despite the energy advantage of FA beta-oxidation, cardiac mitochondria produce more reactive oxygen species, which activates the DNA damage response (DDR) pathway. Here we show that inhibiting FA utilization promotes cardiomyocyte proliferation. First, neonatal mice fed FA deficient milk prolonged the postnatal cardiomyocyte proliferative window, but cell cycle arrest eventually ensued. Next, we generated tamoxifen-inducible cardiomyocyte-specific, Pyruvate Dehydrogenase Kinase 4 (PDK4) knockout mice to selectively enhance oxidation of glycolytically-derived pyruvate in cardiomyocytes. This resulted in an increase in Pyruvate Dehydrogenase activity and consequently an increase in glucose relative to FA oxidation. PDK4 deletion decreased cardiomyocyte size, DNA damage and DDR, but increased cardiomyocyte proliferation. Following myocardial infarction, inducible deletion of PDK4 improved left ventricular function and decreased remodeling. Collectively, inhibition of FA utilization in cardiomyocytes promotes proliferation, and may be a viable target for cardiac regenerative therapies.