Abstract
Alteration in myocardial substrate utilization and energy metabolism is a well-known contributor to the pathogenesis of heart disease. Recent studies suggest the failing heart may benefit from ketone bodies as an energy source. Infants exposed to diabetic pregnancy are at higher risk of cardiomyopathy at birth and early onset cardiovascular disease (CVD) as adults. We showed fetal exposure to excess circulating fuels, especially to the combination of maternal high fat diet (HFD) and diabetes, exaggerates CVD risk through fuel-mediated mitochondrial dysfunction including complex I dysfunction. Diabetic pregnancy increases ketone body exposure in utero, but whether prenatal exposures impair myocardial metabolism of ketones postnatally remains unknown. The objective of this study was to determine whether neonatal rat cardiomyocytes (NRCM) exposed to maternal diabetes and HFD in utero can increase ketone oxidation as a preferred fuel source over glycolysis. To test our hypothesis, we developed a ketone stress test (KST) or modified extracellular flux analyses to compare real-time ß-hydroxy butyrate (ßOHB) metabolism in NRCM and myocardial expression of genes responsible for ketone and lipid metabolism. While control and combination exposed NRCM had similar basal respiration, the presence of ketone (4.5 mM) increased maximal respiration, spare respiratory capacity, and ATP-limited glycolytic rate in the combination exposed group. Interestingly, baseline proton efflux rate (PER) from lactate (anaerobic glycolysis) decreased while PER from CO 2 (aerobic glycolysis) increased in response to ketones in the combination exposed group. Expression of genes responsible for ketone body metabolism ( Hmgcs2 and Bdh1 ) was not different. The study uses a novel KST to analyze real-time ketone body metabolism and demonstrates myocardial ketone body metabolism is preserved and may be protective in the NRCM exposed to maternal overnutrition.
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