Endocrine Abstracts

The late gestation increase in glucocorticoid action promotes the structural and functional maturation of the fetal heart. Metabolic maturation of cardiomyocytes involves a switch from glucose utilization as a fuel source to fatty acid (FA) oxidation. In fetal cardiomyocytes, glucocorticoids induce expression of PGC1a (a master regulator of mitochondrial capacity), lipin1 and KLF15 (genes involved in FA oxidation). We hypothesized that glucocorticoids promote the metabolic switch to FA oxidation during cardiomyocyte maturation. Isolated embryonic day 14.5–15.5 mouse fetal cardiomyocytes were were pre-treated with the glucocorticoid receptor antagonist RU486, or vehicle for 30 mins prior to treatment with dexamethasone (dex) or vehicle for 24 h. A Seahorse XF Analyzer was used to measure glycolysis and mitochondrial respiration. Palmitate was used to measure FA oxidation; with etomoxir to block mitochondrial FA uptake. Mitochondria were stained with Mitotracker-deep red FM and size measured using MitoGraphTo measure mitophagy, fetal cardiomyocytes were isolated from MitoQC miceand the increase in red puncta after exposure to vehicle, dex or DFP (positive control) was analysed. Fetal cardiomyocytes exhibited little dependence on glycolysis and this was unaltered by dex treatment. With palmitate, dex treatment increased basal respiration rate (517.9±48.0 versus 366.7±71 pmol/min/protein, mean±SD, n=5) and oxygen consumption (related to ATP production, 159.5±62.8 versus 297.9±35.5 pmol/min/protein, mean±SD, n=5) compared to vehicle. Etomoxir and RU486 inhibited these dex-dependent increases. No overt changes in mitochondrial phenotype were observed between dex and vehicle treated cells. Mitophagy was unaltered by dex up to 45 h post-treatment. These data support a glucocorticoid-induced switch in substrate preference towards fatty acid oxidation in fetal cardiomyocytes. The mechanism for this involves neither a general increase in mitochondrial volume nor mitochondrial remodeling. Further investigations will identify dex-regulated pathways leading to increased fatty acid oxidation.