REGULATION OF CARBOHYDRATE AND FATTY-ACID UTILIZATION BY L-CARNITINE DURING CARDIAC DEVELOPMENT AND HYPOXIA

This study is designed to investigate whether substrate preference in the myocardium during the neonatal period and hypoxia-induced stress i s controlled intracellularly or by extracellular substrate availabilit y. To determine this, the effect of exogenous L-carnitine on the regul ation of carbohydrate and fatty acid metabolism was determined during cardiac stress (hypoxia) and during the postnatal period. The effect o f L-carnitine on long chain (palmitate) and medium chain (octonoate) f atty acid oxidation was studied in cardiac myocytes isolated from less than 24 h old (new born; NB), 2 week old (2 week) and hypoxic 4 week old (HY) piglets. Palmitate oxidation was severely decreased in NB cel ls compared to those from 2 week animals (0.456 +/- 0.04 vs. 1.207 +/- 0.52 nmol/mg protein/30 min); surprisingly, cells from even older hyp oxic animals appeared shifted toward the new born state (0.695 +/- 0.0 38 nmol/mg protein/30 min). Addition of L-carnitine to the incubation medium, which stimulates carnitine palmitoyl-transferase I (CPTI) acce lerated palmitate oxidation 3 fold in NB and approximately 2 fold in H Y and 2 week cells. In contrast, octanoate oxidation which was greater in new born myocytes than in 2 week cells, was decreased by L-carniti ne suggesting a compensatory response. Furthermore, oxidation of carbo hydrates (glucose, pyruvate, and lactate) was greatly increased in new born myocytes compared to 2 week and HY cells and was accompanied by a parallel increase in pyruvate dehydrogenase (PDH) activity. The conc entration of malonyl-CoA, a potent inhibitor of CPTI was significantly higher in new born heart than at 2 weeks. These metabolic data taken together suggest that intracellular metabolic signals interact to shif t from carbohydrate to fatty acid utilization during development of th e myocardium. The decreased oxidation of palmitate in NB hearts probab ly reflects decreased intracellular L-carnitine and increased malonyl- CoA concentrations. Interestingly, these data further suggest that the cells remain compliant so that under stressful conditions, such as hy poxia, they can revert toward the neonatal state of increased glucose utilization.