Isoproterenol stimulates 5′-AMP-activated protein kinase and fatty acid oxidation in neonatal hearts

Isoproterenol increases phosphorylation of LKB, 5′-AMP-activated protein kinase (AMPK), and acetyl-CoA carboxylase (ACC), enzymes involved in regulating fatty acid oxidation. However, inotropic stimulation selectively increases glucose oxidation in adult hearts. In the neonatal heart, fatty acid oxidation becomes a major energy source, while glucose oxidation remains low. This study tested the hypothesis that increased energy demand imposed by isoproterenol originates from fatty acid oxidation, secondary to increased LKB, AMPK, and ACC phosphorylation. Isolated working hearts from 7-day-old rabbits were perfused with Krebs solution (0.4 mM palmitate, 11 mM glucose, 0.5 mM lactate, and 100 mU/l insulin) with or without isoproterenol (300 nM). Isoproterenol increased myocardial O2 consumption (in J•g dry wt -1•min-1; 11.0 ± 1.4, n = 8 vs. 7.5 ± 0.8, n = 6, P < 0.05), and the phosphorylation of LKB (in arbitrary density units; 0.87 ± 0.09, n = 6 vs. 0.59 ± 0.08, n = 6, P < 0.05), AMPK (0.82 ± 0.08, n = 6 vs. 0.51 ± 0.06, n = 6, P < 0.05), and ACC-β (1.47 ± 0.14, n = 6 vs. 0.97 ± 0.07, n = 6, P < 0.05), with a concomitant decrease in malonyl-CoA levels (in nmol/g dry wt; 0.9 ± 0.9, n = 8 vs. 7.5 ± 1.3, n = 8, P < 0.05) and increase in palmitate oxidation (in nmol•g dry wt-1•min-1; 272 ± 45, n = 8 vs. 114 ± 9, n = 6, P < 0.05). Glucose and lactate oxidation were increased (in nmol•g dry wt -1•min-1; 253±75, n = 8 vs. 63 ± 15, n = 9, P < 0.05 and 246 ± 43, n = 8 vs. 82 ± 11, n = 6, P < 0.05, respectively), independent of alterations in pyruvate dehydrogenase phosphorylation, but occurred secondary to a decrease in acetyl-CoA content and acetyl-CoA-to-free CoA ratio. As acetyl-CoA levels decrease in response to isoproterenol, despite an acceleration of the rates of palmitate and carbohydrate oxidation, these data suggest net rates of acetyl-CoA utilization exceed the net rates of acetyl-CoA generation. Copyright © 2010 the American Physiological Society.link_to_subscribed_fulltex

Cardiac hypertrophy in the newborn delays the maturation of fatty acid β-oxidation and compromises postischemic functional recovery

During the neonatal period, cardiac energy metabolism progresses from a fetal glycolytic profile towards one more dependent on mitochondrial oxidative metabolism. In this study, we identified the effects of cardiac hypertrophy on neonatal cardiac metabolic maturation and its impact on neonatal postischemic functional recovery. Seven-day-old rabbits were subjected to either a sham or a surgical procedure to induce a left-to-right shunt via an aortocaval fistula to cause RV volume-overload. At 3 wk of age, hearts were isolated from both groups and perfused as isolated, biventricular preparations to assess cardiac energy metabolism. Volume-overload resulted in cardiac hypertrophy (16% increase in cardiac mass, P < 0.05) without evidence of cardiac dysfunction in vivo or in vitro. Fatty acid oxidation rates were 60% lower (P < 0.05) in hypertrophied hearts than controls, whereas glycolysis increased 246% (P < 0.05). In contrast, glucose and lactate oxidation rates were unchanged. Overall ATP production rates were significantly lower in hypertrophied hearts, resulting in increased AMP-to-ATP ratios in both aerobic hearts and ischemiareperfused hearts. The lowered energy generation of hypertrophied hearts depressed functional recovery from ischemia. Decreased fatty acid oxidation rates were accompanied by increased malonyl-CoA levels due to decreased malonyl-CoA decarboxylase activity/expression. Increased glycolysis in hypertrophied hearts was accompanied by a significant increase in hypoxia-inducible factor-1α expression, a key transcriptional regulator of glycolysis. Cardiac hypertrophy in the neonatal heart results in a reemergence of the fetal metabolic profile, which compromises ATP production in the rapidly maturing heart and impairs recovery of function following ischemia. © 2012 the American Physiological Society.link_to_OA_fulltex