Abstract 656: Treatment of db/db Mice with the Catalytic Antioxidant MnTBAP Restores Mitochondrial Energetics and Normalizes Fatty Acid Oxidation
Mitochondrial uncoupling and impaired mitochondrial OXPHOS capacity contributes to cardiac dysfunction in diabetes and obesity. To test the hypothesis that increased myocardial ROS generation contributes both to mitochondrial uncoupling and mitochondrial dysfunction in diabetes, 6-week-old male db/db mice, an animal model of obesity and diabetes, and strain-matched controls (con) were treated with MnTBAP, a potent superoxide dismutase (SOD) mimetic, for three weeks (20mg/kg/x3 days per week by i.p. injection). Substrate metabolism was determined in isolated hearts perfused with 5mM glucose and 0.4mM palmitate, and mitochondrial oxygen consumption and ATP production rates were measured in saponin-permeabilized cardiac fibers exposed to palmitoyl-carnitine 0.02mmol/L and malate 2 mmol/L. Treatment of db/db mice with MnTBAP had no effect on body weight or serum levels of insulin, triglycerides and fatty acids. MnTBAP treated db/db mice also remained severely hyperglycemic. State 3 mitochondrial respiration rates were similar in MnTBAP and saline-treated db/db and con mice respectively. However, ATP production rates and ATP/O ratios were significantly reduced in saline-treated db/db relative to saline-treated con (9.7 ± 1.2 vs.17.8 ± 1.6 nmol/ min/mg dwt, p<0.0002 for ATP and 0.9 ± 0.2 vs. 1.6 ± 0.2 p<0.01 for ATP/O) indicating mitochondrial uncoupling and mitochondrial dysfunction. Treatment of db/db mice with MnTBAP increased mitochondrial ATP production rates by 44% (p<0.04) so that ATP production rates were identical to MnTBAP-treated con mice. Similarly, MnTBAP treatment increased ATP/O ratios in db/db mitochondria to 1.4 ± 0.2, which were similar in value to saline or MnTBAP-treated con. FA-oxidation rates (FAO) and MVO2 were increased in hearts from saline-treated db/db vs. saline treated con (200 ± 9 vs. 160 ± 9 nmol/min/g dwt, p<0.008 for FAO and 245 ± 8 vs.182 ± 6 ml/min/g, p<0.0001 for MVO2) and were both normalized by MnTBAP treatment to 152 ± 14 (FAO) and 175 ± 6 (MVO2) respectively, (p<0.003 vs. saline-treated db/db). These data indicate that increased mitochondrial ROS production contributes both to mitochondrial uncoupling and to increased myocardial FA utilization in the heart in obesity -associated diabetes.