Abstract 3725: Cardiac-specific Overexpression of Mitochondrial Superoxide Dismutase Leads to Myocardial Insulin Resistance
Oxidative stress has been proposed to contribute to the development of mitochondrial dysfunction and myocardial insulin resistance in the context of obesity. We therefore hypothesized that cardiac-specific overexpression of mitochondrial manganese superoxide dismutase (SOD2) would scavenge ROS and improve cardiac function and insulin sensitivity in lean animals. 24 week-old transgenic mice with alpha-myosin heavy chain-driven 10 fold overexpression of SOD2 showed no differences in body weight, glucose tolerance, fasting insulin, triglyceride and free fatty acid levels versus controls (WT). Surprisingly, HW/BW ratio and LV wall thickness was significantly increased in SOD2 mice, without increased fibrosis. In isolated working hearts perfused with 5mM glucose and 0.4mM palmitate, cardiac power (CP) was reduced in SOD2 hearts (18.8±0.9 vs. 30.7±1.3 mWatt/gdhw, p<0.0001). Basal glycolysis and glucose oxidation rates were similar between transgenic and WT mice, but SOD2 hearts showed reduced glucose metabolic flux rates (nmol/min/gdhw) in response to insulin (glycolysis 2250±130 vs. 3691±275, p<0.0001; glucose oxidation 305±27 vs. 401±56, p<0.05). Insulin-mediated Akt activation was also impaired (pAktS473/tAkt 1.1 vs. 2.19 AU, p<0.002). Furthermore, SOD2 hearts failed to increase CP in response to 1nM insulin. Mitochondrial dysfunction was also evident. ADP-stimulated oxygen consumption (−31%, p<0.002) and ATP production rates (−30%, p<0.05) were lower in saponin-permeabilized cardiac fibers from SOD2 hearts, with palmitoyl-carnitine as substrate and ATP/O ratios remained unchanged. Electron microscopy revealed that mitochondrial number was reduced but volume density was increased, suggesting altered mitochondrial dynamics. These data indicate that in the absence of obesity, diabetes or caloric excess overexpression of Sod2 will impair mitochondrial function and insulin action. Potential mechanisms include potentially deleterious effects of increased conversion of superoxide to H2O2 or loss of physiological levels of superoxide, which may activate signaling pathways that maintain mitochondrial function.