Limited exercise capacity in heterozygous manganese superoxide dismutase gene-knockout mice - Roles of superoxide anion and nitric oxide

Background - We have reported that there is a limitation of exercise capacity in mice with defects in the expression of endothelial nitric oxide ( NO) synthase, which is associated with a greater increase in whole-body oxygen consumption ((V) over dot O-2). We hypothesized that in states in which superoxide anion (O-2(-)) is increased, especially in the mitochondria, whole-body (V) over dot O-2 will be increased because of the inactivation of NO, and consequently, exercise capacity will be reduced. Methods and Results - Heterozygous manganese superoxide anion dismutase ( SOD2) gene - knockout mice ( SOD2(+/-)), in which SOD2 activity is reduced by 30% to 80%, and wild-type control mice (SOD2(+/+)) were treadmill-tested to measure indices defining exercise capacity. Tempol was given to each mouse for 7 days by an intraperitoneal injection to scavenge O-2(-) before a second treadmill testing. (V) over dot O-2 and carbon dioxide production ((V) over dot CO2) at rest were increased in SOD2(+/-). The work ( vertical distance run x body weight) to exhaustion was decreased in SOD2(+/-). When the maximum (V) over dot O-2 and (V) over dot CO2 were corrected to per work unit, they were increased in SOD2(+/-). Tempol normalized basal (V) over dot O-2 and (V) over dot CO2 and improved the work to exhaustion and corrected (V) over dot O-2 and (V) over dot CO2 in SOD2(+/-). (V) over dot O-2 of skeletal muscle was measured in vitro. Bradykinin-induced reduction in (V) over dot O-2 in vitro was attenuated in SOD2(+/-), and was acutely restored by Tempol. There was a decrease in SOD2 protein level and a concomitant increase in lucigenin-detectable O-2(-) production in skeletal muscle from SOD2(+/-). Conclusions - These results suggest that exercise capacity is reduced in conditions in which superoxide anion is increased, and this is associated with a greater increase in whole-body oxygen consumption in SOD2(+/-) compared with SOD2(+/+).