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 (VO2). We hypothesized that in states in which superoxide anion (O2-) is increased, especially in the mitochondria, whole-body VO2 will be increased because of the inactivation of NO, and consequently, exercise capacity will be reduced.


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 O2- before a second treadmill testing. VO2 and carbon dioxide production (VCO2) at rest were increased in SOD2+/-. The work (vertical distance run x body weight) to exhaustion was decreased in SOD2+/-. When the maximum VO2 and VCO2 were corrected to per work unit, they were increased in SOD2+/-. Tempol normalized basal VO2 and VCO2 and improved the work to exhaustion and corrected VO2 and VCO2 in SOD2+/-. VO2 of skeletal muscle was measured in vitro. Bradykinin-induced reduction in VO2 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 O2- 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+/+.
Kinugawa
Shintaro
S
Department of Physiology, New York Medical College, Valhalla, NY 10595, USA.
Wang
Ziping
Z
Kaminski
Pawel M
PM
Wolin
Michael S
MS
Edwards
John G
JG
Kaley
Gabor
G
Hintze
Thomas H
TH
D000818:Animals; D002245:Carbon Dioxide / Q000378:metabolism; D003497:Cyclic N-Oxides / Q000008:administration & dosage / Q000494:pharmacology; D005080:Exercise Test; D016166:Free Radical Scavengers / Q000008:administration & dosage / Q000494:pharmacology; D006579:Heterozygote; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000201:enzymology / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000032:analysis; D009569:Nitric Oxide / Q000032:analysis; D019001:Nitric Oxide Synthase / Q000032:analysis; D052248:Nitric Oxide Synthase Type I; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D010101:Oxygen Consumption / Q000187:drug effects; D010807:Physical Endurance / Q000187:drug effects / Q000235:genetics*; D013113:Spin Labels; D013482:Superoxide Dismutase / Q000172:deficiency / Q000235:genetics* / Q000502:physiology*; D013481:Superoxides / Q000032:analysis
D003497:Cyclic N-Oxides; D016166:Free Radical Scavengers; D009419:Nerve Tissue Proteins; D013113:Spin Labels; D013481:Superoxides; D002245:Carbon Dioxide; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496321:Nos1 protein, mouse; C496315:Nos3 protein, mouse; D013482:Superoxide Dismutase; C001803:tempol