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

Abstract：

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. 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 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+/+.

journal_name

Circulation

journal_title

Circulation

authors

Kinugawa S,Wang Z,Kaminski PM,Wolin MS,Edwards JG,Kaley G,Hintze TH

doi

10.1161/01.CIR.0000159261.11520.63

subject

Has Abstract

pub_date

2005-03-29 00:00:00

pages

1480-6

issue

eissn

0009-7322

issn

1524-4539

pii

01.CIR.0000159261.11520.63

journal_volume

111

pub_type

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