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

Shintaro Kinugawa, Ziping Wang, Pawel M. Kaminski, Michael S. Wolin, John G. Edwards, Gabor Kaley, Thomas H. Hintze

Research output: Contribution to journalArticle

43 Citations (Scopus)

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 (VCO 2) 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 VO 2 and VCO2 and improved the work to exhaustion and corrected VO2 and VCO2 in SOD2+/-. VO 2 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+/+.

Original languageEnglish
Pages (from-to)1480-1486
Number of pages7
JournalCirculation
Volume111
Issue number12
DOIs
Publication statusPublished - Mar 29 2005
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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