Published Online
on March 21, 2005

A more recent version of this article appeared on March 29, 2005

This Article Full Text (PDF) All Versions of this Article: 111/12/1480    most recent 01.CIR.0000159261.11520.63v1 Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kinugawa, S. Articles by Hintze, T. H. Search for Related Content PubMed PubMed Citation Articles by Kinugawa, S. Articles by Hintze, T. H. Pubmed/NCBI databases Gene GEO Profiles HomoloGene UniGene Compound via MeSH Substance via MeSH Hazardous Substances DB CARBON DIOXIDE NITRIC OXIDE Related Collections Biochemistry and metabolism Other heart failure Energy metabolism Exercise/exercise testing/rehabilitation Oxidant stress Endothelium/vascular type/nitric oxide

Submitted on July 1, 2004
Revised on November 12, 2004
Accepted on November 16, 2004

Limited Exercise Capacity in Heterozygous Manganese Superoxide Dismutase Gene-Knockout Mice. Roles of Superoxide Anion and Nitric Oxide

Shintaro Kinugawa MD, PhD, Ziping Wang AASA, Pawel M. Kaminski MD, PhD, Michael S. Wolin PhD, John G. Edwards PhD, Gabor Kaley PhD, and Thomas H. Hintze PhD^*

From the Department of Physiology, New York Medical College, Valhalla, NY.

^* To whom correspondence should be addressed. E-mail: thomas_hintze{at}nymc.edu.

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^+/+.

Key words: nitric oxide • endothelium-derived factors • exercise • free radicals • metabolism

This article has been cited by other articles:

				M. S. Lustgarten, Y. C. Jang, Y. Liu, F. L. Muller, W. Qi, M. Steinhelper, S. V. Brooks, L. Larkin, T. Shimizu, T. Shirasawa, et al. Conditional knockout of Mn-SOD targeted to type IIB skeletal muscle fibers increases oxidative stress and is sufficient to alter aerobic exercise capacity Am J Physiol Cell Physiol, December 1, 2009; 297(6): C1520 - C1532. [Abstract] [Full Text] [PDF]

				T. Yokota, S. Kinugawa, K. Hirabayashi, S. Matsushima, N. Inoue, Y. Ohta, S. Hamaguchi, M. A. Sobirin, T. Ono, T. Suga, et al. Oxidative stress in skeletal muscle impairs mitochondrial respiration and limits exercise capacity in type 2 diabetic mice Am J Physiol Heart Circ Physiol, September 1, 2009; 297(3): H1069 - H1077. [Abstract] [Full Text] [PDF]

				H. Tsutsui, S. Kinugawa, and S. Matsushima Mitochondrial oxidative stress and dysfunction in myocardial remodelling Cardiovasc Res, February 15, 2009; 81(3): 449 - 456. [Abstract] [Full Text] [PDF]

				D. V. Cuong, M. Warda, N. Kim, W. S. Park, J. H. Ko, E. Kim, and J. Han Dynamic changes in nitric oxide and mitochondrial oxidative stress with site-dependent differential tissue response during anoxic preconditioning in rat heart Am J Physiol Heart Circ Physiol, September 1, 2007; 293(3): H1457 - H1465. [Abstract] [Full Text] [PDF]

				T.-a. Okabe, K. Shimada, M. Hattori, T. Murayama, M. Yokode, T. Kita, and C. Kishimoto Swimming reduces the severity of atherosclerosis in apolipoprotein E deficient mice by antioxidant effects Cardiovasc Res, June 1, 2007; 74(3): 537 - 545. [Abstract] [Full Text] [PDF]

				J. P. De Bono, D. Adlam, D. J. Paterson, and K. M. Channon Novel quantitative phenotypes of exercise training in mouse models Am J Physiol Regulatory Integrative Comp Physiol, April 1, 2006; 290(4): R926 - R934. [Abstract] [Full Text] [PDF]