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Am J Physiol Heart Circ Physiol 289: H1399-H1407, 2005. First published May 6, 2005; doi:10.1152/ajpheart.00170.2005
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Transcriptional basis for exercise limitation in male eNOS-knockout mice with age: heart failure and the fetal phenotype

Caroline Ojaimi,1 Wei Li,1 Shintaro Kinugawa,1 Heiner Post,1 Anna Csiszar,1 Pal Pacher,2 Gabor Kaley,1 and Thomas H. Hintze1

1Department of Physiology, New York Medical College, Valhalla, New York; and 2National Institute of Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland

Submitted 18 February 2005 ; accepted in final form 29 April 2005

Endothelium-derived nitric oxide (NO) is pivotal in regulating mitochondrial O2 consumption (O2) and glucose uptake in mice. The aim of this study was to investigate the mechanism of age- and genotype-related exercise limitation in male endothelial NO synthase (eNOS)-knockout (KO, n = 16) and wild-type (WT, n = 19) mice. Treadmill testing was performed at 12, 14, 16, 18, and 21 mo of age. O2, CO2 production, respiratory exchange ratio, and maximal running distance were determined during treadmill running. There were good linear correlations for increase of speed with increase of O2. The difference between KO and WT mice was not significant at 12 mo but was significant at 18 mo. Linear regression showed that KO mice consumed more O2 at the same absolute and relative workloads, suggesting that O2 was not inhibited by NO in KO mice. KO mice performed 30–50% less work than WT mice at each age (work = vertical distance x weight). In contrast to WT mice, the work performed by KO mice significantly decreased from 17 ± 1.4 m·kg at 12 mo to 9.4 ± 1.7 m·kg at 21 mo. Running distance was significantly decreased from 334 ± 27 m at 12 mo to 178 ± 38 m at 21 mo, and maximal O2, CO2 production, and respiratory exchange ratio per work unit were significantly higher in KO than in WT mice. Gene arrays showed evidence of a fetal phenotype in KO mice at 21 mo. In conclusion, age- and genotype-related exercise limitations in maximal work performed and maximal running distance in male eNOS-KO mice indicated that fetal phenotype and age were related to onset of heart failure.

maximal oxygen consumption; respiratory exchange ratio; work; microarray; endothelial nitric oxide synthase


Address for reprint requests and other correspondence: T. H. Hintze, Dept. of Physiology, New York Medical College, Valhalla, NY 10595 (e-mail: Thomas_Hintze{at}nymc.edu)




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