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Am J Physiol Heart Circ Physiol (May 6, 2005). doi:10.1152/ajpheart.00170.2005
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Submitted on February 18, 2005
Accepted on April 29, 2005

Transcriptional Basis for Exercise Limitation in Male eNOS Knockout Mice with Age: Heart Failure and the Fetal Phenotype

Caroline Ojaimi1, Wei Li1, Shintaro Kinugawa1, Heiner Post1, Anna Csiszar1, Pal Pacher2, Gabor Kaley1, and Thomas H Hintze1*

1 Physiology, New York Medical College, Valhalla, NY, USA
2 NIAAA, National Institutes of Health, Bethesda, MD, USA

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

Endothelium-derived nitric oxide is pivotal in regulating mitochondrial oxygen consumption and glucose uptake in mice. The aim of this study was to investigate the mechanism of age and genotype related exercise limitation in male eNOS knockout (KO) mice. 16 eNOS KO and 19 wild type (WT) male mice were used. Treadmill testing was performed at 12 months (M), 14M, 16M, 18M and 21M of age. Oxygen consumption (VO2), Carbon Dioxide production (VCO2), Respiratory Exchange Ratio (RER) and maximal running distance were determined during treadmill running. There were good linear correlations for increase of speed with increase of VO2. The difference between KO vs. WT was not significant at 12M but was significant at 18M. Linear regression showed KO mice consumed more oxygen at the same absolute and relative workload suggesting that the inhibition of oxygen consumption by NO was not present in KO mice. KO mice performed 30-50% less work than WT mice at each age (work=vertical distance* weight). In contrast to WT, the work performed by KO significantly decreased from 17±1.4 mkg at 12M to 9.4±1.7 mkg at 21M. Running distance (RD) was significantly decreased from 334±27 mkg at 12M to 178±38 m at 21M and the VO2max , VCO2max and RERmax per work unit were significantly higher in KO compared with WT. Using gene arrays, there was evidence of a fetal phenotype in KO at 21M. In conclusion, there are age and genotype related exercise limitations in maximal work performed and maximal running distance in male eNOS KO mice indicative of the fetal phenotype and age related onset of heart failure.




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