Transcriptional basis for exercise limitation in male eNOS-knockout mice with age: heart failure and the fetal phenotype.
Endothelium-derived nitric oxide (NO) is pivotal in regulating mitochondrial O(2) consumption (Vo(2)) 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. Vo(2), CO(2) 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 Vo(2). 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 O(2) at the same absolute and relative workloads, suggesting that Vo(2) 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 Vo(2), CO(2) 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.
Ojaimi
Caroline
C
Department of Physiology, New York Medical College, Valhalla, NY 10595, USA.
Li
Wei
W
Kinugawa
Shintaro
S
Post
Heiner
H
Csiszar
Anna
A
Pacher
Pal
P
Kaley
Gabor
G
Hintze
Thomas H
TH
D000375:Aging / Q000502:physiology*; D000818:Animals; D018507:Gene Expression Regulation, Developmental; D015971:Gene Expression Regulation, Enzymologic; D006333:Heart Failure / Q000235:genetics* / Q000503:physiopathology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000235:genetics*; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D020411:Oligonucleotide Array Sequence Analysis; D010101:Oxygen Consumption / Q000502:physiology; D010641:Phenotype; D005082:Physical Exertion / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014158:Transcription, Genetic / Q000502:physiology
D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse