Voluntary physical activity alterations in endothelial nitric oxide synthase knockout mice

Abstract

Momken, Iman, Patrick Lechêne, Renée Ventura-Clapier, and Vladimir Veksler. Voluntary physical activity alterations in endothelial nitric oxide synthase knockout mice. Am J Physiol Heart Circ Physiol 287: H914 -H920, 2004; 10.1152/ajpheart.00651.2003.-One of the main factors that control vasoreactivity and angiogenesis is nitric oxide produced by endothelial nitric oxide synthase (eNOS). We recently showed that knocking out eNOS induces an important reduction of mitochondrial oxidative capacity in slow-twitch skeletal muscle. Here we investigated eNOS's role in physical activity and contribution to adaptation of muscle energy metabolism to exercise conditions. Physical capacity of mice null for the eNOS isoform (eNOSϪ/Ϫ) was estimated for 8 wk with a voluntary wheel-running protocol. In parallel, we studied energy metabolism enzyme profiles and their response to voluntary exercise in cardiac and slow-twitch soleus (Sol) and fast-twitch gastrocnemius (Gast) skeletal muscles. Weekly averaged running distance was two times lower for eNOSϪ/Ϫ (4.09 Ϯ 0.42 km/day) than for wild-type (WT; 7.74 Ϯ 0.42 km/day; P Ͻ 0.01) mice. Average maximal speed of running was also lower in eNOSϪ/Ϫ (17.2 Ϯ 1.4 m/min) than WT (21.2 Ϯ 0.9 m/min; P Ͻ 0.01) mice. Voluntary exercise influenced adaptation to exercise specifically in Sol muscle. Physical activity significantly increased Sol weight by 22% (P Ͻ 0.05) in WT but not eNOSϪ/Ϫ mice. WT Sol muscle did not change its metabolic profile in response to exercise, in contrast to eNOSϪ/Ϫ muscle, in which physical activity decreased cytochrome-c oxidase (COX; Ϫ36%; P Ͻ 0.05), citrate synthase (Ϫ37%; P Ͻ 0.06), and creatine kinase (Ϫ24%, P Ͻ 0.01) activities. Voluntary exercise did not change energy enzyme profile in heart (except for 39% increase in COX activity in WT) or Gast muscle. These results suggest that eNOS is necessary for maintaining a suitable physical capacity and that when eNOS is downregulated, even moderate exercise could worsen energy metabolism specifically in oxidative skeletal muscle. muscles; exercise; mitochondria; energy metabolism MANY VASOREACTIVE FACTORS contribute to maintain adequate blood flow in muscles under different physiological conditions. One of the main factors that control vasoreactivity and angiogenesis is endothelium-derived NO (1,14,42). This substance is produced in a reaction catalyzed by NO synthase (NOS), transforming L-arginine to L-citrulline. Among the NOS isoenzymes-neuronal (nNOS), inducible (iNOS), and endothelial (eNOS)-the latter is the major isoform expressed in endothelial cells throughout the vascular bed. Mice lacking eNOS show reduced angiogenic ability (41), and inhibition of NOS has been shown to inhibit vascular remodeling in rabbits (51). In turn, it has been demonstrated that the microcirculation is a determinant of oxidative capacity in skeletal muscles (22,27), and severe reductions in blood flow have been shown to deleteriously affect muscle oxidative capacity and related enzyme activities (3, 4). Recent data directly showed a...

Long-term voluntary exercise, representing habitual exercise, lowers visceral fat and alters plasma amino acid levels in mice

“…As shown in Table 2, Exmice had less visceral adipose tissue and a lower liver weight, consistent with results reported for rats using a running wheel for a shorter period [17]. The weight of the soleus muscle increased after long-term exercise (Table 2), which is in agreement with previous findings [31,32]. Qualitative muscular change was also examined in this model [31,32].…”

Endothelial Nitric Oxide Synthase (NOS3) +894 G>T Associates with Physical Activity and Muscle Performance among Young Adults

“…In turn, the NOS3 knockout mice displayed a less favorable cardiovascular risk factor profile than their genetic counterparts [34]. These data reinforce the notion that NOS3 is an important gene to further investigate for its associations with voluntary PA in humans.…”

“…Interestingly, mice without the NOS3 gene (NOS3 knockout mice) were found to participate in lower levels of voluntary PA than the control mice with the NOS3 gene [34]. In turn, the NOS3 knockout mice displayed a less favorable cardiovascular risk factor profile than their genetic counterparts [34].…”

Endothelial nitric oxide synthase negatively regulates hydrogen peroxide-stimulated AMP-activated protein kinase in endothelial cells

“…Likewise, eNOS-dependent responses in both mice and rats appear to affect exercise capacity, oxygen consumption, and aerobic work (40). Interestingly, eNOS Ϫ/Ϫ mice show marked reductions in physical work capacity (41). Our finding that eNOS negatively regulates AMPK activation might suggest that the decreased physical activity in eNOS Ϫ/Ϫ mice could lead to the activation of AMPK-dependent metabolic pathways, which in turn would suppress the accumulation of energy stores and thereby lead to a decrease in exercise capacity.…”