nNOS and eNOS modulate cGMP formation and vascular response in contracting fast-twitch skeletal muscle

Lau, Kim S.; Grange, Robert W.; Isotani, Eiji; Sarelius, Ingrid H.; Kamm, Kristine E.; Huang, Paul L.; Stull, James T.

doi:10.1152/physiolgenomics.2000.2.1.21

Cited by 143 publications

(173 citation statements)

References 30 publications

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“…Such a positive effect of NO has also been found in insulin-resistant muscle cells derived from individuals with type 2 diabetes [21]. In addition, our observations, as those of several other groups, support the view that NO controls glucose transport via insulin-independent signalling pathways [48,49], including activation of cGMP-dependent protein kinase [50,51] and AMP-activated protein kinase-α1 [48,52]. Concerning the possible mechanisms involved, we found that restoration of endogenous nNOS in insulin-resistant muscle cells greatly improved translocation of GLUT4 at the plasma membrane in the presence of insulin, but not in basal conditions.…”

Section: Discussionsupporting

confidence: 89%

Counteracting neuronal nitric oxide synthase proteasomal degradation improves glucose transport in insulin-resistant skeletal muscle from Zucker fa/fa rats

Mezghenna¹,

Leroy²,

Azay-Milhau³

et al. 2013

Diabetologia

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Aims/hypothesis Insulin-mediated glucose transport and utilisation are decreased in skeletal muscle from type 2 diabetic and glucose-intolerant individuals because of alterations in insulin receptor signalling, GLUT4 translocation to the plasma membrane and microvascular blood flow. Catalytic activity of the muscle-specific isoform of neuronal nitric oxide synthase (nNOS) also participates in the regulation of glucose transport and appears to be decreased in a relevant animal model of drastic insulin resistance, the obese Zucker fa/fa rat. Our objective was to determine the molecular mechanisms involved in this defect. Methods Isolated rat muscles and primary cultures of myocytes were used for western blot analysis of protein expression, immunohistochemistry, glucose uptake measurements and GLUT4 translocation assays. Results nNOS expression was reduced in skeletal muscle from fa/fa rats. This was caused by increased ubiquitination of the enzyme and subsequent degradation by the ubiquitin proteasome pathway. The degradation occurred through a greater interaction of nNOS with the chaperone heat-shock protein 70 and the co-chaperone, carboxyl terminus of Hsc70-interacting protein (CHIP). In addition, an alteration in nNOS sarcolemmal localisation was observed. We confirmed the implication of nNOS breakdown in defective insulininduced glucose transport by demonstrating that blockade of proteasomal degradation or overexpression of nNOS improved basal and/or insulin-stimulated glucose uptake and GLUT4 translocation in primary cultures of insulin-resistant myocytes. Conclusions/interpretation Recovery of nNOS in insulinresistant muscles should be considered a potential new approach to address insulin resistance.

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Section: Discussionsupporting

confidence: 89%

Counteracting neuronal nitric oxide synthase proteasomal degradation improves glucose transport in insulin-resistant skeletal muscle from Zucker fa/fa rats

Mezghenna¹,

Leroy²,

Azay-Milhau³

et al. 2013

Diabetologia

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“…This small absolute increase in COX activity was completely reversed by voluntary activity. The relative resistance of glycolytic muscle to eNOS deficiency may be explained by lower eNOS expression (30,34) and relatively lower sensitivity of skeletal glycolytic fiber blood perfusion to NO production (38).…”

Section: Discussionmentioning

confidence: 99%

Voluntary physical activity alterations in endothelial nitric oxide synthase knockout mice

Momken

Lechêne

Ventura‐Clapier

et al. 2004

American Journal of Physiology-Heart and Circulatory Physiology

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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...

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“…Both muscle contraction [42] and SNP [18,42] increase cGMP formation. Furthermore pharmacological manipulation of both soluble guanylate cyclase and cGMP modulates the effect of SNP on glucose uptake [18,43].…”

Section: Signalling Pathwaysmentioning

confidence: 96%

Effects of the nitric oxide donor, sodium nitroprusside, on resting leg glucose uptake in patients with type 2 diabetes

et al. 2005

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Aims/hypothesis: Nitric oxide (NO) has been implicated as an important signalling molecule in the contraction-mediated glucose uptake pathway and may represent a novel strategy for blood glucose control. The current study sought to determine whether acute infusion of the NO donor, sodium nitroprusside (SNP), increases leg glucose uptake at rest in patients with type 2 diabetes. Methods: Fifteen male patients with type 2 diabetes (aged 54±4 years, mean±SD) were entered into a randomised, cross-over design study, examining the effect of a 30-min intra-femoral infusion of SNP on leg glucose uptake. Comparison was made with a 30-min infusion of verapamil, titrated to elicit similar leg blood flow responses to SNP. Leg blood flow was measured by thermodilution in the femoral vein, and leg glucose uptake was calculated as the product of leg blood flow and the femoral arterio-venous (A-V) glucose concentration gradient. Results: The two drugs increased leg blood flow to a similar extent (p= 0.50). Both leg A-V glucose concentration gradient (SNP 0.12±0.05, verapamil −0.06±0.04 mmol/l; mean±SEM, p=0.03) and leg glucose uptake (SNP 0.17±0.09, verapamil −0.09±0.06 mmol/min; p=0.03) were higher with the SNP treatment than with verapamil. These results occurred independently of any significant difference in plasma insulin concentration between drugs (p=0.56). Conclusions/interpretation: Acute infusion of SNP resulted in greater glucose uptake relative to verapamil. NO may therefore be an important mediator of peripheral glucose disposal and a potential therapeutic target in patients with type 2 diabetes.

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nNOS and eNOS modulate cGMP formation and vascular response in contracting fast-twitch skeletal muscle

Cited by 143 publications

References 30 publications

Counteracting neuronal nitric oxide synthase proteasomal degradation improves glucose transport in insulin-resistant skeletal muscle from Zucker fa/fa rats

Counteracting neuronal nitric oxide synthase proteasomal degradation improves glucose transport in insulin-resistant skeletal muscle from Zucker fa/fa rats

Voluntary physical activity alterations in endothelial nitric oxide synthase knockout mice

Effects of the nitric oxide donor, sodium nitroprusside, on resting leg glucose uptake in patients with type 2 diabetes

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