Neuronal nitric oxide synthase mediates insulin- and oxidative stress-induced glucose uptake in skeletal muscle myotubes

Nitric oxide influences intramuscular signaling that affects skeletal muscle glucose uptake during exercise. The role of the main NO-producing enzyme isoform activated during skeletal muscle contraction, neuronal nitric oxide synthase-μ (nNOSμ), in modulating glucose uptake has not been investigated in a physiological exercise model. In this study, conscious and unrestrained chronically catheterized nNOSμ+/+ and nNOSμ−/− mice either remained at rest or ran on a treadmill at 17 m/min for 30 min. Both groups of mice demonstrated similar exercise capacity during a maximal exercise test to exhaustion (17.7 ± 0.6 vs. 15.9 ± 0.9 min for nNOSμ+/+ and nNOSμ−/−, respectively, P > 0.05). Resting and exercise blood glucose levels were comparable between the genotypes. Very low levels of NOS activity were detected in skeletal muscle from nNOSμ−/− mice, and exercise increased NOS activity only in nNOSμ+/+ mice (4.4 ± 0.3 to 5.2 ± 0.4 pmol·mg−1·min−1, P < 0.05). Exercise significantly increased glucose uptake in gastrocnemius muscle (5- to 7-fold) and, surprisingly, more so in nNOSμ−/− than in nNOSμ+/+ mice ( P < 0.05). This is in parallel with a greater increase in AMPK phosphorylation during exercise in nNOSμ−/− mice. In conclusion, nNOSμ is not essential for skeletal muscle glucose uptake during exercise, and the higher skeletal muscle glucose uptake during exercise in nNOSμ−/− mice may be due to compensatory increases in AMPK activation.

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Reduced neuronal nitric oxide synthase expression contributes to cardiac oxidative stress and nitroso-redox imbalance in ob/ob mice

Nitric Oxide ◽

10.1016/j.niox.2006.12.001 ◽

2007 ◽

Vol 16 (3) ◽

pp. 331-338 ◽

Cited By ~ 35

Author(s):

Roberto M. Saraiva ◽

Khalid M. Minhas ◽

Meizi Zheng ◽

Eleanor Pitz ◽

Adriana Treuer ◽

...

Keyword(s):

Oxidative Stress ◽

Nitric Oxide ◽

Nitric Oxide Synthase ◽

Neuronal Nitric Oxide Synthase ◽

Redox Imbalance ◽

Oxide Synthase

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Melatonin, Nitric Oxide Synthase and Oxidative Stress: Implications in Aging

Catecholamine Research - Advances in Behavioral Biology ◽

10.1007/978-1-4757-3538-3_57 ◽

2002 ◽

pp. 245-248

Author(s):

D. K. Lahiri ◽

Y-.W. Ge ◽

J. I. Nurnberger ◽

E. Y. Yang ◽

S. C. Bondy

Keyword(s):

Oxidative Stress ◽

Nitric Oxide ◽

Nitric Oxide Synthase ◽

Oxide Synthase ◽

And Oxidative Stress

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Glucose uptake during contraction in isolated skeletal muscles from neuronal nitric oxide synthase μ knockout mice

Journal of Applied Physiology ◽

10.1152/japplphysiol.00056.2015 ◽

2015 ◽

Vol 118 (9) ◽

pp. 1113-1121 ◽

Cited By ~ 12

Author(s):

Yet Hoi Hong ◽

Tony Frugier ◽

Xinmei Zhang ◽

Robyn M. Murphy ◽

Gordon S. Lynch ◽

...

Keyword(s):

Nitric Oxide ◽

Skeletal Muscle ◽

Nitric Oxide Synthase ◽

Glucose Uptake ◽

Ex Vivo ◽

Organ Bath ◽

Skeletal Muscle Glucose Uptake ◽

Nos Inhibitor ◽

Amp Activated Protein Kinase ◽

Oxide Synthase

Inhibition of nitric oxide synthase (NOS) significantly attenuates the increase in skeletal muscle glucose uptake during contraction/exercise, and a greater attenuation is observed in individuals with Type 2 diabetes compared with healthy individuals. Therefore, NO appears to play an important role in mediating muscle glucose uptake during contraction. In this study, we investigated the involvement of neuronal NOSμ (nNOSμ), the main NOS isoform activated during contraction, on skeletal muscle glucose uptake during ex vivo contraction. Extensor digitorum longus muscles were isolated from nNOSμ−/−and nNOSμ+/+mice. Muscles were contracted ex vivo in a temperature-controlled (30°C) organ bath with or without the presence of the NOS inhibitor NG-monomethyl-l-arginine (L-NMMA) and the NOS substrate L-arginine. Glucose uptake was determined by radioactive tracers. Skeletal muscle glucose uptake increased approximately fourfold during contraction in muscles from both nNOSμ−/−and nNOSμ+/+mice. L-NMMA significantly attenuated the increase in muscle glucose uptake during contraction in both genotypes. This attenuation was reversed by L-arginine, suggesting that L-NMMA attenuated the increase in muscle glucose uptake during contraction by inhibiting NOS and not via a nonspecific effect of the inhibitor. Low levels of NOS activity (∼4%) were detected in muscles from nNOSμ−/−mice, and there was no evidence of compensation from other NOS isoform or AMP-activated protein kinase which is also involved in mediating muscle glucose uptake during contraction. These results indicate that NO regulates skeletal muscle glucose uptake during ex vivo contraction independently of nNOSμ.

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Pulmonary Microvascular Constriction and Oxidative Stress in the Intact‐ventilated Mouse Lung during Acute Inhibition of Nitric Oxide Synthase

The FASEB Journal ◽

10.1096/fasebj.25.1_supplement.1102.8 ◽

2011 ◽

Vol 25 (S1) ◽

Author(s):

Andrew M. Roberts ◽

David Lominadze ◽

Sujith Dassanayaka ◽

Leroy R. Sachleben ◽

Charla L. Juniel ◽

...

Keyword(s):

Oxidative Stress ◽

Nitric Oxide ◽

Nitric Oxide Synthase ◽

Mouse Lung ◽

Oxide Synthase ◽

And Oxidative Stress

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Ac2-26 Alleviates Brain Injury after Cardiac Arrest and Cardiopulmonary Resuscitation in Rats via the eNOS Pathway

Mediators of Inflammation ◽

10.1155/2020/3649613 ◽

2020 ◽

Vol 2020 ◽

pp. 1-10

Author(s):

Jing Gong ◽

Qi-Hang Tai ◽

Guang-Xiao Xu ◽

Xue-Ting Wang ◽

Jing-Li Zhu ◽

...

Keyword(s):

Oxidative Stress ◽

Nitric Oxide ◽

Brain Injury ◽

Nitric Oxide Synthase ◽

Endothelial Nitric Oxide Synthase ◽

Saline Group ◽

Related Factors ◽

Oxide Synthase ◽

Endothelial Nitric Oxide ◽

And Oxidative Stress

Background. Brain injury is the leading cause of death following cardiac arrest (CA) and cardiopulmonary resuscitation (CPR). Ac2-26 and endothelial nitric oxide synthase (eNOS) have been shown to reduce neuroinflammation. This study is aimed at determining the mechanism by which Ac2-26 protects against inflammation during brain injury following CA and CPR. Methods. Sixty-four rats were randomized into sham, saline, Ac2-26, and Ac2-26+L-NIO (endothelial nitric oxide synthase (eNOS) inhibitor) groups. Rats received Ac2-26, Ac2-26+L-NIO, or saline after CPR. Neurologic function was assessed at baseline, 24, and 72 hours after CPR. At 72 hours after resuscitation, serum and brain tissues were collected. Results. Blood-brain barrier (BBB) permeability increased, and the number of surviving neurons and neurological function decreased in the saline group compared to the sham group. Anti-inflammatory and proinflammatory factors, neuron-specific enolase (NSE) levels, and the expression of eNOS, phosphorylated (p)-eNOS, inducible nitric oxide synthase (iNOS), and oxidative stress-related factors in the three CA groups significantly increased (P<0.05). BBB permeability decreased, and the number of surviving neurons and neurological function increased in the Ac2-26 group compared to the saline group (P<0.05). Ac2-26 increased anti-inflammatory and reduced proinflammatory markers, raised NSE levels, increased the expression of eNOS and p-eNOS, and reduced the expression of iNOS and oxidative stress-related factors compared to the saline group (P<0.05). The effect of Ac2-26 on brain injury was reversed by L-NIO (P<0.05). Conclusions. Ac2-26 reduced brain injury after CPR by inhibiting oxidative stress and neuroinflammation and protecting the BBB. The therapeutic effect of Ac2-26 on brain injury was largely dependent on the eNOS pathway.

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