Expression of nitric oxide synthase in skeletal muscle: a novel role for nitric oxide as a modulator of insulin action.
Abstract
Previous studies have shown that nitric oxide synthase (NOS), the enzyme that catalyzes the formation of nitric oxide (NO), is expressed in skeletal muscle. The aim of the present study was to test the hypothesis that NO can modulate glucose metabolism in slow- and fast-twitch skeletal muscles. Calcium-dependent NOS was detected in skeletal muscle, and the enzyme activity was greater in fast-type extensor digitorum longus (EDL) muscles than in slow-type soleus muscles. Both the neuronal-type (nNOS) and endothelial-type (eNOS) enzymes are expressed in resting skeletal muscles. However, nNOS protein was only detected in EDL muscles, whereas eNOS protein contents were comparable in soleus and EDL muscles. NOS expression in muscle cryosections (diaphorase histochemistry) was located in vascular endothelium and in muscle fibers, and the staining was greater in type IIb than in type I and IIa fibers. The macrophage-type inducible NOS (iNOS) was not detected in resting muscle, but endotoxin treatment induced its expression, concomitant with elevated NO production. iNOS induction was associated with impaired insulin-stimulated glucose uptake in isolated rat muscles. In vitro, NOS blockade with specific inhibitors did not affect basal or insulin-stimulated glucose transport in EDL or soleus muscles. In contrast, the NO donors GEA 5024 and sodium nitroprusside induced dose-dependent inhibition (up to 50%) of maximal insulin-stimulated glucose transport in both muscles with minor effects on basal uptake values. GEA 5024 also blunted insulin-stimulated glucose transport and amino acid uptake in cultured L6 muscle cells without affecting insulin binding to its receptor. On the other hand, the permeable cGMP analogue dibutyryl cGMP did not affect muscle glucose transport. These results strongly suggest that NO modulates insulin action in both slow- and fast-type skeletal muscles. This novel autocrine action of NO in muscle appears to be mediated by cGMP-independent pathways.
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In several situations of insulin resistance, such as diet-induced or genetic obesity and endotoxaemia, iNOS is induced in tissues classically related to insulin signalling.
“In several situations of insulin resistance, such as diet-induced or genetic obesity, and endotoxaemia, iNOS is induced in tissues classically related to insulin signalling (Bedard et al. 1997; Kapur et al. 1997; Kapur et al. 1999).”
From Acute physical exercise reverses <i>S</i>‐nitrosation of the insulin receptor, insulin receptor substrate 1 and protein kinase B/Akt in diet‐induced obese Wistar rats (2008) · cites this paper as Kapur et al. 1997
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“Both NO and TNF-α decrease insulin-stimulated glucose uptake in muscle (72, 73).”
BackgroundInsulin and insulin resistance:
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“NO has a broad impact on glucose uptake, insulin resistance , exercise, blood flow, and contractility (Balon and Nadler , 1994; Shen et al., 1995, 1997; Joyner and Dietz, 1997; Kapur et al., 1997; Chen et al., 1998; Young and Leighton, 1998).”
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“The interaction between NO and insulin during exercise may have synergistic effects on muscle metabolism, promoting muscle maintenance and potentially attenuating sarcopenia 144 .”
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“It is well established that proinflammatory cytokines (tumor necrosis factor- and interleukin-6) and endotoxins synergistically increase NO production via increased expression of iNOS in rat skeletal muscle and cultured myocytes and adipocytes (8,17,18).”
BackgroundS-Nitrosylation-dependent Inactivation of Akt/Protein Kinase B in Insulin Resistance
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“This finding is consistent with the observations of several other studies (6,8,9,35).”
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“Constitutive NO production inside skeletal muscle fi bers modulates glucose transport and insulin-mediated skeletal muscle vasodilation (Steinberg et al 1994; Baron 1996; Balon and Nadler 1997; Kapur et al 1998; Roberts et al 1998).”
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“Nitric oxide stimulates glucose transport in isolated skeletal muscle (2, 48), where it is thought to have a role in mediating both insulin- (20, 22) and exercise-stimulated glucose uptake (34).”
BackgroundNO production results in suspension-induced muscle atrophy through dislocation of neuronal NOS
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“Sarcolemmal nNOS is reported to be a versatile molecule that modulates satellite cell activation (34), formation of neuromuscular junction (35), glucose uptake (36), muscle contraction, and vasodilation (37).”
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“It has been reported that iNOS induction in metabolic tissues and insulin target cells interferes with the insulin receptor beta (IR )/IRS/PI3K/Akt insulin signaling pathway [72, 80, 99, 102].”
BackgroundMediators of cytokine-induced insulin resistance in obesity and other inflammatory settings
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“This is possibly caused by the intracellular production of the potent oxidant peroxynitrite, further supporting the supposition that oxidative stress may impair insulin action [9].”
BackgroundACE Inhibitor Improves Insulin Resistance in Diabetic Mouse Via Bradykinin and NO
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“Finally, one investigation indicates that the induction of NO in skeletal muscle invitro isassociated witha diminutionof insulinstimulated glucose transport activity (Kapur et al., 1997).”
BackgroundCook, S., Hügli, O., Egli, M., Ménard, B., Thalmann, S., Sartori, C. S., Perrin, C., NICOD, P. H., Thorens, B., Vollenweider, P., et al. (2004) · Diabetes · doi:10.2337/diabetes.53.8.2067 · Cited by 130 · see citing works
“Moreover, eNOS is expressed in the skeletal muscle (9), and NO donors stimulate glucose transport in isolated rat muscle preparations in vitro (10–12).”
BackgroundInducible nitric oxide synthase plays a role in LPS-induced hyperglycemia and insulin resistance
Sugita, H., Kaneki, M., Tokunaga, E., Sugita, M., Koike, C., Yasuhara, S., Tompkins, R. G., & Martyn, J. A. J. (2002) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00087.2001 · Cited by 130 · see citing works
“tions include infection (6), sepsis, burn (33), autoimmune deficiency syndrome (36), and elevated levels of tumor necrosis factor- (TNF- ) (2, 19) and endotoxin (17, 18).”
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“Whereas some studies have indicated that NO or NO donors, such as sodium nitroprusside, can enhance insulin-stimulated glucose oxidation (31, 32) or insulinindependent glucose transport (1, 2, 9, 25) in isolated rat skeletal muscle, others have reported that enhancement of muscle NO in vitro causes a decrease in insul…”
BackgroundInsulin Reduces Plasma Arginase Activity in Type 2 Diabetic Patients
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“…in part through the induction of expression of inducible nitric oxide synthase (iNOS) and nitric oxide production in peripheral tissue and islet beta cells (Sandler et al., 1990; Lang et al., 1992; Hotamisligil et al., 1993, 1994; Kapur et al., 1997; Sprangers et al., 1998; Kwon et al., 1999).”
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“This was evidenced by studies showing that knockout mice for eNOS or nNOS ( NOS-1) developed insulin resistance, hypertension, and dys lipidemia (65, 66), while iNOS induction by pro-inflammatory cytokines caused impa ired insulin-stimulated glucose uptake in skeletal muscles isolated from rats (67).”
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“Vasoconstriction with inhibitors of NO synthase reliably reduces both flow and tissue glucose uptake as previously reported (27,28) and recapitulated here.”
ResultInducible Nitric Oxide Synthase Induction Underlies Lipid-Induced Hepatic Insulin Resistance in Mice
Charbonneau, A., & Marette, A. (2010) · Diabetes · doi:10.2337/db09-1238 · Cited by 113 · see citing works
“It has been previously reported that iNOS induction in metabolic tissues and insulin target cells interferes with the IR /IRS/PI3K/Akt insulin signaling pathway (1,5,6,28).”
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“[37] found no effect on either basal or”
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“Data from different sources indicate that AMPK activation reduces iNOS induction and blunts iNOS-mediated NO production (Bedard et al. 1997; Kapur et al. 1997; Pilon et al. 2004).”
BackgroundEvidence for iNOS-dependent peroxynitrite production in diabetic platelets
Tannous, M., Rabini, R. A., Vignini, A., Moretti, N., Fumelli, P., Zielinski, B. S., Mazzanti, L., & Mutus, B. (1999) · Diabetologia · doi:10.1007/s001250051192 · Cited by 97 · see citing works
“It has been hypothesized recently that iNOS expression in macrophages and other tissues after experimental animals have been treated with endotoxin might be responsible for the inhibition of insulin action in that condition and that it might contribute to the development of TNF-a-induced skeletal-muscle insulin resist…”
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“Both endogenous and neuronal nitric oxide synthase (NOS) proteins are expressed in skeletal muscle (Nakane et al. 1993; Kapur et al. 1997) and induce the activation of matrix metalloproteinases, causing the breakdown of the extra-cellular matrix (ECM) that contains bound HGF.”
BackgroundCytokines and endotoxin induce cytokine receptors in skeletal muscle
Zhang, Y., Pilon, G., Marette, A., & Baracos, V. E. (2000) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.2000.279.1.e196 · Cited by 94 · see citing works
“INJECTION OF BACTERIA or their endotoxin [lipopolysaccharide (LPS)] in animals results in metabolic alterations in skeletal muscle, including enhanced protein breakdown, decreased protein synthesis (18), decreased fatty acid uptake and oxidation (30), insulin resistance (24), and increased expression of inducible nitr…”
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“LPS decreases glucose uptake and induces iNOS expression in isolated soleus (8) and induces insulin resistance in rats (1).”
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Regulation of Cellular Gas Exchange, Oxygen Sensing, and Metabolic Control
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Mechanism of adipose tissue iNOS induction in endotoxemia
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“We have recently demonstrated that cytokines and LPS impair insulin-stimulated glucose transport by inducing iNOS expression and NO production in skeletal muscle cells (3, 19).”
BackgroundMethodSelf-citationSkeletal Muscle Function during Exercise—Fine-Tuning of Diverse Subsystems by Nitric Oxide
Suhr, F., Gehlert, S., Grau, M., & Bloch, W. (2013) · International Journal of Molecular Sciences · doi:10.3390/ijms14047109 · Cited by 78 · see citing works
“Examination of nNOS distribution in different muscle fiber types reveals that nNOS is mainly concentrated at the surface membrane of type II (fast-twitch) fibers (EDL, gastrocnemius, plantaris), whereas type I (slow-twitch; soleus) fibers shows no or only weak reaction [86,88,89].”
BackgroundWadley, G. D., Choate, J., & McConell, G. K. (2007) · The Journal of Physiology · doi:10.1113/jphysiol.2007.141309 · Cited by 75 · see citing works
“Both endothelial (eNOS) and neuronal (nNOS) isoforms are expressed within skeletal muscle fibres, with eNOS more abundant in oxidative, and nNOS more abundant in glycolytic rodent skeletal muscle (Kobzik et al. 1995; Hussain et al. 1997; Kapur et al. 1997; Lau et al. 2000).”
BackgroundEffect of nitric oxide synthase inhibition on mitochondrial biogenesis in rat skeletal muscle
Wadley, G. D., & McConell, G. K. (2006) · Journal of Applied Physiology · doi:10.1152/japplphysiol.00549.2006 · Cited by 73 · see citing works
“expressed in the soleus compared with the EDL (18) and gastrocnemius (14).”
BackgroundCsibi, A., Communi, D., Müller, N., & Bottari, S. P. (2010) · PLoS ONE · doi:10.1371/journal.pone.0010070 · Cited by 73 · see citing works
“Accordingly, the deleterious effects of iNOS, which generates high levels of NO, on insulin sensitivity have been demonstrated more than a decade ago by the seminal work of Marette and coworkers [36,37].”
BackgroundPilon, G., Charbonneau, A., White, P. J., Dallaire, P., Perreault, M., Kapur, S., & Marette, A. (2010) · PLoS ONE · doi:10.1371/journal.pone.0015912 · Cited by 74 · see citing works
“Glucose uptake determinations Glucose transport in isolated soleus muscles was measured using 2-[(3)H]2-deoxy-D-glucose as previously described [9].”
BackgroundMethodSelf-citationIRS‐1 Regulation in Health and Disease
Schmitz‐Peiffer, C., & Whitehead, J. P. (2003) · IUBMB Life · doi:10.1080/1521654031000138569 · Cited by 73 · see citing works
“…also mediate insulin resistance by activation of NF k B and enhanced transcription of inducible nitric oxide synthase (iNOS): NO production has been linked to insulin resistance in skeletal muscle ( 27 ), and targeted deletion of iNOS in muscle prevents insulin resistance in fat-fed mice ( 28 ).”
BackgroundGlutamine and arginine: immunonutrients for improved health
Field, C. J., JOHNSON, I., & Pratt, V. C. (2000) · Medicine & Science in Sports & Exercise · doi:10.1097/00005768-200007001-00002 · Cited by 70 · see citing works
Wang, R., Jiao, H., Zhao, J., Wang, X., & Lin, H. (2018) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2018/7569127 · Cited by 69 · see citing works
“The nNOS/NO system modulates muscle functions such as insulin sensitivity and glucose uptake, muscle contraction, vasodilation, and activation of satellite cells [37, 55, 56].”
BackgroundDallaire, P., Bellmann, K., Laplante, M., Gélinas, S., Centeno-Baez, C., Penfornis, P., Peyot, M., Latour, M. G., Lamontagne, J., Trujillo, M. E., et al. (2008) · Diabetes · doi:10.2337/db08-0540 · Cited by 65 · see citing works
“muscles, leading to defective insulin stimulation of glucose transport (21,22).”
BackgroundMethodSelf-citationNitric Oxide in Myogenesis and Therapeutic Muscle Repair
Palma, C. D., & Clementi, E. (2012) · Molecular Neurobiology · doi:10.1007/s12035-012-8311-8 · Cited by 66 · see citing works
“Such an effect is complemented by NO-dependent stimulation of glucose transport [7], both in the case of insulin [5, 21] and exercise-stimulated glucose uptake [21].”
BackgroundRegulation of GLUT4 traffic and function by insulin and contraction in skeletal muscle
Marette, A. (2003) · Frontiers in bioscience · doi:10.2741/1137 · Cited by 65 · see citing works
Self-citationStretch-induced nitric oxide modulates mechanical properties of skeletal muscle cells
Zhang, J. S., Kraus, W. E., & Truskey, G. A. (2004) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00018.2004 · Cited by 62 · see citing works
“Although endothelial NOS (eNOS, type III) expressed in skeletal muscle is responsive to mechanical stimulation as well, eNOS isoform is expressed at a low level relative to nNOS in skeletal muscle (2, 20).”
BackgroundUpregulation of neuronal nitric oxide synthase in skeletal muscle by swim training
Tatchum‐Talom, R., Schulz, R., McNeill, J. R., & Khadour, F. (2000) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.2000.279.4.h1757 · Cited by 62 · see citing works
Angiotensin converting enzyme inhibitors and modulation of skeletal muscle insulin resistance
Henriksen, E. J., & Jacob, S. (2003) · Diabetes Obesity and Metabolism · doi:10.1046/j.1463-1326.2003.00265.x · Cited by 60 · see citing works
Centeno-Baez, C., Dallaire, P., & Marette, A. (2011) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00530.2010 · Cited by 60 · see citing works
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“Both exercise and insulin mediated glucose uptake was found to be stimulated by nitric oxide (18, 19, 37).”
Akt/protein kinase B in skeletal muscle physiology and pathology
Wu, M., Falasca, M., & Blough, E. R. (2010) · Journal of Cellular Physiology · doi:10.1002/jcp.22353 · Cited by 58 · see citing works
“…in muscle iNOS expression are common in several insulin resistant models, including genetic obesity, diet-induced obesity, diabetic (db/db) mice, aging and endotoxemia- or LPS-treated animal models (Kapur et al., 1997; Carvalho-Filho et al., 2005, 2006; Yasukawa et al., 2005; Wu et al., 2009c).”
BackgroundShin, H., Park, Y., Kim, S.-U., Moon, H., Park, D., Han, Y., Lee, C., Lee, D., Song, I.-S., Lee, D. H., et al. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.259978 · Cited by 58 · see citing works
Dai, X., Ye, D., Zhang, Z., Cai, X., Bao, L., & Li, Y. (2013) · Biological and Pharmaceutical Bulletin · doi:10.1248/bpb.b12-00947 · Cited by 58 · see citing works
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Rottman, J. N., Bracy, D. P., Malabanan, C. M., Yue, Z., Clanton, J., & Wasserman, D. H. (2002) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00545.2001 · Cited by 58 · see citing works
“The lack of change in basal glucose uptake with L-NAME is consistent with earlier ex vivo studies (26).”
ResultLefort, N., St.-Amand, E., Morasse, S., Côté, C. H., & Marette, A. (2008) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.90362.2008 · Cited by 57 · see citing works
Self-citationExercise Reverses Peripheral Insulin Resistance in Trained L-NAME–Hypertensive Rats
d’Avila, K. D. A. L., Gadonski, G., Fang, J., et al. (1999) · Hypertension · doi:10.1161/01.hyp.34.4.768 · Cited by 57 · see citing works
Krause, M. D. S., Rodrigues-Krause, J. D. C., O’Hagan, C., VITO, G. D., Boreham, C. A., Susta, D., Newsholme, P., & Murphy, C. (2012) · Metabolism · doi:10.1016/j.metabol.2012.05.003 · Cited by 56 · see citing works
“Mice with gene disruption of endothelial nitric oxide synthase (eNOS) [21] or neuronalNOS (nNOS) [22] exhibit insulin resistance, hypertension, and dyslipidemia, whereas induction of inducible NO synthase (iNOS) by endotoxin and proinflammatory cytokines is associated with impaired insulin-stimulated skeletal muscle g…”
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“TNF-a and IFN-c are strong inducers of iNOS in both L6 myocytes and 3T3-L1 adipocytes (Bedard et al.,1997; Kapur et al.,1997,1999).”
BackgroundeNOS deletion impairs mitochondrial quality control and exacerbates Western diet-induced NASH
Sheldon, R. D., Meers, G. M.-E., Morris, E. M., Linden, M. A., Cunningham, R. P., Ibdah, J. A., Thyfault, J. P., Laughlin, M. H., & Rector, R. S. (2019) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00096.2019 · Cited by 55 · see citing works
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“peripheral tissues such as skeletal muscle.(8,9) On the other hand, ADMA has been shown to be a negative predictor of insulin sensitivity, independent of confounding factors,(10) and to increase blood pressure and arterial stiffness and reduce cerebral blood flow even at subpressor doses(11) in human participants.”
BackgroundCellular and molecular regulation of cardiac glucose transport
Young, L. H., Coven, D. L., & Russell, R. R. (2000) · Journal of Nuclear Cardiology · doi:10.1016/s1071-3581(00)70016-x · Cited by 55 · see citing works
Nitric oxide: a new player in the modulation of energy metabolism
Kapur, S., Picard, F., Perreault, M., Deshaies, Y., & Marette, A. (2000) · International Journal of Obesity · doi:10.1038/sj.ijo.0801502 · Cited by 52 · see citing works
Self-citationInvolvement of Bradykinin and Nitric Oxide in Leptin-Mediated Glucose Uptake in Skeletal Muscle
Shiuchi, T., Hironori Nakagami, A., Iwai, M., Takeda, Y., Cui, T., Chen, R., Minokoshi, Y., & Horiuchi, M. (2001) · Endocrinology · doi:10.1210/endo.142.2.7964 · Cited by 50 · see citing works
Skeletal Muscle Dysfunction in Patients with Chronic Obstructive Pulmonary Disease
Kim, H. C., Lee, G. D., & Hwang, Y. S. (2010) · Tuberculosis & respiratory diseases · doi:10.4046/trd.2010.68.3.125 · Cited by 50 · see citing works
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Emanuelli, B., Glondu, M., Filloux, C., et al. (2004) · Diabetes · doi:10.2337/diabetes.53.suppl_3.s97 · Cited by 46 · see citing works
Cook, S. (2006) · Swiss Medical Weekly · doi:10.4414/smw.2006.11068 · Cited by 45 · see citing works
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“In the IL-1ß/TNF-α/-induced acute inflammatory response, skeletal muscle uptake of glucose is suppressed, which suggests an inhibitory effect of these proinflammatory cytokines on insulin sensitivity (Ling et al., 1994; Kapur et al., 1997).”
Background
- Authors
- Kapur, S., Bédard, S., Marcotte, B., Côté, C. H., & Marette, A.
- Affiliations
- Université Laval (CA)
- Department of Physiology and Lipid Research Unit, Laval University Hospital Research Center Quebec, G1V 4G2, Canada
- Venue
- Diabetes
- Publisher
- American Diabetes Association
- Published
- 1997-11-01
- Volume
- 46
- Issue
- 11
- Pages
- 1691-1700
- ISSN
- 0012-1797 (ISSN-L)
- 1939-327X
- OpenAlex
- W2104847030
- Cited by
- 225
- References
- 0
- Citations by year
- 2026: 2 · 2024: 1 · 2023: 3 · 2022: 2 · 2020: 2 · 2019: 4 · 2018: 4 · 2017: 5 · 2016: 5 · 2015: 8 · 2014: 5 · 2013: 5 · 2012: 11
- FWCI
- 5.70
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Diabetes (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
- Keywords
- nitric oxide synthase, nitric oxide, skeletal muscle, insulin action, insulin-stimulated glucose transport, fast-twitch muscle, slow-twitch muscle, extensor digitorum longus, soleus muscle, neuronal nitric oxide synthase, endothelial nitric oxide synthase, inducible nitric oxide synthase, endotoxin, amino acid uptake, cGMP-independent signaling, autocrine signaling
- MeSH terms
- Amino Acids, Animals, Cell Line, Dibutyryl Cyclic GMP, Endothelium, Vascular, Glucose, Insulin, Isoenzymes, Kinetics, Dihydrolipoamide Dehydrogenase, Myosins, Nitric Oxide, Organ Specificity, Triazoles, Rats, Sprague-Dawley, Muscle, Skeletal, Muscle Fibers, Fast-Twitch, Muscle Fibers, Slow-Twitch, Nitric Oxide Synthase, Rats
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