Skip to main content
SpringerLink
Log in

nNOS regulation of skeletal muscle fatigue and exercise performance

  • Review
  • Published:
Biophysical Reviews Aims and scope Submit manuscript

Abstract

Neuronal nitric oxide synthases (nNOS) are Ca2+/calmodulin-activated enzymes that synthesize the gaseous messenger nitric oxide (NO). nNOSμ and the recently described nNOSβ, both spliced nNOS isoforms, are important enzymatic sources of NO in skeletal muscle, a tissue long considered to be a paradigmatic system for studying NO-dependent redox signaling. nNOS is indispensable for skeletal muscle integrity and contractile performance, and deregulation of nNOSμ signaling is a common pathogenic feature of many neuromuscular diseases. Recent evidence suggests that both nNOSμ and nNOSβ regulate skeletal muscle size, strength, and fatigue resistance, making them important players in exercise performance. nNOSμ acts as an activity sensor and appears to assist skeletal muscle adaptation to new functional demands, particularly those of endurance exercise. Prolonged inactivity leads to nNOS-mediated muscle atrophy through a FoxO-dependent pathway. nNOS also plays a role in modulating exercise performance in neuromuscular disease. In the mdx mouse model of Duchenne muscular dystrophy, defective nNOS signaling is thought to restrict contractile capacity of working muscle in two ways: loss of sarcolemmal nNOSμ causes excessive ischemic damage while residual cytosolic nNOSμ contributes to hypernitrosylation of the ryanodine receptor, causing pathogenic Ca2+ leak. This defect in Ca2+ handling promotes muscle damage, weakness, and fatigue. This review addresses these recent advances in the understanding of nNOS-dependent redox regulation of skeletal muscle function and exercise performance under physiological and neuromuscular disease conditions.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  • Adams ME, Kramarcy N, Krall SP, Rossi SG, Rotundo RL, Sealock R, Froehner SC (2000) Absence of alpha-syntrophin leads to structurally aberrant neuromuscular synapses deficient in utrophin. J Cell Biol 150:1385–1398

    Article  PubMed  CAS  Google Scholar 

  • Adams ME, Tesch Y, Percival JM, Albrecht DE, Conhaim JI, Anderson K, Froehner SC (2008) Differential targeting of nNOS and AQP4 to dystrophin-deficient sarcolemma by membrane-directed alpha-dystrobrevin. J Cell Sci 121:48–54

    Article  PubMed  CAS  Google Scholar 

  • Allen DG, Lamb GD, Westerblad H (2008) Skeletal muscle fatigue: cellular mechanisms. Physiol Rev 88:287–332

    Article  PubMed  CAS  Google Scholar 

  • Aracena P, Tang W, Hamilton SL, Hidalgo C (2005) Effects of S-glutathionylation and S-nitrosylation on calmodulin binding to triads and FKBP12 binding to type 1 calcium release channels. Antioxid Redox Signal 7:870–881

    Article  PubMed  CAS  Google Scholar 

  • Asai A, Sahani N, Kaneki M, Ouchi Y, Martyn JA, Yasuhara SE (2007) Primary role of functional ischemia, quantitative evidence for the two-hit mechanism, and phosphodiesterase-5 inhibitor therapy in mouse muscular dystrophy. PLoS One 2:e806

    Article  PubMed  Google Scholar 

  • Ayata C, Ayata G, Hara H, Matthews RT, Beal MF, Ferrante RJ, Endres M, Kim A, Christie RH, Waeber C, Huang PL, Hyman BT, Moskowitz MA (1997) Mechanisms of reduced striatal NMDA excitotoxicity in type I nitric oxide synthase knock-out mice. J Neurosci 17:6908–6917

    PubMed  CAS  Google Scholar 

  • Balon TW, Nadler JL (1997) Evidence that nitric oxide increases glucose transport in skeletal muscle. J Appl Physiol 82:359–363

    PubMed  CAS  Google Scholar 

  • Bassel-Duby R, Olson EN (2006) Signaling pathways in skeletal muscle remodeling. Annu Rev Biochem 75:19–37

    Article  PubMed  CAS  Google Scholar 

  • Bellinger AM, Reiken S, Dura M, Murphy PW, Deng SX, Landry DW, Nieman D, Lehnart SE, Samaru M, LaCampagne A, Marks AR (2008) Remodeling of ryanodine receptor complex causes “leaky” channels: a molecular mechanism for decreased exercise capacity. Proc Natl Acad Sci USA 105:2198–2202

    Article  PubMed  CAS  Google Scholar 

  • Bellinger AM, Reiken S, Carlson C, Mongillo M, Liu X, Rothman L, Matecki S, Lacampagne A, Marks AR (2009) Hypernitrosylated ryanodine receptor calcium release channels are leaky in dystrophic muscle. Nat Med 15:325–330

    Article  PubMed  CAS  Google Scholar 

  • Bramble DM, Lieberman DE (2004) Endurance running and the evolution of Homo. Nature 432:345–352

    Article  PubMed  CAS  Google Scholar 

  • Bredt DS, Snyder SH (1990) Isolation of nitric oxide synthetase, a calmodulin-requiring enzyme. Proc Natl Acad Sci USA 87:682–685

    Article  PubMed  CAS  Google Scholar 

  • Bredt DS, Hwang PM, Glatt CE, Lowenstein C, Reed RR, Snyder SH (1991) Cloned and expressed nitric oxide synthase structurally resembles cytochrome P-450 reductase. Nature 351:714–718

    Article  PubMed  CAS  Google Scholar 

  • Brenman JE, Chao DS, Xia H, Aldape K, Bredt DS (1995) Nitric oxide synthase complexed with dystrophin and absent from skeletal muscle sarcolemma in Duchenne muscular dystrophy. Cell 82:743–752

    Article  PubMed  CAS  Google Scholar 

  • Brenman JE, Chao DS, Gee SH, McGee AW, Craven SE, Santillano DR, Wu Z, Huang F, Xia H, Peters MF, Froehner SC, Bredt DS (1996) Interaction of nitric oxide synthase with the postsynaptic density protein PSD-95 and alpha1-syntrophin mediated by PDZ domains. Cell 84:757–767

    Article  PubMed  CAS  Google Scholar 

  • Carter GT, Wineinger MA, Walsh SA, Horasek SJ, Abresch RT, Fowler WM Jr (1995) Effect of voluntary wheel-running exercise on muscles of the mdx mouse. Neuromuscul Disord 5:323–332

    Article  PubMed  CAS  Google Scholar 

  • Chang WJ, Iannaccone ST, Lau KS, Masters BS, McCabe TJ, McMillan K, Padre RC, Spencer MJ, Tidball JG, Stull JT (1996) Neuronal nitric oxide synthase and dystrophin-deficient muscular dystrophy. Proc Natl Acad Sci USA 93:9142–9147

    Article  PubMed  CAS  Google Scholar 

  • Cheong E, Tumbev V, Stoyanovsky D, Salama G (2005) Effects of pO2 on the activation of skeletal muscle ryanodine receptors by NO: a cautionary note. Cell Calcium 38:481–488

    Article  PubMed  CAS  Google Scholar 

  • Crimi E, Ignarro LJ, Cacciatore F, Napoli C (2009) Mechanisms by which exercise training benefits patients with heart failure. Nat Rev Cardiol 6:292–300

    Article  PubMed  Google Scholar 

  • Crosbie RH, Barresi R, Campbell KP (2002) Loss of sarcolemma nNOS in sarcoglycan-deficient muscle. FASEB J 16:1786–1791

    Article  PubMed  CAS  Google Scholar 

  • Durham WJ, Aracena-Parks P, Long C, Rossi AE, Goonasekera SA, Boncompagni S, Galvan DL, Gilman CP, Baker MR, Shirokova N, Protasi F, Dirksen R, Hamilton SL (2008) RyR1 S-nitrosylation underlies environmental heat stroke and sudden death in Y522S RyR1 knockin mice. Cell 133:53–65

    Article  PubMed  CAS  Google Scholar 

  • Eu JP, Sun J, Xu L, Stamler JS, Meissner G (2000) The skeletal muscle calcium release channel: coupled O2 sensor and NO signaling functions. Cell 102:499–509

    Article  PubMed  CAS  Google Scholar 

  • Eu JP, Hare JM, Hess DT, Skaf M, Sun J, Cardenas-Navina I, Sun QA, Dewhirst M, Meissner G, Stamler JS (2003) Concerted regulation of skeletal muscle contractility by oxygen tension and endogenous nitric oxide. Proc Natl Acad Sci USA 100:15229–15234

    Article  PubMed  CAS  Google Scholar 

  • Finanger-Hedderick EL, Simmers JL, Soleimani A, Andres-Mateos E, Marx R, Files DC, King L, Crawford TO, Corse AM, Cohn RD (2011) Loss of sarcolemmal nNOS is common in acquired and inherited neuromuscular disorders. Neurology 76:960–967

    Article  PubMed  CAS  Google Scholar 

  • Foster MW, Hess DT, Stamler JS (2009) Protein S-nitrosylation in health and disease: a current perspective. Trends Mol Med 15:391–404

    Article  PubMed  CAS  Google Scholar 

  • Frandsen U, Höffner L, Betak A, Saltin B, Bangsbo J, Hellsten Y (2000) Endurance training does not alter the level of neuronal nitric oxide synthase in human skeletal muscle. J Appl Physiol 89:1033–1038

    PubMed  CAS  Google Scholar 

  • Glass DJ (2010) Signaling pathways perturbing muscle mass. Curr Opin Clin Nutr Metab Care 13:225–229

    Article  PubMed  CAS  Google Scholar 

  • Gonzalez DR, Beigi F, Treuer AV, Hare JM (2007) Deficient ryanodine receptor S-nitrosylation increases sarcoplasmic reticulum calcium leak and arrhythmogenesis in cardiomyocytes. Proc Natl Acad Sci USA 104:20612–20617

    Article  PubMed  CAS  Google Scholar 

  • Grady RM, Zhou H, Cunningham JM, Henry MD, Campbell KP, Sanes JR (2000) Maturation and maintenance of the neuromuscular synapse: genetic evidence for roles of the dystrophin-glycoprotein complex. Neuron 25:279–293

    Article  PubMed  CAS  Google Scholar 

  • Handschin C, Spiegelman BM (2008) The role of exercise and PGC1alpha in inflammation and chronic disease. Nature 454:463–469

    Article  PubMed  CAS  Google Scholar 

  • Huang Z, Huang PL, Panahian N, Dalkara T, Fishman MC, Moskowitz MA (1994) Effects of cerebral ischemia in mice deficient in neuronal nitric oxide synthase. Science 265:1883–1885

    Article  PubMed  CAS  Google Scholar 

  • Kameya S, Miyagoe Y, Nonaka I, Ikemoto T, Endo M, Hanaoka K, Nabeshima Y, Takeda S (1999) alpha1-syntrophin gene disruption results in the absence of neuronal-type nitric-oxide synthase at the sarcolemma but does not induce muscle degeneration. J Biol Chem 274:2193–2200

    Article  PubMed  CAS  Google Scholar 

  • Keyser RE (2010) Peripheral fatigue: high-energy phosphates and hydrogen ions. PM R 2:347–358

    Article  PubMed  Google Scholar 

  • Kobayashi YM, Rader EP, Crawford RW, Iyengar NK, Thedens DR, Faulkner JA, Parikh SV, Weiss RM, Chamberlain JS, Moore SA, Campbell KP (2008) Sarcolemma-localized nNOS is required to maintain activity after mild exercise. Nature 456:511–515

    Article  PubMed  CAS  Google Scholar 

  • Kushnir A, Betzenhauser MJ, Marks AR (2010) Ryanodine receptor studies using genetically engineered mice. FEBS Lett 584:1956–1965

    Article  PubMed  CAS  Google Scholar 

  • Lai Y, Thomas GD, Yue Y, Yang HT, Li D, Long C, Judge L, Bostick B, Chamberlain JS, Terjung RL, Duan D (2009) Dystrophins carrying spectrin-like repeats 16 and 17 anchor nNOS to the sarcolemma and enhance exercise performance in a mouse model of muscular dystrophy. J Clin Invest 119:624–635

    Article  PubMed  CAS  Google Scholar 

  • Lanner JT, Georgiou DK, Joshi AD, Hamilton SL (2010) Ryanodine receptors: structure, expression, molecular details, and function in calcium release. Cold Spring Harb Perspect Biol 2:a003996

    Article  PubMed  CAS  Google Scholar 

  • Lerman I, Harrison BC, Freeman K, Hewett TE, Allen DL, Robbins J, Leinwand LA (2002) Genetic variability in forced and voluntary endurance exercise performance in seven inbred mouse strains. J Appl Physiol 92:2245–2255

    PubMed  Google Scholar 

  • Li D, Yue Y, Lai Y, Hakim CH, Duan D (2011a) Nitrosative stress elicited by nNOSμ delocalization inhibits muscle force in dystrophin-null mice. J Pathol 223:88–98

    Article  PubMed  CAS  Google Scholar 

  • Li D, Shin J-H, Duan D (2011b) INOS ablation does not improve specific force of the extensor digitorum longus muscle in dystrophin-deficient mdx4cv mice. PLoS One 6:e21618

    Article  PubMed  CAS  Google Scholar 

  • Lieberman DE, Bramble DM (2007) The evolution of marathon running: capabilities in humans. Sports Med 37:288–290

    Article  PubMed  Google Scholar 

  • Lou JS, Weiss MD, Carter GT (2010) Assessment and management of fatigue in neuromuscular disease. Am J Hosp Palliat Care 27:145–157

    Article  PubMed  Google Scholar 

  • McConell GK, Bradley SJ, Stephens TJ, Canny BJ, Kingwell BA, Lee-Young RS (2007) Skeletal muscle nNOS mu protein content is increased by exercise training in humans. Am J Physiol Regul Integr Comp Physiol 293:R821–R828

    Article  PubMed  CAS  Google Scholar 

  • Meissner G (2010) Regulation of ryanodine receptor ion channels through posttranslational modifications. Curr Top Membr 66:91–113

    Article  PubMed  CAS  Google Scholar 

  • Percival JM, Anderson KN, Gregorevic P, Chamberlain JS, Froehner SC (2008) Functional deficits in nNOSmu-deficient skeletal muscle: myopathy in nNOS knockout mice. PLoS One 3:e3387

    Article  PubMed  Google Scholar 

  • Percival JM, Anderson KN, Huang P, Adams ME, Froehner SC (2010) Golgi and sarcolemmal neuronal NOS differentially regulate contraction-induced fatigue and vasoconstriction in exercising mouse skeletal muscle. J Clin Invest 120:816–826

    Article  PubMed  CAS  Google Scholar 

  • Percival JM, Adamo CM, Beavo JA, Froehner SC (2011) Evaluation of the therapeutic utility of phosphodiesterase 5A inhibition in the mdx mouse model of duchenne muscular dystrophy. Handb Exp Pharmacol 204:323–344

    Article  PubMed  Google Scholar 

  • Piétri-Rouxel F, Gentil C, Vassilopoulos S, Baas D, Mouisel E, Ferry A, Vignaud A, Hourdé C, Marty I, Schaeffer L, Voit T, Garcia L (2010) DHPR alpha1S subunit controls skeletal muscle mass and morphogenesis. EMBO J 29:643–654

    Article  PubMed  Google Scholar 

  • Powers SK, Jackson MJ (2008) Exercise-induced oxidative stress: cellular mechanisms and impact on muscle force production. Physiol Rev 88:1243–1276

    Article  PubMed  CAS  Google Scholar 

  • Rudnick J, Püttmann B, Tesch PA, Alkner B, Schoser BG, Salanova M, Kirsch K, Gunga HC, Schiffl G, Lück G, Blottner D (2004) Differential expression of nitric oxide synthases (NOS 1–3) in human skeletal muscle following exercise countermeasure during 12 weeks of bed rest. FASEB J 18:1228–1230

    PubMed  CAS  Google Scholar 

  • Salanova M, Schiffl G, Rittweger J, Felsenberg D, Blottner D (2008) Ryanodine receptor type-1 (RyR1) expression and protein S-nitrosylation pattern in human soleus myofibres following bed rest and exercise countermeasure. Histochem Cell Biol 130:105–118

    Article  PubMed  CAS  Google Scholar 

  • Sander M, Chavoshan B, Harris SA, Iannaccone ST, Stull JT, Thomas GD, Victor RG (2000) Functional muscle ischemia in neuronal nitric oxide synthase-deficient skeletal muscle of children with Duchenne muscular dystrophy. Proc Natl Acad Sci USA 97:13818–13823

    Article  PubMed  CAS  Google Scholar 

  • Schiaffino S, Sandri M, Murgia M (2007) Activity-dependent signaling pathways controlling muscle diversity and plasticity. Physiology (Bethesda) 22:269–278

    Article  CAS  Google Scholar 

  • Silvagno F, Xia H, Bredt DS (1996) Neuronal nitric-oxide synthase-mu, an alternatively spliced isoform expressed in differentiated skeletal muscle. J Biol Chem 271:11204–11208

    Article  PubMed  CAS  Google Scholar 

  • Smerdu V, Karsch-Mizrachi I, Campione M, Leinwand L, Schiaffino S (1994) Type IIx myosin heavy chain transcripts are expressed in type IIb fibers of human skeletal muscle. Am J Physiol 267:C1723–C1728

    PubMed  CAS  Google Scholar 

  • Song W, Kwak HB, Kim JH, Lawler JM (2009) Exercise training modulates the nitric oxide synthase profile in skeletal muscle from old rats. J Gerontol A Biol Sci Med Sci 64:540–549

    Article  PubMed  Google Scholar 

  • Stamler JS, Meissner G (2001) Physiology of nitric oxide in skeletal muscle. Physiol Rev 81:209–237

    PubMed  CAS  Google Scholar 

  • Stoyanovsky D, Murphy T, Anno PR, Kim YM, Salama G (1997) Nitric oxide activates skeletal and cardiac ryanodine receptors. Cell Calcium 21:19–29

    Article  PubMed  CAS  Google Scholar 

  • Stuehr DJ, Santolini J, Wang ZQ, Wei CC, Adak S (2004) Update on mechanism and catalytic regulation in the NO synthases. J Biol Chem 279:36167–36170

    Article  PubMed  CAS  Google Scholar 

  • Suko J, Maurer-Fogy I, Plank B, Bertel O, Wyskovsky W, Hohenegger M, Hellmann G (1993) Phosphorylation of serine 2843 in ryanodine receptor-calcium release channel of skeletal muscle by cAMP-, cGMP- and CaM-dependent protein kinase. Biochim Biophys Acta 1175:193–206

    Article  PubMed  CAS  Google Scholar 

  • Sun J, Xin C, Eu JP, Stamler JS, Meissner G (2001) Cysteine-3635 is responsible for skeletal muscle ryanodine receptor modulation by NO. Proc Natl Acad Sci USA 98:11158–11162

    Article  PubMed  CAS  Google Scholar 

  • Suzuki N, Motohashi N, Uezumi A, Fukada S, Yoshimura T, Itoyama Y, Aoki M, Miyagoe-Suzuki Y, Takeda S (2007) NO production results in suspension-induced muscle atrophy through dislocation of neuronal NOS. J Clin Invest 117:2468–2476

    Article  PubMed  CAS  Google Scholar 

  • Tatchum-Talom R, Schulz R, McNeill JR, Khadour FH (2000) Upregulation of neuronal nitric oxide synthase in skeletal muscle by swim training. Am J Physiol Heart Circ Physiol 279:H1757–H1766

    PubMed  CAS  Google Scholar 

  • Thomas GD, Sander M, Lau KS, Huang PL, Stull JT, Victor RG (1998) Impaired metabolic modulation of alpha-adrenergic vasoconstriction in dystrophin-deficient skeletal muscle. Proc Natl Acad Sci USA 95:15090–15095

    Article  PubMed  CAS  Google Scholar 

  • Thomas GD, Shaul PW, Yuhanna IS, Froehner SC, Adams ME (2003) Vasomodulation by skeletal muscle-derived nitric oxide requires alpha-syntrophin-mediated sarcolemmal localization of neuronal nitric oxide synthase. Circ Res 92:554–560

    Article  PubMed  CAS  Google Scholar 

  • Tidball JG, Lavergne E, Lau KS, Spencer MJ, Stull JT, Wehling M (1998) Mechanical loading regulates NOS expression and activity in developing and adult skeletal muscle. Am J Physiol 275:C260–C266

    PubMed  CAS  Google Scholar 

  • Vassilakopoulos T, Deckman G, Kebbewar M, Rallis G, Harfouche R, Hussain SN (2003) Regulation of nitric oxide production in limb and ventilatory muscles during chronic exercise training. Am J Physiol Lung Cell Mol Physiol 284:L452–L457

    PubMed  CAS  Google Scholar 

  • Wang X, Weisleder N, Collet C, Zhou J, Chu Y, Hirata Y, Zhao X, Pan Z, Brotto M, Cheng H, Ma J (2005) Uncontrolled calcium sparks act as a dystrophic signal for mammalian skeletal muscle. Nat Cell Biol 7:525–530

    Article  PubMed  CAS  Google Scholar 

  • Webster C, Silberstein L, Hays AP, Blau HM (1988) Fast muscle fibers are preferentially affected in Duchenne muscular dystrophy. Cell 52:503–513

    Article  PubMed  CAS  Google Scholar 

  • Wehling-Henricks M, Oltmann M, Rinaldi C, Myung KH, Tidball JG (2009) Loss of positive allosteric interactions between neuronal nitric oxide synthase and phosphofructokinase contributes to defects in glycolysis and increased fatigability in muscular dystrophy. Hum Mol Genet 18:3439–3451

    Article  PubMed  CAS  Google Scholar 

  • Xu KY, Huso DL, Dawson TM, Bredt DS, Becker LC (1999) Ntric oxide synthase in cardiac sarcoplasmic reticulum. Proc Natl Acad Sci USA 96:657–662

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

I wish to thank Drs Kimberley Craven, Stanley Froehner, Marvin Adams, and Nicholas Whitehead for insightful discussions and critical comment. Funding sources include the Muscular Dystrophy Association (69075), Parent Project Muscular Dystrophy, and NIH grants R01 AR056221, R01 NS33145, and PO1 NS046788.

Conflict of Interest

None

Author information

Authors and Affiliations

  1. Department of Physiology & Biophysics, University of Washington, Box 357290, Seattle, WA, 98195-7290, USA

    Justin M. Percival

Authors
  1. Justin M. Percival
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Justin M. Percival.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Percival, J.M. nNOS regulation of skeletal muscle fatigue and exercise performance. Biophys Rev 3, 209–217 (2011). https://doi.org/10.1007/s12551-011-0060-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12551-011-0060-9

Keywords

Search

Navigation