McArdle Disease: A Unique Study Model in Sports Medicine


McArdle disease is arguably the paradigm of exercise intolerance in humans. This disorder is caused by inherited deficiency of myophosphorylase, the enzyme isoform that initiates glycogen breakdown in skeletal muscles. Because patients are unable to obtain energy from their muscle glycogen stores, this disease provides an interesting model of study for exercise physiologists, allowing insight to be gained into the understanding of glycogen-dependent muscle functions. Of special interest in the field of muscle physiology and sports medicine are also some specific (if not unique) characteristics of this disorder, such as the so-called ‘second wind’ phenomenon, the frequent exercise-induced rhabdomyolysis and myoglobinuria episodes suffered by patients (with muscle damage also occurring under basal conditions), or the early appearance of fatigue and contractures, among others. In this article we review the main pathophysiological features of this disorder leading to exercise intolerance as well as the currently available therapeutic possibilities. Patients have been traditionally advised by clinicians to refrain from exercise, yet sports medicine and careful exercise prescription are their best allies at present because no effective enzyme replacement therapy is expected to be available in the near future. As of today, although unable to restore myophosphorylase deficiency, the ‘simple’ use of exercise as therapy seems probably more promising and practical for patients than more ‘complex’ medical approaches.

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

Access options

Buy single article

Instant unlimited access to the full article PDF.

US$ 49.95

Price includes VAT for USA

Subscribe to journal

Immediate online access to all issues from 2019. Subscription will auto renew annually.

US$ 199

This is the net price. Taxes to be calculated in checkout.

Fig. 1
Fig. 2


  1. 1.

    McArdle B. Myopathy due to a defect in muscle glycogen breakdown. Clin Sci. 1951;10:20.

  2. 2.

    Lucia A, Ruiz JR, Santalla A, et al. Genotypic and phenotypic features of McArdle disease: insights from the Spanish national registry. J Neurol Neurosurg Psychiatry. 2012;83(3):322–8.

  3. 3.

    Bruno C, Cassandrini D, Martinuzzi A, et al. McArdle disease: the mutation spectrum of PYGM in a large Italian cohort. Hum Mut. 2006;27(7):718.

  4. 4.

    Quinlivan R, Buckley J, James M, et al. McArdle disease: a clinical review. J Neurol Neurosurg Psychiatry. 2010;81(11):1182–8.

  5. 5.

    Dubowith VSC, Oldfors A. Muscle biopsy; practical approach. 4th ed. New York: Elsevier; 2013.

  6. 6.

    Di Mauro S. Muscle glycogenoses: an overview. Acta Myol. 2007;26(1):35–41.

  7. 7.

    Lucia A, Nogales-Gadea G, Perez M, et al. McArdle disease: what do neurologists need to know? Nat Clin Pract Neurol. 2008;4(10):568–77.

  8. 8.

    Lucia AQR, Wakelin A, Martín MA, et al. The ‘McArdle paradox’: exercise is a good advice for the exercise intolerant. Br J Sports Med. 2013;47(12):2.

  9. 9.

    Haller RG, Vissing J. Spontaneous, “second wind” and glucose-induced second “second wind” in McArdle disease: oxidative mechanisms. Arch Neurol. 2002;59(9):1395–402.

  10. 10.

    Martin MA, Rubio JC, Buchbinder J, et al. Molecular heterogeneity of myophosphorylase deficiency (McArdle’s disease): a genotype-phenotype correlation study. Ann Neurol. 2001;50(5):574–81.

  11. 11.

    Di Mauro SHA, Tsujino S. Nonlysosomal glycogenoses. In: Engel AGFAC, editor. Myology. New York: McGraw-Hill; 2004. p. 1535–58.

  12. 12.

    Vissing J, Haller RG. A diagnostic cycle test for McArdle’s disease. Ann Neurol. 2003;54(4):539–42.

  13. 13.

    Braakhekke JP, de Bruin MI, Stegeman DF, et al. The second wind phenomenon in McArdle’s disease. Brain. 1986;109(Pt 6):1087–101.

  14. 14.

    Vissing J, Haller RG. The effect of oral sucrose on exercise tolerance in patients with McArdle’s disease. N Engl J Med. 2003;349(26):2503–9.

  15. 15.

    Nadaj-Pakleza AA, Vincitorio CM, Laforet P, et al. Permanent muscle weakness in McArdle disease. Muscle Nerve. 2009;40(3):350–7.

  16. 16.

    Wolfe GI, Baker NS, Haller RG, et al. McArdle’s disease presenting with asymmetric, late-onset arm weakness. Muscle Nerve. 2000;23(4):641–5.

  17. 17.

    Hultman E. Physiological role of muscle glycogen in man, with special reference to exercise. Circ Res. 1967;10:I99–114.

  18. 18.

    Hargreaves M. Skeletal muscle metabolism during exercise in humans. Clin Exp Pharmacol Physiol. 2000;27(3):225–8.

  19. 19.

    Pernow B, Saltin B. Availability of substrates and capacity for prolonged heavy exercise in man. J Appl Physiol. 1971;31(3):416–22.

  20. 20.

    Bergstrom J, Hermansen L, Hultman E, et al. Diet, muscle glycogen and physical performance. Acta Physiol Scand. 1967;71(2):140–50.

  21. 21.

    Hermansen L, Hultman E, Saltin B. Muscle glycogen during prolonged severe exercise. Acta Physiol Scand. 1967;71(2):129–39.

  22. 22.

    Hargreaves M, McConell G, Proietto J. Influence of muscle glycogen on glycogenolysis and glucose uptake during exercise in humans. J Appl Physiol. 1995;78(1):288–92.

  23. 23.

    Bangsbo J, Graham TE, Kiens B, et al. Elevated muscle glycogen and anaerobic energy production during exhaustive exercise in man. J Physiol. 1992;451:205–27.

  24. 24.

    Gollnick PD, Piehl K, Saubert CWT, et al. Diet, exercise, and glycogen changes in human muscle fibers. J Appl Physiol. 1972;33(4):421–5.

  25. 25.

    Chin ER, Allen DG. Effects of reduced muscle glycogen concentration on force, Ca2+ release and contractile protein function in intact mouse skeletal muscle. J Physiol. 1997;498(Pt 1):17–29.

  26. 26.

    Duhamel TA, Perco JG, Green HJ. Manipulation of dietary carbohydrates after prolonged effort modifies muscle sarcoplasmic reticulum responses in exercising males. Am J Physiol Regul Integr Comp Physiol. 2006;291(4):R1100–10.

  27. 27.

    Ortenblad N, Nielsen J, Saltin B, et al. Role of glycogen availability in sarcoplasmic reticulum Ca2+ kinetics in human skeletal muscle. J Physiol. 2011;589(Pt 3):711–25.

  28. 28.

    Ortenblad N, Westerblad H, Nielsen J. Muscle glycogen stores and fatigue. J Physiol. 2013;591(18):4405–13.

  29. 29.

    Dutka TL, Lamb GD. Na+–K+ pumps in the transverse tubular system of skeletal muscle fibers preferentially use ATP from glycolysis. Am J Physiol Cell Physiol. 2007;293(3):C967–77.

  30. 30.

    James JH, Wagner KR, King JK, et al. Stimulation of both aerobic glycolysis and Na(+)–K(+)–ATPase activity in skeletal muscle by epinephrine or amylin. Am J Physiol. 1999;277(1 Pt 1):E176–86.

  31. 31.

    Friden J, Seger J, Ekblom B. Topographical localization of muscle glycogen: an ultrahistochemical study in the human vastus lateralis. Acta Physiol Scand. 1989;135(3):381–91.

  32. 32.

    Marchand I, Chorneyko K, Tarnopolsky M, et al. Quantification of subcellular glycogen in resting human muscle: granule size, number, and location. J Appl Physiol. 2002;93(5):1598–607.

  33. 33.

    Wanson JC, Drochmans P. Rabbit skeletal muscle glycogen. A morphological and biochemical study of glycogen beta-particles isolated by the precipitation–centrifugation method. J Cell Biol. 1968;38(1):130–50.

  34. 34.

    Nielsen J, Suetta C, Hvid LG, et al. Subcellular localization-dependent decrements in skeletal muscle glycogen and mitochondria content following short-term disuse in young and old men. Am J Physiol Endocrinol Metab. 2010;299(6):E1053–60.

  35. 35.

    Graham TE, Yuan Z, Hill AK, et al. The regulation of muscle glycogen: the granule and its proteins. Acta Physiol. 2010;199(4):489–98.

  36. 36.

    Wanson JC, Drochmans P. Role of the sarcoplasmic reticulum in glycogen metabolism. Binding of phosphorylase, phosphorylase kinase, and primer complexes to the sarcovesicles of rabbit skeletal muscle. J Cell Biol. 1972;54(2):206–24.

  37. 37.

    Nielsen J, Ortenblad N. Physiological aspects of the subcellular localization of glycogen in skeletal muscle. Appl Physiol Nutr Metab. 2013;38(2):91–9.

  38. 38.

    Nielsen JCA, Ortenblad N, Westerblad H. Subcellular distribution of glycogen and decreased tetanic Ca2+ in fatigued single intact mouse muscle fibres. J Physiol. 2014;592(9):2003–12.

  39. 39.

    Nielsen J, Schroder HD, Rix CG, et al. Distinct effects of subcellular glycogen localization on tetanic relaxation time and endurance in mechanically skinned rat skeletal muscle fibres. J Physiol. 2009;587(Pt 14):3679–90.

  40. 40.

    Entman ML, Keslensky SS, Chu A, et al. The sarcoplasmic reticulum-glycogenolytic complex in mammalian fast twitch skeletal muscle. Proposed in vitro counterpart of the contraction-activated glycogenolytic pool. J Biol Chem. 1980;255(13):6245–52.

  41. 41.

    Xu KY, Becker LC. Ultrastructural localization of glycolytic enzymes on sarcoplasmic reticulum vesticles. J Histochem Cytochem. 1998;46(4):419–27.

  42. 42.

    Hirata Y, Atsumi M, Ohizumi Y, et al. Mastoparan binds to glycogen phosphorylase to regulate sarcoplasmic reticular Ca2+ release in skeletal muscle. Biochem J. 2003;371(Pt 1):81–8.

  43. 43.

    Krishnamoorthy N, Santosh V, Yasha TC, et al. Glycogen storage disease type V (Mc Ardle’s disease): a report on three cases. Neurol India. 2011;59(6):884–6.

  44. 44.

    Tachi N, Sasaki K, Tachi M, et al. Histochemical and biochemical studies in a patient with myophosphorylase deficiency. Eur Neurol. 1990;30(1):52–5.

  45. 45.

    De Stefano N, Argov Z, Matthews PM, et al. Impairment of muscle mitochondrial oxidative metabolism in McArdles’s disease. Muscle Nerve. 1996;19(6):764–9.

  46. 46.

    Haller RG, Clausen T, Vissing J. Reduced levels of skeletal muscle Na+K+–ATPase in McArdle disease. Neurology. 1998;50(1):37–40.

  47. 47.

    Lewis SF, Haller RG. The pathophysiology of McArdle’s disease: clues to regulation in exercise and fatigue. J Appl Physiol. 1986;61(2):391–401.

  48. 48.

    Zange J, Grehl T, Disselhorst-Klug C, et al. Breakdown of adenine nucleotide pool in fatiguing skeletal muscle in McArdle’s disease: a noninvasive 31P-MRS and EMG study. Muscle Nerve. 2003;27(6):728–36.

  49. 49.

    Haller RG, Lewis SF, Cook JD, et al. Hyperkinetic circulation during exercise in neuromuscular disease. Neurology. 1983;33(10):1283–7.

  50. 50.

    Vissing J, Vissing SF, MacLean DA, et al. Sympathetic activation in exercise is not dependent on muscle acidosis. Direct evidence from studies in metabolic myopathies. J Clin Invest. 1998;101:1654–60.

  51. 51.

    Rae DE, Noakes TD, San Juan AF, et al. Excessive skeletal muscle recruitment during strenuous exercise in McArdle patients. Eur J Appl Physiol. 2010;110(5):1047–55.

  52. 52.

    Allen DG, Lamb GD, Westerblad H. Skeletal muscle fatigue: cellular mechanisms. Physiol Rev. 2008;88(1):287–332.

  53. 53.

    Dirksen RT. Sarcoplasmic reticulum-mitochondrial through-space coupling in skeletal muscle. Appl Physiol Nutr Metab. 2009;34(3):389–95.

  54. 54.

    Nogales-Gadea G, Consuegra-Garcia I, Rubio JC, et al. A transcriptomic approach to search for novel phenotypic regulators in McArdle disease. PLoS One. 2012;7(2):e31718.

  55. 55.

    Odermatt A, Taschner PE, Khanna VK, et al. Mutations in the gene-encoding SERCA1, the fast-twitch skeletal muscle sarcoplasmic reticulum Ca2+ ATPase, are associated with Brody disease. Nat Genet. 1996;14(2):191–4.

  56. 56.

    Odermatt A, Barton K, Khanna VK, et al. The mutation of Pro789 to Leu reduces the activity of the fast-twitch skeletal muscle sarco(endo)plasmic reticulum Ca2+ ATPase (SERCA1) and is associated with Brody disease. Hum Genet. 2000;106(5):482–91.

  57. 57.

    Pan Y, Zvaritch E, Tupling AR, et al. Targeted disruption of the ATP2A1 gene encoding the sarco(endo)plasmic reticulum Ca2+ ATPase isoform 1 (SERCA1) impairs diaphragm function and is lethal in neonatal mice. J Biol Chem. 2003;278(15):13367–75.

  58. 58.

    Periasamy M, Kalyanasundaram A. SERCA pump isoforms: their role in calcium transport and disease. Muscle Nerve. 2007;35(4):430–42.

  59. 59.

    Cairns SP. Lactic acid and exercise performance: culprit or friend? Sports Med. 2006;36(4):279–91.

  60. 60.

    Vissing J, Haller RG. Mechanisms of exertional fatigue in muscle glycogenoses. Neuromuscul Disord. 2012;22(Suppl 3):S168–71.

  61. 61.

    Overgaard K, Nielsen OB. Activity-induced recovery of excitability in K(+)-depressed rat soleus muscle. Am J Physiol Regul Integr Comp Physiol. 2001;280(1):R48–55.

  62. 62.

    Nielsen OB, de Paoli F, Overgaard K. Protective effects of lactic acid on force production in rat skeletal muscle. J Physiol. 2001;536(Pt 1):161–6.

  63. 63.

    O’Dochartaigh CS, Ong HY, Lovell SM, et al. Oxygen consumption is increased relative to work rate in patients with McArdle’s disease. Eur J Clin Invest. 2004;34(11):731–7.

  64. 64.

    Mate-Munoz JL, Moran M, Perez M, et al. Favorable responses to acute and chronic exercise in McArdle patients. Clin J Sports Med. 2007;17(4):297–303.

  65. 65.

    Chavarren J, Calbet JA. Cycling efficiency and pedalling frequency in road cyclists. Eur J Appl Physiol Occup Physiol. 1999;80(6):555–63.

  66. 66.

    Brooks GA, Butterfield GE, Wolfe RR, et al. Increased dependence on blood glucose after acclimatization to 4,300 m. J Appl Physiol. 1991;70(2):919–27.

  67. 67.

    Keel BR, Brit M. McArdle’s disease: a clinical review and case report. Tenn Med. 2013;106(10):33, 37.

  68. 68.

    Miteff F, Potter HC, Allen J, et al. Clinical and laboratory features of patients with myophosphorylase deficiency (McArdle disease). J Clin Neurosci. 2011;18(8):1055–8.

  69. 69.

    Pillarisetti J, Ahmed A. McArdle disease presenting as acute renal failure. South Med J. 2007;100(3):313–6.

  70. 70.

    Getachew E, Prayson RA. Pathologic quiz case: a man with exertion-induced cramps and myoglobinuria. McArdle disease (glycogenosis type V or myophosphorylase deficiency). Arch Pathol Lab Med. 2003;127(9):1227–8.

  71. 71.

    Leite AON, Rocha M. McArdle diesease: a case report and review. Int Med Case Rep J. 2012;20(5):1–4. doi:10.2147/IMCRJ.S28664.

  72. 72.

    Mineo I, Kono N, Shimizu T, et al. Excess purine degradation in exercising muscles of patients with glycogen storage disease types V and VII. J Clin Invest. 1985;76(2):556–60.

  73. 73.

    Brooke MH, Patterson VH, Kaiser KK. Hypoxanthine and Mcardle disease: a clue to metabolic stress in the working forearm. Muscle Nerve. 1983;6(3):204–6.

  74. 74.

    Kitaoka Y, Ogborn DI, Nilsson MI, et al. Oxidative stress and Nrf2 signaling in McArdle disease. Mol Genet Metab. 2013;110(3):297–302.

  75. 75.

    Russo PJ, Phillips JW, Seidler NW. The role of lipid peroxidation in McArdle’s disease: applications for treatment of other myopathies. Med Hypotheses. 1992;39(2):147–51.

  76. 76.

    Tidball JG. Inflammatory cell response to acute muscle injury. Med Sci Sport Exerc. 1995;27(7):1022–32.

  77. 77.

    Pedersen BK, Ostrowski K, Rohde T, et al. The cytokine response to strenuous exercise. Can J Physiol Pharmacol. 1998;76(5):505–11.

  78. 78.

    Petersen AMW, Pedersen BK. The anti-inflammatory effect of exercise. J Appl Physiol. 2005;98(4):1154–62.

  79. 79.

    Bruunsgaard H. Physical activity and modulation of systemic low-level inflammation. J Leukoc Biol. 2005;78(4):819–35.

  80. 80.

    Fiuza-Luces C, Garatachea N, Berger NA, et al. Exercise is the real polypill. Physiology. 2013;28(5):330–58.

  81. 81.

    Lucia A, Smith L, Naidoo M, et al. McArdle disease: another systemic low-inflammation disorder? Neurosci Lett. 2008;431(2):106–11.

  82. 82.

    Lawrence JC Jr, Roach PJ. New insights into the role and mechanism of glycogen synthase activation by insulin. Diabetes. 1997;46(4):541–7.

  83. 83.

    Nielsen JN, Vissing J, Wojtaszewski JFP, et al. Decreased insulin action in skeletal muscle from patients with McArdle’s disease. Am J Physiol Endocrinol Metab. 2002;282(6):E1267–75.

  84. 84.

    Nielsen JN, Wojtaszewski JFP, Haller RG, et al. Role of 5′AMP-activated protein kinase in glycogen synthase activity and glucose utilization: insights from patients with McArdle’s disease. J Physiol. 2002;541(Pt 3):979–89.

  85. 85.

    Nogales-Gadea G, Mormeneo E, Garcia-Consuegra I, et al. Expression of glycogen phosphorylase isoforms in cultured muscle from patients with McArdle’s disease carrying the p.R771PfsX33 PYGM mutation. PLoS One. 2010;5(10):pii.e13164.

  86. 86.

    Valdes S, Rojo-Martinez G, Soriguer F. Evolution of prevalence of type 2 diabetes in adult Spanish population. Med Clin. 2007;129(9):352–5.

  87. 87.

    Roach PJ, Cao Y, Corbett CA, et al. Glycogen metabolism and signal transduction in mammals and yeast. Adv Enzyme Regul. 1991;31:101–20.

  88. 88.

    Prats C, Helge JW, Nordby P, et al. Dual regulation of muscle glycogen synthase during exercise by activation and compartmentalization. J Biol Chem. 2009;284(23):15692–700.

  89. 89.

    Meyer F, Heilmeyer LM Jr, Haschke RH, et al. Control of phosphorylase activity in a muscle glycogen particle: I. Isolation and characterization of the protein-glycogen complex. J Biol Chem. 1970;245(24):6642–8.

  90. 90.

    Nielsen JN, Richter EA. Regulation of glycogen synthase in skeletal muscle during exercise. Acta Physiol Scand. 2003;178(4):309–19.

  91. 91.

    Zachwieja JJ, Costill DL, Pascoe DD, et al. Influence of muscle glycogen depletion on the rate of resynthesis. Med Sci Sport Exerc. 1991;23(1):44–8.

  92. 92.

    Aschenbach WG, Suzuki Y, Breeden K, et al. The muscle-specific protein phosphatase PP1G/R(GL)(G(M))is essential for activation of glycogen synthase by exercise. J Biol Chem. 2001;276(43):39959–67.

  93. 93.

    Roelofs RI, Engel WK, Chauvin PB. Histochemical phosphorylase activity in regenerating muscle fibers from myophosphorylase-deficient patients. Science. 1972;177(4051):795–7.

  94. 94.

    Mitsumoto H. McArdle disease: phosphorylase activity in regenerating muscle fibers. Neurology. 1979;29(2):258–62.

  95. 95.

    Felice KJ, Grunnet ML, Sima AA. Selective atrophy of type 1 muscle fibers in McArdle’s disease. Neurology. 1996;47(2):581–3.

  96. 96.

    Bresolin N, Miranda A, Jacobson M, et al. Phosphorylase isoenzymes of human brain. Neurochem Pathol. 1983;1:171–8.

  97. 97.

    Pfeiffer-Guglielmi B, Fleckenstein B, Jung G, et al. Immunocytochemical localization of glycogen phosphorylase isozymes in rat nervous tissues by using isozyme-specific antibodies. J Neurochem. 2003;85(1):73–81.

  98. 98.

    Schmid H, Pfeiffer-Guglielmi B, Dolderer B, et al. Expression of the brain and muscle isoforms of glycogen phosphorylase in rat heart. Neurochem Res. 2009;34(3):581–6.

  99. 99.

    Rommel O, Kley RA, Dekomien G, et al. Muscle pain in myophosphorylase deficiency (McArdle’s disease): the role of gender, genotype, and pain-related coping. Pain. 2006;124(3):295–304.

  100. 100.

    Di Mauro S, Bresolin N. Phosphorylase deficiency. New York: McAGraw-Hill; 1986.

  101. 101.

    Edelstyn NM, Quinlivan R. A pilot study of neuropsychological performance in McArdle disease. Neuromuscul Disord. 2007;17(9):860 [Poster: M.P4.04].

  102. 102.

    Mancuso M, Orsucci D, Volterrani D, et al. Cognitive impairment and McArdle disease: is there a link? Neuromuscul Disord. 2011;21(5):356–8.

  103. 103.

    Nicholls DP, Campbell NP, Stevenson HP, et al. Angina in McArdle’s disease. Heart. 1996;76(4):372–3.

  104. 104.

    Ratinov G, Baker WP, Swaiman KF. Mcardle’s syndrome with previously unreported electrocardiographic and serum enzyme abnormalities. Ann Intern Med. 1965;62:328–34.

  105. 105.

    Wheeler SD, Brooke MH. Vascular insufficiency in McArdle’s disease. Neurology. 1983;33(2):249–50.

  106. 106.

    Moustafa SPD, Connelly MS. Unforeseen cardiac involvement in McArdle’s patients. Heart Lung Circ. 2013;22:769–71.

  107. 107.

    Angelos S, Valberg SJ, Smith BP, et al. Myophosphorylase deficiency associated with rhabdomyolysis and exercise intolerance in 6 related Charolais cattle. Muscle Nerve. 1995;18(7):736–40.

  108. 108.

    Tan P, Allen JG, Wilton SD, et al. A splice-site mutation causing ovine McArdle’s disease. Neuromuscul Disord. 1997;7(5):336–42.

  109. 109.

    Howell JM, Walker KR, Creed KE, et al. Phosphorylase re-expression, increase in the force of contraction and decreased fatigue following notexin-induced muscle damage and regeneration in the ovine model of McArdle disease. Neuromuscul Disord. 2014;24(2):167-77.

  110. 110.

    Nogales-Gadea G, Pinos T, Lucia A, et al. Knock-in mice for the R50X mutation in the PYGM gene present with McArdle disease. Brain. 2012;135(Pt 7):2048–57.

  111. 111.

    MacLean D, Vissing J, Vissing SF, et al. Oral branched-chain amino acids do not improve exercise capacity in McArdle disease. Neurology. 1998;51(5):1456–9.

  112. 112.

    Day TJ, Mastaglia FL. Depot-glucagon in the treatment of McArdle’s disease. Aust N Z J Med. 1985;15(6):748–50.

  113. 113.

    Poels PJ, Braakhekke JP, Joosten EM, et al. Dantrolene sodium does influence the second-wind phenomenon in McArdle’s disease. Electrophysiological evidence during exercise in a double-blind placebo-controlled, cross-over study in 5 patients. J Neurol Sci. 1990;100(1–2):108–12.

  114. 114.

    Lane RJ, Turnbull DM, Welch JL, et al. A double-blind, placebo-controlled, crossover study of verapamil in exertional muscle pain. Muscle Nerve. 1986;9(7):635–41.

  115. 115.

    Phoenix J, Hopkins P, Bartram C, et al. Effect of vitamin B6 supplementation in McArdle’s disease: a strategic case study. Neuromuscul Disord. 1998;8(3–4):210–2.

  116. 116.

    Sato S, Ohi T, Nishino I, et al. Confirmation of the efficacy of vitamin B6 supplementation for McArdle disease by follow-up muscle biopsy. Muscle Nerve. 2012;45(3):436–40.

  117. 117.

    Steele IC, Patterson VH, Nicholls DP. A double blind, placebo controlled, crossover trial of d-ribose in McArdle’s disease. J Neurol Sci. 1996;136(1–2):174–7.

  118. 118.

    Vorgerd M, Grehl T, Jager M, et al. Creatine therapy in myophosphorylase deficiency (McArdle disease): a placebo-controlled crossover trial. Arch Neurol. 2000;57(7):956–63.

  119. 119.

    Vorgerd M, Zange J, Kley R, et al. Effect of high-dose creatine therapy on symptoms of exercise intolerance in McArdle disease: double-blind, placebo-controlled crossover study. Arch Neurol. 2002;59(1):97–101.

  120. 120.

    Frischmeyer PA, Dietz HC. Nonsense-mediated mRNA decay in health and disease. Hum Mol Genet. 1999;8(10):1893–900.

  121. 121.

    Nogales-Gadea G, Rubio JC, Fernandez-Cadenas I, et al. Expression of the muscle glycogen phosphorylase gene in patients with McArdle disease: the role of nonsense-mediated mRNA decay. Hum Mut. 2008;29(2):277–83.

  122. 122.

    Schroeder R, Waldsich C, Wank H. Modulation of RNA function by aminoglycoside antibiotics. EMBO J. 2000;19(1):1–9.

  123. 123.

    Welch EM, Barton ER, Zhuo J, et al. PTC124 targets genetic disorders caused by nonsense mutations. Nature. 2007;447(7140):87–91.

  124. 124.

    Kayali R, Ku J-M, Khitrov G, et al. Read-through compound 13 restores dystrophin expression and improves muscle function in the mdx mouse model for Duchenne muscular dystrophy. Hum Mol Genet. 2012;21(18):4007–20.

  125. 125.

    Gonzalez-Hilarion S, Beghyn T, Jia J, et al. Rescue of nonsense mutations by amlexanox in human cells. Orphanet J Rare Dis. 2012;7:58.

  126. 126.

    Barton-Davis ER, Cordier L, Shoturma DI, et al. Aminoglycoside antibiotics restore dystrophin function to skeletal muscles of mdx mice. J Clin Invest. 1999;104(4):375–81.

  127. 127.

    Bedwell DM, Kaenjak A, Benos DJ, et al. Suppression of a CFTR premature stop mutation in a bronchial epithelial cell line. Nat Med. 1997;3(11):1280–4.

  128. 128.

    Schroers A, Kley RA, Stachon A, et al. Gentamicin treatment in McArdle disease: failure to correct myophosphorylase deficiency. Neurology. 2006;66(2):285–6.

  129. 129.

    Howell JM, Quinlinan R, Sewry C. Investigation of possible treatment regimes for McArdle’s disease using the sheep model of the disease. Neuromuscul Disord. 2008;18(9):828 [Poster: G.P.16.06].

  130. 130.

    Howell JM, Walker KR, Davies L, et al. Adenovirus and adeno-associated virus-mediated delivery of human myophosphorylase cDNA and LacZ cDNA to muscle in the ovine model of McArdle’s disease: expression and re-expression of glycogen phosphorylase. Neuromuscul Disord. 2008;18(3):248–58.

  131. 131.

    Gregorevic P, Blankinship MJ, Allen JM, et al. Systemic delivery of genes to striated muscles using adeno-associated viral vectors. Nat Med. 2004;10(8):828–34.

  132. 132.

    Andersen ST, Vissing J. Carbohydrate- and protein-rich diets in McArdle disease: effects on exercise capacity [published erratum appears in J Neurol Neurosurg Psychiatry. 2010;81(12):1414]. J Neurol Neurosurg Psychiatry. 2008;79(12):1359–63.

  133. 133.

    Andersen ST, Haller RG, Vissing J. Effect of oral sucrose shortly before exercise on work capacity in McArdle disease. Arch Neurol. 2008;65(6):786–9.

  134. 134.

    Perez M, Mate-Munoz JL, Foster C, et al. Exercise capacity in a child with McArdle disease. J Child Neurol. 2007;22(7):880–2.

  135. 135.

    Perez M, Foster C, Gonzalez-Freire M, et al. One-year follow-up in a child with McArdle disease: exercise is medicine. Pediatr Neurol. 2008;38(2):133–6.

  136. 136.

    Vissing J, Duno M, Schwartz M, et al. Splice mutations preserve myophosphorylase activity that ameliorates the phenotype in McArdle disease. Brain. 2009;132(Pt 6):1545–52.

  137. 137.

    Perez M, Moran M, Cardona C, et al. Can patients with McArdle’s disease run? Br J Sports Med. 2007;41(1):53–4.

  138. 138.

    Haller RG, Wyrick P, Taivassalo T, et al. Aerobic conditioning: an effective therapy in McArdle’s disease. Ann Neurol. 2006;59(6):922–8.

  139. 139.

    Garcia-Benitez S, Fleck SJ, Naclerio F, et al. Resistance (weight lifting) training in an adolescent with McArdle disease. J Child Neurol. 2013;28(6):805–8.

Download references


No sources of funding were used to assist in the preparation of this review. Alfredo Santalla, Gisela Nogales-Gadea, Niels Ørtenblad, Astrid Brull, Noemi de Luna, Tomàs Pinós and Alejandro Lucia have no potential conflicts of interest that are directly relevant to the content of this review. The authors original research in the field is supported by grants from the Spanish Ministry of Economy and Competitiveness [Fondo de Investigaciones Sanitarias (FIS), grants number PI12/00914 and PI13/00855]. Gisela Nogales-Gadea and Noemi de Luna are supported by Sara Borrell contracts of ISCIII CD10/00027 and CD11/00060, respectively. Astrid Brull is supported by an FIS grant of ISCIII FI11/00709.

Author information

Correspondence to Tomàs Pinós.

Additional information

A. Santalla, G. Nogales-Gadea, T. Pinós, and A. Lucia contributed equally to this article.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Santalla, A., Nogales-Gadea, G., Ørtenblad, N. et al. McArdle Disease: A Unique Study Model in Sports Medicine. Sports Med 44, 1531–1544 (2014).

Download citation


  • Sarcoplasmic Reticulum
  • Muscle Glycogen
  • Glycogen Phosphorylase
  • Exercise Intolerance
  • Premature Termination Codon