Ronald G. Haller, MD

Archives of Neurology
Vol. 57 No. 7, July 2000
© 2000 American Medical Association. All rights reserved.

Used with permission

Author/Article Information
Ronald G. Haller, MD
Institute for Exercise and Environmental Medicine
Presbyterian Hospital of Dallas,
VA Medical Center, and Neuromuscular Center
University of Texas Southwestern Medical Center
7232 Greenville Ave
Dallas, TX 75231

We are approaching the 50th anniversary of the classical description by Brian McArdle¹ of the metabolic myopathy that bears his name. It was recognized 40 years ago that the symptoms of McArdle disease,exertional muscle fatigue, pain, cramps (contractures), and myoglobinuria, were due to deficiency of the muscle form of glycogen phosphorylase, and thus were related specifically to the unavailability of muscle glycogen as a source of energy for muscle contraction.^{2, 3} In the last few years, understanding of the molecular pathogenesis of McArdle disease has advanced with the description of approximately 20 different mutations in the phosphorylase gene on chromosome 11.⁴ However, treatment of McArdle disease has lagged and remains an important clinical challenge.

The opportunity for therapy begins with diagnosis, and diagnosis in McArdle disease rarely is timely. Symptoms of exercise intolerance typically are life long, but the diagnosis is usually not made until the third decade of life, and often much later. This delay is fostered by the rarity of the condition, although it is probably more common than generally assumed. I would estimate that the prevalence in the Dallas-Fort Worth area is, conservatively, 1 in 100,000. Diagnostic delay is also promoted by the fact that symptoms typically occur during exercise, and therefore are often mistaken for poor physical conditioning, poor motivation, or both. The physical and psychological toll of delayed diagnosis is difficult to estimate but includes premature death as a result of swimming or climbing accidents, life-threatening episodes of myoglobinuria, and, arguably, increased risk of significant fixed muscle weakness due to unrecognized recurrent episodes of muscle injury. Improvement in diagnosing McArdle disease requires a greater index of suspicion and a more quantitative approach to evaluating symptoms of exercise intolerance.⁵

Once a diagnosis is established, the ideal treatment is correction of the enzyme deficiency. Gene replacement utilizing an adenovirus vector has achieved some success in an ovine model of muscle phosphorylase deficiency, and a human trial of such therapy is under active consideration.⁶ However, substantial problems remain before this can become a therapeutic option. Thus, current management revolves around attempts to reduce symptoms by minimizing activities that require muscle glycogen as a fuel and by promoting the use of alternative muscle energy pathways. This coincides with 2 fundamental questions: What should patients do about physical activity? and What should patients do about diet?

A common but probably ill-advised response to the first question is a recommendation to shun exercise and adopt as sedentary a lifestyle as possible. Certainly intense isometric exercise such as weight lifting or maximal aerobic exercise such as sprinting should be avoided since these activities depend on the integrity of anaerobic and aerobic glycogenolysis, respectively, and commonly trigger muscle injury.⁵ However, a sedentary existence may promote a vicious cycle of declining muscle energy resources in which exercise limitations are magnified from tolerable to disabling. This may occur because of a decline in cardiovascular fitness which limits the delivery of blood-borne substrates (principally free fatty acids and glucose) on which muscle oxidative metabolism depends when glycogen metabolism is blocked.⁷ Also, deconditioning reduces levels of muscle mitochondrial enzymes, which may restrict the ability to oxidize available fuels, especially fat. Recent results indicate that regular, moderate exercise improves exercise capacity by increasing circulatory capacity, thereby increasing the rate of delivery of blood-borne fuels, and may promote an increase in mitochondrial biogenesis.⁸ Furthermore, any single bout of moderate exercise should be preceded by 5 to 15 minutes of low level "warm up" exercise. This promotes the transition to a "second wind" in which exercise capacity is increased because of increased mobilization and delivery of extramuscular fuels via enhanced neural, hormonal, and circulatory responses to exercise typical of McArdle disease.^9-11

Dietary attempts to improve muscle energy availability generally have been disappointing, and identifying the ideal nutritional regimen for patients with McArdle disease remains a work in progress. Patients certainly should shun surplus calories to avoid the exercise handicap of excess weight. A diet relatively high in protein seems beneficial.^{12, 13} This may relate to an increased protein requirement to repair recurrent exertional muscle injury. In addition, a benefit of protein has been attributed to increased availability of branched chain amino acids, the major amino acids oxidized by skeletal muscle.^{12, 13} However, oral branched chain amino acids have been shown to actually lower exercise capacity due, in part, to an insulin-mediated fall in availability of free fatty acids.¹⁴ The desirable level of carbohydrate vs fat in the diet has not been settled, but clearly, adequate dietary carbohydrate is important to maintain hepatic glycogen stores and support the high rates of hepatic glycogenolysis and muscle utilization of glucose during exercise that are typical of this condition.¹¹ Pyridoxine hydrochloride (B6) supplements have been recommended to correct a postulated secondary pyridoxine deficiency.¹⁵ This relates to the fact that B6 covalently bound to phosphorylase accounts for 80% of total muscle B6, so a fall in muscle vitamin B6 levels to about 20% of normal levels accompanies muscle phosphorylase deficiency.¹⁶ However, the view that vitamin B6 supplements benefit patients remains to be confirmed.

In the current issue of the ARCHIVES, Vorgerd et al¹⁷ have taken another nutritional approach using the dietary supplement creatine. In this well-conceived placebo-controlled crossover study, the authors found that oral creatine produced a statistically significant increase in ischemic, isometric forearm exercise capacity with no improvement in nonischemic isometric exercise or in cycle exercise. The rationale for creatine supplements in McArdle disease includes observations that oral creatine increases muscle creatine levels and enhances maximal anaerobic exercise capacity in some healthy individuals ^{18, 19} as well as in patients with a variety of neuromuscular disorders.^{20, 21} These benefits usually are attributed to a creatine-mediated increase in muscle levels of phosphocreatine.²² Phosphocreatine is an important source of energy in McArdle disease and an exaggerated decline in phosphocreatine levels relative to workload is typical of this condition.⁷ Curiously, however, muscle phosphocreatine levels as determined by phosphorus³¹ magnetic resonance spectroscopy were not significantly increased with creatine supplement use when compared with placebo use in the study of Vorgerd et al.¹⁷ Instead, increased work capacity was associated with increased phosphocreatine breakdown and with higher end-exercise levels of inorganic phosphate. This implies that the beneficial effect was not due to an increase in energy availability but instead to an effect that somehow permitted exercise to continue to a level of greater energy depletion.

The relationship between cellular energy availability and fatigue in McArdle disease is incompletely understood but presumably ultimately involves energy-limited function of the cellular adenosine triphosphatases (ATPase) that couple adenosine triphosphate hydrolysis to cellular work.²³ Limited Na+K+ ATPase function may contribute to exertional fatigue in McArdle disease owing to energy limitations and to the fact that patients have reduced numbers of Na+K+ pumps.²⁴ The result is an exaggerated rise in extracellular potassium during exercise that ultimately may promote fatigue by inactivating sodium channels and causing membrane inexcitability.^{23, 24} Vorgerd et al identified a significantly lower median frequency in surface electromyograms with creatine supplements and suggest that this may relate to a moderating effect of creatine on potassium-mediated changes in membrane excitability.¹⁷ These results are provocative and encouraging; but it is probably premature to recommend that patients with McArdle disease routinely receive creatine. The overall effects were small and the benefits were restricted to ischemic isometric exercise, and though there was a trend to reduced muscle symptoms, creatine kinase levels were actually higher in 8 of 9 patients, when creatine was taken.¹⁷ These findings encourage further studies to confirm a benefit of creatine in McArdle disease and to illuminate the mechanism of creatine action in this and other neuromuscular disorders.

[For more information see McArdle disease page]
http://www.mda.org/disease/mpd.html

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