Why do patients with McArdle's disease have decreased exercise capacity?

Disorders of myoglycogenolysis, such as myophosphorylase deficiency(McArdle's disease), and myoglycolysis, such as phosphofructokinase deficiency (Tarui disease), are characterized by electrically silent, exercise-provoked contractions called "contractures," premature exertional fatigue and excessive cardiovascular responses to exercise.^1-3 McArdle's disease and Tarui disease as well as other disorders of myoglycolysis, such as phosphoglycerate kinase deficiency, phosphoglycerate mutase deficiency, and lactate dehydrogenase deficiency, are important to neurology because these disorders allow us to explore the interactions between muscle metabolism and muscle contraction.¹ Beyond providing the power for movement, skeletal muscle is the largest protein store in the human body and is important in the regulation of glucose metabolism.⁴ The article by Haller et al.⁵ in this issue of Neurology focuses on physiologic alterations of skeletal muscle in McArdle's disease that contribute to exercise intolerance and exaggerated cardiovascular responses to exercise. Their work represents the collaboration of well-respected muscle physiologists from both sides of the Atlantic Ocean.

Contracture was initially thought to be similar to the rigor of rigor mortis. Ischemic exercise would deplete adenosine triphosphate (ATP) because the muscle fiber could not generate ATP through the glycolytic pathway under anaerobic conditions. Without ATP, cycling of the contractile protein cross-bridges would stop, and the cross-bridges would lock in a rigor state. This initial explanation of contracture, although superficially tempting, was not true. Rowland et al.⁶ demonstrated that contractures in McArdle's disease were not caused by depletion of ATP. Subsequent studies utilizing phosphorus magnetic resonance spectroscopy demonstrated that ATP was not depleted during exercise in patients with McArdle's disease,^7,8 Tarui disease,^9-11 or other disorders of human muscle glycolysis or glycogenolysis.^12,13 Experiments using an animal model of Tarui disease in which the glycolytic enzyme glyceraldehyde-3-phosphate was blocked¹⁴ demonstrated four important differences between muscles with impaired glycolysis at the onset of contracture and ischemically exercised control muscles^15,16: (1) adenosine diphosphate (ADP) values increased more than 10-fold compared with control values; (2) intracellular pH in muscles with blocked glycolysis did not acidify in response to ischemic exercise; (3) inorganic phosphate levels in muscles with impaired glycolysis at contracture were 50% lower than in ischemically exercised control muscles; and (4) intracellular calcium level at the onset of contracture was more than 10-fold greater than in ischemically exercised control muscles. In ischemically exercised control muscles, muscle acidification and elevated inorganic phosphate reduced the calcium sensitivity of the contractile proteins.¹⁷ In contrast, the combination of increased ADP, reduced inorganic phosphate concentration, and lack of acidification in muscles with impaired glycolysis increased the calcium sensitivity of the contractile proteins.¹⁷ Therefore, contracture resulted from a combination of increased calcium sensitivity of the contractile proteins and elevated intracellular calcium.¹⁷ Contractures developed because of disruption of the complex interplay among the contractile proteins, calcium release, and calcium sequestration mechanisms. Contractures are painful and can lead to myonecrosis. To avoid contractures, patients limit their motor activities.

Haller et al.⁵ examined the skeletal muscle Na⁺-K⁺ pumps in patients with McArdle's disease compared with those in a group of sedentary controls. The investigators examined muscle ouabain binding and exercise-induced changes in venous potassium concentration and heart rate. Subjects with McArdle's disease had lower concentrations of Na⁺-K⁺ pumps (normalized to muscle weight), higher exercise-induced serum K⁺ concentrations, and greater increases in heart rate during exercise. The reduction in skeletal muscle Na⁺-K⁺ ATPase activity may be a direct consequence of the impaired glycogenolysis or may be a secondary consequence of reduced activity levels in patients. In addition, elevated intracellular ADP will reduce the transport rate of the remaining Na⁺-K⁺ pumps.^3,10,18 The authors suggest that the reduced concentration of skeletal muscle Na⁺-K⁺ pumps contributes to exercise-induced hyperkalemia in subjects with McArdle's disease because the muscle is not able to uptake K⁺ released from skeletal muscle during contraction. Impaired uptake of K⁺ during muscle contraction will result in appreciable elevation of the extracellular K⁺ surrounding the muscle fibers. Elevated extracellular K⁺ will depolarize the muscle membrane, which will reduce membrane excitability due to inactivation of Na⁺ channels.¹⁹ Prior studies, cited by Haller et al.,⁵ demonstrated that the compound muscle action potential in patients with McArdle's disease progressively declines during repetitive nerve stimulation, indicating a failure in membrane excitability. Muscle force declines in parallel with the reduction in compound action potential amplitude. Consequently, the reduced skeletal muscle Na⁺-K⁺ pump activity limits the exercise potential of skeletal muscle in McArdle's disease, which will reduce the ability of skeletal muscle to contract vigorously enough to trigger a contracture.

Haller et al.⁵ indicate that the exaggerated extracellular potassium increase produced by exercise in patients with McArdle's disease contributes to the exaggerated cardiopulmonary responses manifested by these patients. They demonstrated that patients with McArdle's disease develop higher heart rates in response to exercise compared with sedentary control subjects. The exaggerated cardiopulmonary responses of patients with McArdle's disease will limit their exercise capacity.

Therefore, Haller et al.⁵ demonstrate that a lower density of Na⁺-K⁺ pumps on skeletal muscle fibers of patients with McArdle's disease limits their exercise capacity by inducing a failure of skeletal muscle fiber membrane excitability and by compromising the usual cardiopulmonary responses to exercise. The reduced exercise capacity may reduce the likelihood of contractures. Although the reduced Na⁺-K⁺ pump density may have developed in part due to reduced activity levels, the lower pump density will also protect skeletal muscle from contracture-induced injury.