McArdle's patients experience lifelong premature exertional fatigue and are subject to exertional muscle pain, contractures, and rhabdomyolysis when muscle energy demands exceed supply. Later in life, McArdle's patients may develop fixed weakness.

The main goals for managing patients with McArdle's disease are to improve exercise tolerance and to reduce the frequency and severity of muscle injury. Success hinges on efforts to avoid patterns of activity that require glycogen as an energy source and to promote the utilization of preserved energy pathways - especially lipid oxidation - to meet muscle energy needs. Glycogen has anaerobic and oxidative functions. Anaerobic glycogenolysis can support rates of energy turnover more than twice that achieved by oxidative metabolism, and it is necessary to fuel intense exercise and when oxygen delivery is blocked. No substitute for anaerobic glycogenolysis exists. To avoid muscle injury, it is therefore necessary for patients to avoid ischemic or isometric exercise such as heavy lifting and arm wrestling.

Glycogen also fuels pyruvate-dependent oxidative metabolism, and glycogen unavailability makes muscle dependent on the availability of blood-borne oxidative fuels. This is exemplified by the second wind phenomenon, in which exercise tolerance improves and the rate of muscle oxidative phosphorylation is augmented when the availability of blood-borne oxidative substrate (particularly free fatty acids and glucose) to muscle is increased. The mobilization, delivery, and cellular transport of blood-borne substrates are sluggish in comparison with the availability of glycogen-derived pyruvate, so the oxidative energy deficit is apparent in the transition from rest to exercise. Also, maximal rates of oxidative phosphorylation able to be achieved by blood-borne fuels are low compared with that achieved with pyruvate. Warming up before engaging in any sustained activity improves substrate availability by increasing muscle blood flow and facilitating substrate mobilization.

A diet rich in protein and adequate in carbohydrate is recommended for McArdle's disease. Protein requirements are increased by the ongoing muscle injury and increased muscle regeneration that are typical of this condition. Also, amino acids provide a potential alternative oxidative fuel for skeletal muscle. When combined with a program of regular exercise, a high-protein diet was found to improve exercise capacity significantly.

Dietary carbohydrate sufficient to maintain hepatic glycogen stores is desirable, because glucose utilization and hepatic glycogenolysis are increased during exercise in McArdle's disease. The immediate effect of a carbohydrate meal may be to reduce exercise capacity, owing to homeostatic mechanisms that maintain blood glucose in a narrow range and the corresponding reduction in plasma fatty acids levels. Intravenous glucose raises blood glucose levels, increases glucose transport into muscle, and augments exercise capacity, but it is useful primarily in a hospital. Glucagon increases hepatic glycogenolysis and may improve exercise capacity in the short term, but indications for chronic treatment are unproven.

Long-chain free fatty acids (FFAs) represent the dominant available oxidative fuel in glycolytic defects, but a high-fat diet has not provided consistent benefits. Epinephrine increases exercise capacity by augmenting lipolysis and increasing muscle blood flow. A medium-chain triglyceride (MCT) diet increases medium-chain fatty acids, which are preferentially oxidized in liver to ketones, which can be oxidized by skeletal muscle. MCT oil supplements may improve exercise tolerance, but some patients experience nausea, diarrhea, and meager improvement in exercise capacity, if any.

Regular aerobic exercise, by promoting mitochondrial biogenesis and increasing the activity of rate-limiting oxidative enzymes, increases fat oxidation and reduces the requirement for carbohydrate utilization to supply muscle energy needs. Conditioning exercise must be undertaken with caution, as overexertion may precipitate muscle injury. We prescribe "low-level" exercise (approximately 50 percent of maximal) performed for 20-40 minutes, three to four times per week. Because exercise intolerance often varies in the course of a given exercise session owing to patterns of substrate mobilization, exercise intensity should be varied accordingly. Heart rate is a good objective index of relative exercise intensity that the patient can monitor with a pulsemeter (preferably) or by timing the pulse. Serum CK should be monitored to ensure that the exercise program is not producing increased muscle injury.

The most devastating acute consequence of McArdle's disease is massive exertional muscle injury with myoglobinuria. It is crucial to recognize muscle injury that is sufficient to cause myoglobinuria, so that appropriate treatment can be instituted. The major long-term consequence of McArdle's disease is muscle weakness. A likely mechanism is recurrent muscle injury, which ultimately exceeds the regenerative capacity of skeletal muscle. Muscle magnetic resonance imaging sensitively identifies focal muscle injury and decreased mass. For patients with focal muscle atrophy, special attention should be given to eliminating patterns of exercise that promote muscle injury; to measures to augment substrate availability and improve the capacity to oxidize available substrates; and to providing adequate dietary protein to promote protein synthesis.