Description of the condition

McArdle disease (Glycogen Storage disease type V, GSDV) is a rare metabolic disorder of skeletal muscle which affects about 1:100,000 people. Symptoms are frequently reported from early childhood, although the diagnosis is rarely made before the second or third decade. The condition is relatively stable throughout life, however, with advancing age some people develop muscle wasting and mild proximal weakness. The condition is caused by autosomal recessive mutations in the muscle glycogen phosphorylase gene (PYGM), which is located on chromosome 11q13. The gene spans 20 exons and, by December 2006, more than 80 mutations have been identified, many of which are population specific (Andreu 2007; Quinlivan 2007). To date there is no reported correlation between genotype and phenotype severity (Aquaron 2007; Deschauer 2007). The most common mutation affecting people originating from Northern Europe and North America is a nonsense mutation at Arg50X (R50X) in exon 1 (previously referred to as R49X) (Bartram 1993). The diagnosis of McArdle disease is confirmed by finding a raised serum creatine kinase, muscle biopsy demonstrating an increase in subsarcolemmal glycogen with histochemistry and biochemical analysis demonstrating a virtual absence of the enzyme muscle glycogen phosphorylase and DNA analysis identifying homozygous or compound heterozygous mutations in PYGM.

Symptoms are caused by an inability to produce the enzyme muscle glycogen phosphorylase which is crucial for glyconeogenesis (the metabolic pathway which converts glycogen to glucose‐1‐phosphate) and is essential to provide substrate (fuel) for energy through glycolysis (the metabolic pathway that converts glucose to pyruvate) during anaerobic exercise. In the resting state and during low‐intensity aerobic activity, skeletal muscle is mainly dependent upon aerobic energy metabolism (oxidative phosphorylation), which utilizes free fatty acids as the primary energy substrate. During higher intensity aerobic and anaerobic eccentric exercise, skeletal muscle is dependent upon glycolysis for energy. Thus, in people with McArdle disease during short‐term moderate to vigorous physical exertion, when there is a need for anaerobic metabolism and a high glycolytic flux for oxidative combustion, an acute energy crisis occurs. Under such circumstances within minutes of initiating exercise, and when exercise increases in intensity, unpleasant symptoms occur which include: tachycardia, severe muscle pain and fatigue. If exercise continues at the same intensity despite these symptoms, a muscle contracture (which is a painful paralysis) occurs and will lead to muscle tenderness, swelling and muscle damage, which when severe, is termed rhabdomyolysis. Rhabdomyolysis leads to the release of the muscle protein, myoglobin, which is excreted in the kidneys causing a reddish black discolouration of the urine known as myoglobinuria. Myoglobinuria can lead to reversible acute renal failure requiring dialysis and intensive care.

By pacing the intensity of physical activity, affected people will notice that after a few minutes of low‐intensity activity, the symptoms of pain and fatigue begin to ease and exercise can continue safely. This is known as the second wind phenomenon, and it is universally present in people with McArdle disease. The phenomenon is attributable to a better supply of extra‐muscular fuels (glucose from the liver and fatty acids from adipose tissue) to the contracting muscles, as exercise progresses (Vissing 2003).

People with McArdle disease also have a secondary impairment of oxidative phosphorylation, which further impedes the ability of people with the condition to achieve physical fitness. This effect is due to a virtual absence of pyruvate which would normally be generated as a by‐product of glycolysis (Haller 1985). In the absence of regular physical training, people with McArdle disease may have a relatively limited capacity for fatty acid oxidation during exercise (De Stefano 1996), even though absolute levels of fat oxidation are enhanced in this disease (Orngreen 2009). The effect of this diminished oxidative phosphorylation is a reduction in oxygen consumption to approximately 35% of normal and a disproportionate increase in heart rate during exercise when compared with normal controls (Vissing 1998).

There is considerable heterogeneity in the severity of symptoms in people with McArdle disease, even in individuals carrying the same genetic mutations. The exact reasons are unclear, but could relate to the co‐existence of modifying genes which affect one's normal response to exercise such as the angiotensin converting enzyme gene phenotype (ACE) and alpha actinin 3 (ACTN3) and C34T muscle adenosine monophosphate deaminase (AMPD1) (Gomez‐Gallego 2008; Lucia 2007; Martinuzzi 2003; Rubio 2007). However, differences in dietary habits, fitness and psychological factors may also be key determinants of disease severity. In a study of 99 Spanish people with McArdle disease there was a significant gender effect, with females being more severely affected than males (Rubio 2007). Polymorphic variants leading to insertions or deletions (I/D) in the ACE gene may possibly affect the efficiency of muscle adaptation to training. Reduced ACE activity is associated with the I allelle and is associated with enhanced performance after aerobic training (Gomez‐Gallego 2008; Martinuzzi 2003). These people with McArdle disease may potentially benefit the most from aerobic training.

Description of the intervention

This review will focus upon the effects of physical training in people with McArdle disease. Physical training will include a regular programme of aerobic activities such as swimming, jogging, walking, cycling and /or flexibility training conducted over a 12‐week period of time. Strength training will not be included as it is likely to be detrimental to people with McArdle disease.

How the intervention might work

Physical exercise training may improve the delivery of extramuscular fuels to contracting muscle and also improve the ability to use free fatty acids as an alternative fuel for muscle exercise. This may then allow people with McArdle disease to be more active and to function better in everyday life.

Why it is important to do this review

A systematic review of pharmacological and nutritional treatment found no effective treatment for McArdle disease ( Quinlivan 2008 ). A symptomatic benefit can be obtained from sucrose ingestion prior to planned exercise (Vissing 2003), and a diet rich in carbohydrate may be superior to a high protein diet (Andersen 2008). Many people who have McArdle disease shun exercise, because they fear the consequences of exercise‐induced pain and rhabdomyolysis. However, paradoxically, a regular aerobic training programme could improve their metabolic capacity and their exercise tolerance by conditioning their muscles for oxidative phosphorylation.