We recently described the genotype/phenotype features of all Spanish patients diagnosed with McArdle disease as of January 2011 (n = 239, prevalence of ~1/167,000) (J Neurol Neurosurg Psychiatry 2012;83:322–8). Several caveats were however identified suggesting that the prevalence of the disease is actually higher. We have now updated main genotype/phenotype data, as well as potential associations within/between them, of all Spanish individuals currently diagnosed with McArdle disease (December 2016). Ninety-four new patients (all Caucasian) have been diagnosed, yielding a prevalence of ~1/139,543 individuals. Around 55% of the mutated alleles have the commonest PYGM pathogenic mutation p.R50X, whereas p.W798R and p.G205S account for 10 and 9% of the allelic variants, respectively. Seven new mutations were identified: p.H35R, p.R70C, p.R94Q, p.L132WfsX163, p.Q176P, p.R576Q, and c.244-3_244-2CA. Almost all patients show exercise intolerance, the second wind phenomenon and high serum creatine kinase activity. There is, however, heterogeneity in clinical severity, with 8% of patients being asymptomatic during normal daily life, and 21% showing limitations during daily activities and fixed muscle weakness. A major remaining challenge is one of diagnosis, which is often delayed until the third decade of life in 72% of new patients despite the vast majority (86%) reporting symptoms before 20 years. An important development is the growing proportion of those reporting a 4-year improvement in disease severity (now 34%) and following an active lifestyle (50%). Physically active patients are more likely to report an improvement after a 4-year period in the clinical course of the disease than their inactive peers (odds ratio: 13.98; 95% confidence interval: 5.6, 34.9; p < 0.001). Peak oxygen uptake is also higher in the former (20.7 ± 6.0 vs. 16.8 ± 5.3 mL/kg/min, p = 0.0013). Finally, there is no association between PYGM genotype and phenotype manifestation of the disease. The reported prevalence of McArdle disease grows exponentially despite frequent, long delays in genetic diagnosis, suggesting that many patients remain undiagnosed. Until a genetic cure is available (which is not predicted in the near future), current epidemiologic data support that adoption of an active lifestyle is the best medicine for these patients.

GSD are a group of disorders characterized by a defect in gene expression of specific enzymes involved in glycogen breakdown or synthesis, commonly resulting in the accumulation of glycogen in various tissues (primarily the liver and skeletal muscle). Several different GSD animal models have been found to naturally present spontaneous mutations and others have been developed and characterized in order to further understand the physiopathology of these diseases and as a useful tool to evaluate potential therapeutic strategies. In the present work we have reviewed a total of 42 different animal models of GSD, including 26 genetically modified mouse models, 15 naturally occurring models (encompassing quails, cats, dogs, sheep, cattle and horses), and one genetically modified zebrafish model. To our knowledge, this is the most complete list of GSD animal models ever reviewed. Importantly, when all these animal models are analyzed together, we can observe some common traits, as well as model specific differences, that would be overlooked if each model was only studied in the context of a given GSD.

McArdle disease, also termed ‘glycogen storage disease type V’, is a disorder of skeletal muscle carbohydrate metabolism caused by inherited deficiency of the muscle-specific isoform of glycogen phosphorylase (GP-MM). It is an autosomic recessive disorder that is caused by mutations in the PYGM gene and typically presents with exercise intolerance, i.e. episodes of early exertional fatigue frequently accompanied by rhabdomyolysis and myoglobinuria. Muscle biopsies from affected individuals contain subsarcolemmal deposits of glycogen. Besides GP-MM, two other GP isoforms have been described: the liver (GP-LL) and brain (GP-BB) isoforms, which are encoded by the PYGL and PYGB genes, respectively; GP-BB is the main GP isoform found in human and rat foetal tissues, including the muscle, although its postnatal expression is dramatically reduced in the vast majority of differentiated tissues with the exception of brain and heart, where it remains as the major isoform. We developed a cell culture model from knock-in McArdle mice that mimics the glycogen accumulation and GP-MM deficiency observed in skeletal muscle from individuals with McArdle disease. We treated mouse primary skeletal muscle cultures in vitro with sodium valproate (VPA), a histone deacetylase inhibitor. After VPA treatment, myotubes expressed GP-BB and a dose-dependent decrease in glycogen accumulation was also observed. Thus, this in vitro model could be useful for high-throughput screening of new drugs to treat this disease. The immortalization of these primary skeletal muscle cultures could provide a never-ending source of cells for this experimental model. Furthermore, VPA could be considered as a gene-expression modulator, allowing compensatory expression of GP-BB and decreased glycogen accumulation in skeletal muscle of individuals with McArdle disease.

Key points This is the first study to analyse the effect of muscle glycogen phosphorylase depletion in metabolically different muscle types. In McArdle mice, muscle glycogen phosphorylase is absent in both oxidative and glycolytic muscles. In McArdle mice, the glycogen debranching enzyme (catabolic) is increased in oxidative muscles, whereas the glycogen branching enzyme (anabolic) is increased in glycolytic muscles. In McArdle mice, total glycogen synthase is decreased in both oxidative and glycolytic muscles, whereas the phosphorylated inactive form of the enzyme is increased in both oxidative and glycolytic enzymes. In McArdle mice, glycogen content is higher in glycolytic muscles than in oxidative muscles. Additionally, in all muscles analysed, the glycogen content is higher in males than in females. The maximal endurance capacity of the McArdle mice is significantly lower compared to heterozygous and wild‐type mice. Abstract McArdle disease, caused by inherited deficiency of the enzyme muscle glycogen phosphorylase (GP‐MM), is arguably the paradigm of exercise intolerance. The recent knock‐in (p.R50X/p.R50X) mouse disease model allows an investigation of the phenotypic consequences of muscle glycogen unavailability and the physiopathology of exercise intolerance. We analysed, in 2‐month‐old mice [wild‐type (wt/wt), heterozygous (p.R50X/wt) and p.R50X/p.R50X)], maximal endurance exercise capacity and the molecular consequences of an absence of GP‐MM in the main glycogen metabolism regulatory enzymes: glycogen synthase, glycogen branching enzyme and glycogen debranching enzyme, as well as glycogen content in slow‐twitch (soleus), intermediate (gastrocnemius) and glycolytic/fast‐twitch (extensor digitorum longus; EDL) muscles. Compared with wt/wt, exercise capacity (measured in a treadmill test) was impaired in p.R50X/p.R50X (∼48%) and p.R50X/wt mice (∼18%). p.R50X/p.R50X mice showed an absence of GP‐MM in the three muscles. GP‐MM was reduced in p.R50X/wt mice, especially in the soleus, suggesting that the function of ‘slow‐twitch’ muscles is less dependent on glycogen catabolism. p.R50X/p.R50X mice showed increased glycogen debranching enzyme in the soleus, increased glycogen branching enzyme in the gastrocnemius and EDL, as well as reduced levels of mucle glycogen synthase protein in the three muscles (mean ∼70%), reflecting a protective mechanism for preventing deleterious glycogen accumulation. Additionally, glycogen content was highest in the EDL of p.R50X/p.R50X mice. Amongst other findings, the present study shows that the expression of the main muscle glycogen regulatory enzymes differs depending on the muscle phenotype (slow‐ vs. fast‐twitch) and that even partial GP‐MM deficiency affects maximal endurance capacity. Our knock‐in model might help to provide insights into the importance of glycogen on muscle function.