McArdle disease (
glycogenosis type V), the most common muscle
glycogenosis, is a recessive disorder caused by mutations in PYGM, the gene encoding
myophosphorylase. Patients with
McArdle disease typically experience exercise intolerance manifested as acute crises of early
fatigue and
contractures, sometimes with
rhabdomyolysis and myoblobinuria, triggered by static muscle contractions or dynamic exercises. Currently, there are no
therapies to restore
myophosphorylase activity in patients. Although two spontaneous animal models for
McArdle disease have been identified (cattle and sheep), they have rendered a limited amount of information on the pathophysiology of the disorder; therefore, there have been few opportunities for experimental research in the field. We have developed a knock-in mouse model by replacing the wild-type allele of Pygm with a modified allele carrying the common human mutation, p.R50X, which is the most frequent cause of
McArdle disease. Histochemical, biochemical and molecular analyses of the phenotype, as well as exercise tests, were carried out in homozygotes, carriers and wild-type mice. p.R50X/p.R50X mice showed undetectable
myophosphorylase protein and activity in skeletal muscle. Histochemical and biochemical analyses revealed massive muscle
glycogen accumulation in homozygotes, in contrast to heterozygotes or wild-type mice, which did not show
glycogen accumulation in this tissue. Additional characterization confirmed a
McArdle disease-like phenotype in p.R50X/p.R50X mice, i.e. they had hyperCKaemia and very poor exercise performance, as assessed in the wire grip and treadmill tests (6% and 5% of the wild-type values, respectively). This model represents a powerful tool for in-depth studies of the pathophysiology of
McArdle disease and other neuromuscular disorders, and for exploring new therapeutic approaches for
genetic disorders caused by
premature stop codon mutations.