title: Phenotype consequences of myophosphorylase dysfunction: insights from the McArdle mouse model.
abstract: CONCLUSIONS
  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.
  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.
authors: Neuromuscular and Mitochondrial Disorders Laboratory, Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona, Barcelona, Spain.|Biomedical Network Research Centre on Rare Diseases (CIBERER), Instituto de Salud Carlos III, Spain.
authors: Astrid
authors: A
authors: Brull
authors: Neuromuscular and Mitochondrial Disorders Laboratory, Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona, Barcelona, Spain.|Biomedical Network Research Centre on Rare Diseases (CIBERER), Instituto de Salud Carlos III, Spain.
authors: Noemí
authors: N
authors: de Luna
authors: Neuromuscular and Mitochondrial Disorders Laboratory, Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona, Barcelona, Spain.
authors: Albert
authors: A
authors: Blanco-Grau
authors: Universidad Europea, Madrid, Spain.|Instituto de Investigación 'i+12', Madrid, Spain.
authors: Alejandro
authors: A
authors: Lucia
authors: Instituto de Investigación 'i+12', Madrid, Spain.
authors: Miguel Angel
authors: MA
authors: Martin
authors: Instituto de Investigación 'i+12', Madrid, Spain.
authors: Joaquin
authors: J
authors: Arenas
authors: Neuromuscular and Mitochondrial Disorders Laboratory, Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona, Barcelona, Spain.|Biomedical Network Research Centre on Rare Diseases (CIBERER), Instituto de Salud Carlos III, Spain.
authors: Ramon
authors: R
authors: Martí
authors: Neuromuscular and Mitochondrial Disorders Laboratory, Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona, Barcelona, Spain.|Biomedical Network Research Centre on Rare Diseases (CIBERER), Instituto de Salud Carlos III, Spain.
authors: Antoni L
authors: AL
authors: Andreu
authors: Neuromuscular and Mitochondrial Disorders Laboratory, Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona, Barcelona, Spain.|Biomedical Network Research Centre on Rare Diseases (CIBERER), Instituto de Salud Carlos III, Spain.
authors: Tomàs
authors: T
authors: Pinós
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D006003:Glycogen / Q000378:metabolism; D024981:Glycogen Phosphorylase / Q000235:genetics / Q000502:physiology*; D006012:Glycogen Storage Disease Type V / Q000378:metabolism / Q000503:physiopathology*; D008297:Male; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000502:physiology*; D010641:Phenotype; D010805:Physical Conditioning, Animal / Q000502:physiology*; D020033:Protein Isoforms / Q000235:genetics / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism
chemical_list: D020033:Protein Isoforms; D012333:RNA, Messenger; D006003:Glycogen; D024981:Glycogen Phosphorylase