title: Sodium valproate increases the brain isoform of glycogen phosphorylase: looking for a compensation mechanism in McArdle disease using a mouse primary skeletal-muscle culture in vitro.
abstract: 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.
authors.affiliation: Mitochondrial Pathology and Neuromuscular Disorders Laboratory, Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona, Barcelona 08035, Spain Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid 28029, Spain.
authors.forename: Noemí
authors.initials: N
authors.lastname: de Luna
authors.affiliation: Mitochondrial Pathology and Neuromuscular Disorders Laboratory, Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona, Barcelona 08035, Spain Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid 28029, Spain.
authors.forename: Astrid
authors.initials: A
authors.lastname: Brull
authors.affiliation: Mitochondrial Pathology and Neuromuscular Disorders Laboratory, Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona, Barcelona 08035, Spain Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid 28029, Spain.
authors.forename: Josep Maria
authors.initials: JM
authors.lastname: Guiu
authors.affiliation: Universidad Europea, Madrid 28670, Spain Instituto de Investigación 'i+12', Madrid 28041, Spain.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Lucia
authors.affiliation: Instituto de Investigación 'i+12', Madrid 28041, Spain.
authors.forename: Miguel Angel
authors.initials: MA
authors.lastname: Martin
authors.affiliation: Instituto de Investigación 'i+12', Madrid 28041, Spain.
authors.forename: Joaquin
authors.initials: J
authors.lastname: Arenas
authors.affiliation: Mitochondrial Pathology and Neuromuscular Disorders Laboratory, Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona, Barcelona 08035, Spain Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid 28029, Spain.
authors.forename: Ramon
authors.initials: R
authors.lastname: Martí
authors.affiliation: Mitochondrial Pathology and Neuromuscular Disorders Laboratory, Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona, Barcelona 08035, Spain Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid 28029, Spain toniandreu.bcn@gmail.com tomas.pinos@vhir.org.
authors.forename: Antoni L
authors.initials: AL
authors.lastname: Andreu
authors.affiliation: Mitochondrial Pathology and Neuromuscular Disorders Laboratory, Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona, Barcelona 08035, Spain Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid 28029, Spain toniandreu.bcn@gmail.com tomas.pinos@vhir.org.
authors.forename: Tomàs
authors.initials: T
authors.lastname: Pinós
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D002478:Cells, Cultured; D006003:Glycogen / Q000378:metabolism; D024981:Glycogen Phosphorylase / Q000378:metabolism*; D006012:Glycogen Storage Disease Type V / Q000201:enzymology* / Q000473:pathology; D006720:Homozygote; D006801:Humans; D051379:Mice; D018485:Muscle Fibers, Skeletal / Q000187:drug effects / Q000473:pathology; D018482:Muscle, Skeletal / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D020033:Protein Isoforms / Q000378:metabolism; D014635:Valproic Acid / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D020033:Protein Isoforms; D014635:Valproic Acid; D006003:Glycogen; D024981:Glycogen Phosphorylase
keywords: Glycogen phosphorylase; Glycogenolysis; McArdle disease; Myotubes; Sodium valproate