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
| Autor: | de Luna Salva, Noemí, Brull, Astrid, Guiu, Josep Maria, Lucia, Alejandro, Martin, Miguel Angel, Arenas, Joaquín, Martí, Ramon A., Andreu, Antoni L., Pinós Figueras, Tomàs, Universitat Autònoma de Barcelona |
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| Rok vydání: | 2015 |
| Předmět: |
Ciencia
medicine.medical_specialty Glycogenolysis McArdle disease Muscle Fibers Skeletal Neuroscience (miscellaneous) lcsh:Medicine Medicine (miscellaneous) Salud Biology General Biochemistry Genetics and Molecular Biology Glycogen debranching enzyme Mice Glycogen phosphorylase chemistry.chemical_compound Sodium valproate Immunology and Microbiology (miscellaneous) Internal medicine lcsh:Pathology medicine Animals Humans Protein Isoforms Glycogen storage disease Muscle Skeletal Cells Cultured Glycogen Myogenesis Valproic Acid lcsh:R Glycogen Phosphorylase Homozygote Enfermedades - McArdle Brain Skeletal muscle medicine.disease Ejercicio físico Genética Endocrinology medicine.anatomical_structure chemistry Myotubes Glycogen Storage Disease Type V Glycogen storage disease type V lcsh:RB1-214 Research Article |
| Zdroj: | ABACUS. Repositorio de Producción Científica Universidad Europea (UEM) Disease Models & Mechanisms Repositorio Institucional de la Consejería de Sanidad de la Comunidad de Madrid Consejería de Sanidad de la Comunidad de Madrid Disease Models & Mechanisms, Vol 8, Iss 5, Pp 467-472 (2015) Dipòsit Digital de Documents de la UAB Universitat Autònoma de Barcelona |
| Popis: | 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. Summary: Use of this in vitro model showed that sodium valproate (VPA) can reverse the muscle phenotype from a McArdle-like to a normal histological and biochemical profile. |
| Databáze: | OpenAIRE |
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