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
de Luna Salva, Noemí (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Brull, Astrid (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Guiu, Josep Maria (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Lucia, Alejandro (Instituto de Investigación Sanitaria Hospital 12 de Octubre (i+12))
Martin, Miguel Angel (Instituto de Investigación Sanitaria Hospital 12 de Octubre (i+12))
Arenas, Joaquín (Instituto de Investigación Sanitaria Hospital 12 de Octubre (i+12))
Martí, Ramon A. (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Andreu Périz, Antoni Lluís (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Pinós Figueras, Tomàs (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Universitat Autònoma de Barcelona

Date:	2015
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. 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.
Grants:	Instituto de Salud Carlos III PI13-00855
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Subject:	Glycogen phosphorylase ; Glycogenolysis ; McArdle disease ; Myotubes ; Sodium valproate
Published in:	Disease Models & Mechanisms, Vol. 8 (may 2015) , p. 467-472, ISSN 1754-8411

DOI: 10.1242/dmm.020230
PMID: 25762569

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