Sodium valproate increases glycogen phosphorylase brain isoform: looking for a compensation mechanism in McArdle disease

McArdle disease, also termed ‘glycogen storage disease type V’ is a disorder of skeletal muscle carbohydrate metabolism originated by inherited deficiency of the musclespecific isoform of glycogen phosphorylase (GP-MM). It is an autosomic recessive disorder caused by mutations in the PYGM gene which typically presents with exercise intolerance, i.e., episodes of early exertional fatigue frequently accompanied by rhabdomyolysis and myoglobinuria. Muscle biopsies from these patients contain subsarcolemmal deposits of glycogen. Besides GP-MM, two other GP isoforms have been described: the liver (GP-LL) and brain isoforms (GP-BB), which are encoded by 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 GPMM deficiency observed in skeletal muscle from McArdle patients. We treated mice primary skeletal muscle cultures in vitro with sodium valproate (VPA), a histone deacetylase inhibitor. After VPA treatment, myotubes expressed GP-BB and a dosedependent 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 to obtain 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 McArdle patients. D ise as e M od el s & M ec ha ni sm s D M M Ac ce pt ed m an us cr ip t