Year-end Sale % OFF 
Abstract
ABSTRACTMcArdle 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.
Highlights
McArdle disease, termed glycogen storage disease type V (OMIM® number 232600), is a disorder of skeletal muscle carbohydrate metabolism caused by inherited deficiency of the skeletal-muscle isoform of glycogen phosphorylase (GP-MM)
The authors analyzed the expression of different GP isoforms [the brain (GP-BB) and liver (GP-LL) isoforms in addition to GP-MM] in cultured cells that were previously obtained from skeletal muscles of KI (GP-MMdeficient) or wild-type mice, at different stages of differentiation
The primary skeletal-muscle cultures derived from p.R50X KI mice represent a good cellular model of McArdle disease because they mimic the glycogen accumulation that is commonly found in the skeletal muscle from individuals with McArdle disease (Lucia et al, 2008)
Summary
McArdle disease, termed glycogen storage disease type V (OMIM® number 232600), is a disorder of skeletal muscle carbohydrate metabolism caused by inherited deficiency of the skeletal-muscle isoform of glycogen phosphorylase (GP-MM). It is caused by pathogenic mutations in both copies of the GP-MMencoding gene (PYGM), which is located in chromosome 11q1211q13. Human primary skeletal-muscle cultures obtained from biopsies of affected individuals do not differ from controls in that there is no excessive accumulation of periodic acid Schiff (PAS) staining material, and no abnormal glycogen deposits (Martinuzzi et al, 1993). Other authors have failed to detect GP-MM in human primary skeletal-muscle cultures obtained from affected individuals or healthy controls (DiMauro et al, 1978; Sato et al, 1977)
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
