title: Differential Muscle Involvement in Mice and Humans Affected by McArdle Disease.
abstract: McArdle disease (muscle glycogenosis type V) is caused by myophosphorylase deficiency, which leads to impaired glycogen breakdown. We investigated how myophosphorylase deficiency affects muscle physiology, morphology, and glucose metabolism in 20-week-old McArdle mice and compared the findings to those in McArdle disease patients. Muscle contractions in the McArdle mice were affected by structural degeneration due to glycogen accumulation, and glycolytic muscles fatigued prematurely, as occurs in the muscles of McArdle disease patients. Homozygous McArdle mice showed muscle fiber disarray, variations in fiber size, vacuoles, and some internal nuclei associated with cytosolic glycogen accumulation and ongoing regeneration; structural damage was seen only in a minority of human patients. Neither liver nor brain isoforms of glycogen phosphorylase were upregulated in muscles, thus providing no substitution for the missing muscle isoform. In the mice, the tibialis anterior (TA) muscles were invariably more damaged than the quadriceps muscles. This may relate to a 7-fold higher level of myophosphorylase in TA compared to quadriceps in wild-type mice and suggests higher glucose turnover in the TA. Thus, despite differences, the mouse model of McArdle disease shares fundamental physiological and clinical features with the human disease and could be used for studies of pathogenesis and development of therapies.
authors.affiliation: From the Copenhagen Neuromuscular Center, Department of Neurology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark (TOK, TLN, JV); and Mitochondrial Pathology and Neuromuscular Disorders Laboratory, Vall d'Hebron Research Institute, Barcelona, Spain and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain (TP, AB, ALA). thomas.krag@regionh.dk.
authors.forename: Thomas O
authors.initials: TO
authors.lastname: Krag
authors.affiliation: From the Copenhagen Neuromuscular Center, Department of Neurology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark (TOK, TLN, JV); and Mitochondrial Pathology and Neuromuscular Disorders Laboratory, Vall d'Hebron Research Institute, Barcelona, Spain and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain (TP, AB, ALA).
authors.forename: Tomàs
authors.initials: T
authors.lastname: Pinós
authors.affiliation: From the Copenhagen Neuromuscular Center, Department of Neurology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark (TOK, TLN, JV); and Mitochondrial Pathology and Neuromuscular Disorders Laboratory, Vall d'Hebron Research Institute, Barcelona, Spain and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain (TP, AB, ALA).
authors.forename: Tue L
authors.initials: TL
authors.lastname: Nielsen
authors.affiliation: From the Copenhagen Neuromuscular Center, Department of Neurology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark (TOK, TLN, JV); and Mitochondrial Pathology and Neuromuscular Disorders Laboratory, Vall d'Hebron Research Institute, Barcelona, Spain and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain (TP, AB, ALA).
authors.forename: Astrid
authors.initials: A
authors.lastname: Brull
authors.affiliation: From the Copenhagen Neuromuscular Center, Department of Neurology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark (TOK, TLN, JV); and Mitochondrial Pathology and Neuromuscular Disorders Laboratory, Vall d'Hebron Research Institute, Barcelona, Spain and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain (TP, AB, ALA).
authors.forename: Antoni L
authors.initials: AL
authors.lastname: Andreu
authors.affiliation: From the Copenhagen Neuromuscular Center, Department of Neurology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark (TOK, TLN, JV); and Mitochondrial Pathology and Neuromuscular Disorders Laboratory, Vall d'Hebron Research Institute, Barcelona, Spain and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain (TP, AB, ALA).
authors.forename: John
authors.initials: J
authors.lastname: Vissing
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D005260:Female; D006012:Glycogen Storage Disease Type V / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000473:pathology*; D013045:Species Specificity; D055815:Young Adult
keywords: Glycogen phosphorylase; Glycogen storage disease Type V; McArdle disease; Muscle contraction; Muscle regeneration.