Differential glucose metabolism in mice and humans affected by McArdle disease.
McArdle disease (muscle glycogenosis type V) is a disease caused by myophosphorylase deficiency leading to "blocked" glycogen breakdown. A significant but varying glycogen accumulation in especially distal hind limb muscles of mice affected by McArdle disease has recently been demonstrated. In this study, we investigated how myophosphorylase deficiency affects glucose metabolism in hind limb muscle of 20-wk-old McArdle mice and vastus lateralis muscles from patients with McArdle disease. Western blot analysis and activity assay demonstrated that glycogen synthase was inhibited in glycolytic muscle from McArdle mice. The level and activation of proteins involved in contraction-induced glucose transport (AMPK, GLUT4) and glycogen synthase inhibition were increased in quadriceps muscle of McArdle mice. In addition, pCaMKII in quadriceps was reduced, suggesting lower insulin-induced glucose uptake, which could lead to lower glycogen accumulation. In comparison, tibialis anterior, extensor digitorum longus, and soleus had massive glycogen accumulation, but few, if any, changes or adaptations in glucose metabolism compared with wild-type mice. The findings suggest plasticity in glycogen metabolism in the McArdle mouse that is related to myosin heavy chain type IIB content in muscles. In patients, the level of GLUT4 was vastly increased, as were hexokinase II and phosphofructokinase, and glycogen synthase was more inhibited, suggesting that patients adapt by increasing capture of glucose for direct metabolism, thereby significantly reducing glycogen buildup compared with the mouse model. Hence, the McArdle mouse may be a useful tool for further comparative studies of disease mechanism caused by myophosphorylase deficiency and basic studies of metabolic adaptation in muscle.
Copenhagen Neuromuscular Center, Department of Neurology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark; thomas.krag@regionh.dk.
Thomas O
TO
Krag
Copenhagen Neuromuscular Center, Department of Neurology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark; Mitochondrial Pathology and Neuromuscular Disorders Laboratory, Vall d'Hebron Research Institute, Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Raras, Barcelona, Spain;
Tomàs
T
Pinós
Copenhagen Neuromuscular Center, Department of Neurology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark;
Tue L
TL
Nielsen
Institute for Research in Biomedicine, The Barcelona Institute of Science and Technology, Barcelona, Spain; and Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas, Barcelona, Spain.
Jordi
J
Duran
Institute for Research in Biomedicine, The Barcelona Institute of Science and Technology, Barcelona, Spain; and.
Mar
M
García-Rocha
Mitochondrial Pathology and Neuromuscular Disorders Laboratory, Vall d'Hebron Research Institute, Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Raras, Barcelona, Spain;
Antoni L
AL
Andreu
Copenhagen Neuromuscular Center, Department of Neurology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark;
John
J
Vissing
D000293:Adolescent; D000328:Adult; D000818:Animals; D005260:Female; D005947:Glucose / Q000378:metabolism*; D006012:Glycogen Storage Disease Type V / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D009097:Multienzyme Complexes; D018482:Muscle, Skeletal / Q000378:metabolism*; D013045:Species Specificity; D055815:Young Adult
D009097:Multienzyme Complexes; D005947:Glucose
McArdle disease; glycogen; glycogen metabolism; knock-in mouse model; myophosphorylase