Dystrophic phenotype induced in vitro by antibody blockade of muscle alpha-dystroglycan-laminin interaction.
alpha-dystroglycan is a glycoprotein expressed on the surface of skeletal muscle fibres and other cell types. In muscle, alpha-dystroglycan provides a link between the myofibre cytoskeleton through its indirect binding to dystrophin, and the basal lamina through its binding to laminin-2, a protein of the extracellular matrix. The disruption of this linkage between the myofibre cytoskeleton and the extracellular matrix is a common feature of Duchenne and other muscular dystrophies, though the pathogenic mechanisms leading to muscle wasting remain unknown. By treating primary mouse muscle cultures with a monoclonal antibody which blocks alpha-dystroglycan binding to laminin, we show here the induction of a dystrophic phenotype in vitro. The phenotype is inducible in differentiated cultures only, is characterised by reduced myotube size, myofibril disorganisation, loss of contractile activity, reduced spontaneous clustering of acetylcholine receptors and is reversed by addition of excess exogenous laminin-2. Thus, alpha-dystroglycan may be part of a signalling pathway for the maturation and maintenance of skeletal myofibres. Detailed knowledge of this signalling pathway may provide insights into the molecular pathology of the various inherited muscular dystrophies, and identify valuable pharmacological targets and new therapeutic strategies.
Brown
S C
SC
Division of Biochemistry, School of Biological Sciences, Royal Holloway College, University of London, Egham, Surrey TW20 0EX, UK.
Fassati
A
A
Popplewell
L
L
Page
A M
AM
Henry
M D
MD
Campbell
K P
KP
Dickson
G
G
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D002454:Cell Differentiation; D002459:Cell Fusion; D002478:Cells, Cultured; D003598:Cytoskeletal Proteins / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism*; D049030:Dystroglycans; D007797:Laminin / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008854:Microscopy, Electron; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000648:ultrastructure; D009137:Muscular Dystrophy, Animal / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D011485:Protein Binding
D000911:Antibodies, Monoclonal; D003598:Cytoskeletal Proteins; D007797:Laminin; D008562:Membrane Glycoproteins; D049030:Dystroglycans