title: MuSK antibody positive myasthenia gravis plasma modifies MURF-1 expression in C2C12 cultures and mouse muscle in vivo.
abstract: MG is an antibody-mediated disease that is often treated with corticosteroids. Antibodies to the muscle specific tyrosine kinase (MuSK) have been identified in a proportion of patients with myasthenia gravis (MG) without acetylcholine receptor (AChR) antibodies. MuSK-MG patients often suffer from marked facial muscle weakness, and some patients develop facial and tongue muscle atrophy. MuSK is a receptor tyrosine kinase that plays an essential role during development and is thought to play a trophic role in mature muscle. It is possible, therefore, that the muscle atrophy results from the action of the MuSK antibodies themselves, but effects of corticosteroids on muscle might also be involved. Muscle atrophy in vivo is associated with upregulation of striated Muscle RING-Finger protein-1 (MURF-1), and MURF-1 is also upregulated in C2C12 myotubes exposed to the corticosteroid, dexamethasone (Dex). Here we investigated the effects of MuSK antibodies or Dex on MURF-1 expression in C2C12 cultures and in mouse muscles after treatment in vivo, using quantitative Western blotting. We also looked at expression of neural cell adhesion molecule (NCAM, CD56) that is upregulated after denervation in vivo. MuSK-MG plasma and purified IgG from a patient with marked muscle atrophy modestly increased MURF-1 expression in C2C12 cells in culture, and MURF-1 expression in mouse masseter (facial) muscle, but not in gastrocnemius (leg). Dex had a more marked effect on MURF-1 expression in C2C12 cells, but did not affect MURF-1 expression in either muscle. However, both in C2C12 cells and in vivo, Dex substantially reduced NCAM expression. These results provide the first evidence that MuSK-MG plasma can influence expression of an atrophy-related protein, and preliminary evidence that a facial muscle, the masseter, is more susceptible to this effect. They indicate the need for further studies on muscle atrophy, MuSK-MG antibodies, the effects of steroids, and the intracellular pathways involved.
authors.affiliation: Department of Clinical Neurology, University of Oxford OX3 9DS, UK. olivier.benveniste@psl.aphp.fr
authors.forename: Olivier
authors.initials: O
authors.lastname: Benveniste
authors.forename: Leslie
authors.initials: L
authors.lastname: Jacobson
authors.forename: Maria Elena
authors.initials: ME
authors.lastname: Farrugia
authors.forename: Linda
authors.initials: L
authors.lastname: Clover
authors.forename: Angela
authors.initials: A
authors.lastname: Vincent
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000097:blood*; D015153:Blotting, Western; D002460:Cell Line; D003907:Dexamethasone / Q000494:pharmacology; D006801:Humans; D007074:Immunoglobulin G / Q000494:pharmacology; D008406:Masseter Muscle / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018485:Muscle Fibers, Skeletal / Q000378:metabolism*; D009124:Muscle Proteins / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000378:metabolism*; D009133:Muscular Atrophy / Q000276:immunology; D009157:Myasthenia Gravis / Q000097:blood* / Q000276:immunology*; D019006:Neural Cell Adhesion Molecules / Q000037:antagonists & inhibitors / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000276:immunology*; D011950:Receptors, Cholinergic / Q000276:immunology*; D000070584:Tripartite Motif Proteins; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*
chemical_list: D001323:Autoantibodies; D007074:Immunoglobulin G; D009124:Muscle Proteins; D019006:Neural Cell Adhesion Molecules; D011950:Receptors, Cholinergic; D000070584:Tripartite Motif Proteins; D003907:Dexamethasone; C499084:Trim63 protein, mouse; D044767:Ubiquitin-Protein Ligases; C095714:MUSK protein, human; D020794:Receptor Protein-Tyrosine Kinases