Résumé :
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Communication n° 537 Introduction: Recently, antibodies to the muscle specific tyrosine kinase (MuSK) have been identified in a proportion of patients with myasthenia gravis without acetylcholine receptor (AChR) antibodies. MuSK is a receptor tyrosine kinase that is crucial for organizing the agrin-induced clustering of AChRs at the neuromuscular junction during development. Patients with MuSK antibodies often present with severe facial and bulbar symptoms and there may be permanent muscle atrophy. It is not clear whether long-term corticosteroid treatment might also be involved. Objectives: Here we studied the serum of two patients with MuSK antibodies to see whether they induced changes consistent with muscle atrophy in C2C12 cultures and in mouse muscles in vivo. We compared the serum results with dexamethasone (dex), which is known to induce muscle atrophy. We looked for induction of Striated Muscle RING-Finger Protein-1 (MuRF-1), an atrophy-related protein. Methods: C2C12 cells were differentiated and incubated in the sera or dex at different concentrations, before extracting the cells, and performing quantitative western blotting. Mice were injected daily for 23 days with dex (5 g/g/day) or vehicle alone, with MuSK antibody positive serum or control serum injected for the final five days. Muscles were taken from leg (grastrocnemius) and face (masseter) for immunohistochemistry and western blotting. Results: In C2C12 myotubes, both MuSK antibody positive sera induced MuRF-1 over-expression (respectively x 2.5 and 4) with maximum effect around 1:80 dilution. Dex also induced MuRF-1 over-expression (x 15) with maximal effect at 1 M. In vivo, dex injections prevented weight gain in 4 week old mice. Interestingly, MuRF-1 expression was upregulated in masseter but not in gastrocnemius of mice injected by MuSK antibody positive serum compared to control serum. This effect is potentiated by dex. Conclusions: These preliminary results suggest that MuSK-MG antibodies do induce atrophy-related gene expression, and suggest that possible interactions with the dexamethasone-induced pathways that might throw light on the cause of facial atrophy in MuSK-MG patients.
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