{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T03:09:55Z","timestamp":1790651395420,"version":"4.1.0"},"reference-count":71,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2013,3,25]],"date-time":"2013-03-25T00:00:00Z","timestamp":1364169600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["The Journal of Physiology"],"published-print":{"date-parts":[[2013,5]]},"abstract":"<jats:title>Key points<\/jats:title><jats:p><jats:list list-type=\"explicit-label\"><jats:list-item><jats:p>A mouse model of anti\u2010muscle\u2010specific kinase (MuSK) myasthenia gravis was used to study the effect of pyridostigmine (a cholinesterase inhibitor drug commonly used in myasthenia) on the disease process at the neuromuscular junction.<\/jats:p><\/jats:list-item><jats:list-item><jats:p>In mice receiving injections of anti\u2010MuSK\u2010positive patient IgG, pyridostigmine treatment for 7\u20139 days did not prevent myasthenia, and even precipitated weakness.<\/jats:p><\/jats:list-item><jats:list-item><jats:p>Pyridostigmine treatment potentiated the anti\u2010MuSK\u2010induced reductions in postsynaptic acetylcholine receptor density and endplate potential (EPP) amplitude.<\/jats:p><\/jats:list-item><jats:list-item><jats:p>3,4\u2010Diaminopyridine, a drug that increases the number of quanta released (rather than the duration of each quantal response), elevated EPP amplitude without exacerbating the anti\u2010MuSK\u2010induced loss of acetylcholine receptors.<\/jats:p><\/jats:list-item><jats:list-item><jats:p>The results suggest that cholinergic\u2010 and MuSK\u2010mediated signalling may converge postsynaptically to regulate the mature acetylcholine receptor scaffold.<\/jats:p><\/jats:list-item><\/jats:list><\/jats:p><jats:p><jats:bold>Abstract\u2002<\/jats:bold>In myasthenia gravis, the neuromuscular junction is impaired by the antibody\u2010mediated loss of postsynaptic acetylcholine receptors (AChRs). Muscle weakness can be improved upon treatment with pyridostigmine, a cholinesterase inhibitor, or with 3,4\u2010diaminopyridine, which increases the release of ACh quanta. The clinical efficacy of pyridostigmine is in doubt for certain forms of myasthenia. Here we formally examined the effects of these compounds in the antibody\u2010induced mouse model of anti\u2010muscle\u2010specific kinase (MuSK) myasthenia gravis. Mice received 14 daily injections of IgG from patients with anti\u2010MuSK myasthenia gravis. This caused reductions in postsynaptic AChR densities and in endplate potential amplitudes. Systemic delivery of pyridostigmine at therapeutically relevant levels from days 7 to 14 exacerbated the anti\u2010MuSK\u2010induced structural alterations and functional impairment at motor endplates in the diaphragm muscle. No such effect of pyridostigmine was found in mice receiving control human IgG. Mice receiving smaller amounts of MuSK autoantibodies did not display overt weakness, but 9 days of pyridostigmine treatment precipitated generalised muscle weakness. In contrast, one week of treatment with 3,4\u2010diaminopyridine enhanced neuromuscular transmission in the diaphragm muscle. Both pyridostigmine and 3,4\u2010diaminopyridine increase ACh in the synaptic cleft yet only pyridostigmine potentiated the anti\u2010MuSK\u2010induced decline in endplate ACh receptor density. These results thus suggest that ongoing pyridostigmine treatment potentiates anti\u2010MuSK\u2010induced AChR loss by prolonging the activity of ACh in the synaptic cleft.<\/jats:p>","DOI":"10.1113\/jphysiol.2013.251827","type":"journal-article","created":{"date-parts":[[2013,2,26]],"date-time":"2013-02-26T03:50:45Z","timestamp":1361850645000},"page":"2747-2762","source":"Crossref","is-referenced-by-count":69,"title":["Pyridostigmine but not 3,4\u2010diaminopyridine exacerbates ACh receptor loss and myasthenia induced in mice by muscle\u2010specific kinase autoantibody"],"prefix":"10.1113","volume":"591","author":[{"given":"Marco","family":"Morsch","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen 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