Modulation of the acetylcholine receptor clustering pathway improves neuromuscular junction structure and muscle strength in a mouse model of congenital myasthenic syndrome

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• dc.contributor.author Spendiff, Sally
• dc.contributor.author Howarth, Rachel M.
• dc.contributor.author McMacken, Grace M.
• dc.contributor.author Davey, Tracey
• dc.contributor.author Quinlan, Kaitlyn
• dc.contributor.author O'Connor, Emily
• dc.contributor.author Slater, Clarke R.
• dc.contributor.author Hettwer, Stefan
• dc.contributor.author Mäder, Armin
• dc.contributor.author Roos, Andreas
• dc.contributor.author Horvath, Rita
• dc.contributor.author Lochmüller, Hanns
• dc.date.accessioned 2021-03-17T09:56:36Z
• dc.date.available 2021-03-17T09:56:36Z
• dc.date.issued 2020
• dc.description.abstract Introduction: Congenital myasthenic syndromes (CMS) are a diverse group of inherited neuromuscular disorders characterized by a failure of synaptic transmission at the neuromuscular junction (NMJ). CMS often present early with fatigable weakness and can be fatal through respiratory complications. The AGRN gene is one of over 30 genes known to harbor mutations causative for CMS. In this study, we aimed to determine if a compound (NT1654), developed to stimulate the acetylcholine receptor (AChR) clustering pathway, would benefit a mouse model of CMS caused by a loss-of-function mutation in Agrn (Agrn nmf380 mouse). Methods: Agrn nmf380 mice received an injection of either NT1654 or vehicle compound daily, with wild-type litter mates used for comparison. Animals were weighed daily and underwent grip strength assessments. After 30 days of treatment animals were sacrificed, and muscles collected. Investigations into NMJ and muscle morphology were performed on collected tissue. Results: While minimal improvements in NMJ ultrastructure were observed with electron microscopy, gross NMJ structure analysis using fluorescent labelling and confocal microscopy revealed extensive postsynaptic improvements in Agrn nmf380 mice with NT1654 administration, with variables frequently returning to wild type levels. An improvement in muscle weight and myofiber characteristics helped increase forelimb grip strength and body weight. Conclusions: We conclude that NT1654 restores NMJ postsynaptic structure and improves muscle strength through normalization of muscle fiber composition and the prevention of atrophy. We hypothesize this occurs through the AChR clustering pathway in Agrn nmf380 mice. Future studies should investigate if this may represent a viable treatment option for patients with CMS, especially those with mutations in proteins of the AChR clustering pathway.
• dc.description.sponsorship This research was funded by the Wellcome Trust (Pathfinder Award, 201064/Z/16/Z) and the Medical Research Council (Confidence in Concept Fund). HL receives support from the Canadian Institutes of Health Research (Foundation Grant FDN-167281), the Canadian Institutes of Health Research and Muscular Dystrophy Canada (Network Catalyst Grant for NMD4C), the Canada Foundation for Innovation (CFI-JELF 38412), and the Canada Research Chairs program (Canada Research Chair in Neuromuscular Genomics and Health, 950-232279). RH received funding from the Newton Fund UK/Turkey (MR/N027302/1), the Medical Research Council (UK) (MR/N025431/1), the Wellcome Investigator fund (109915/Z/15/Z), the Lily Foundation UK, and the Evelyn Trust (19/14). EO was supported by a postdoctoral fellowship from AFM-Téléthon (22569). GM was supported by a Guarantors of Brain/Association of British Neurologists Clinical Research Training Fellowship
• dc.format.mimetype application/pdf
• dc.identifier.citation Spendiff S, Howarth R, McMachek G, Davey T, Quinlan K, O'Connor E et al. Modulation of the acetylcholine receptor clustering pathway improves neuromuscular junction structure and muscle strength in a mouse model of congenital myasthenic syndrome. Front Mol Neurosci. 2020 Dec 17;13:594220. DOI: 10.3389/fnmol.2020.594220
• dc.identifier.doi http://dx.doi.org/10.3389/fnmol.2020.594220
• dc.identifier.issn 1662-5099
• dc.identifier.uri http://hdl.handle.net/10230/46822
• dc.language.iso eng
• dc.publisher Frontiers Media
• dc.relation.ispartof Frontiers in Molecular Neuroscience. 2020 Dec 17;13:594220
• dc.rights © 2020 Spendiff, Howarth, McMacken, Davey, Quinlan, O'Connor, Slater, Hettwer, Mäder, Roos, Horvath and Lochmüller. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri https://creativecommons.org/licenses/by/4.0/
• dc.subject.other Síndrome miastènic congènit
• dc.subject.other Malalties neuromusculars
• dc.title Modulation of the acetylcholine receptor clustering pathway improves neuromuscular junction structure and muscle strength in a mouse model of congenital myasthenic syndrome
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion