Salbutamol modifies the neuromuscular junction in a mouse model of ColQ myasthenic syndrome

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• dc.contributor.author McMacken, Grace M.
• dc.contributor.author Spendiff, Sally
• dc.contributor.author Whittaker, Roger G.
• dc.contributor.author O'Connor, Emily
• dc.contributor.author Howarth, Rachel M.
• dc.contributor.author Boczonadi, Veronika
• dc.contributor.author Horvath, Rita
• dc.contributor.author Slater, Clarke R.
• dc.contributor.author Lochmüller, Hanns
• dc.date.accessioned 2019-09-30T09:48:09Z
• dc.date.available 2019-09-30T09:48:09Z
• dc.date.issued 2019
• dc.description.abstract The β-adrenergic agonists salbutamol and ephedrine have proven to be effective as therapies for human disorders of the neuromuscular junction, in particular many subsets of congenital myasthenic syndromes. However, the mechanisms underlying this clinical benefit are unknown and improved understanding of the effect of adrenergic signalling on the neuromuscular junction is essential to facilitate the development of more targeted therapies. Here, we investigated the effect of salbutamol treatment on the neuromuscular junction in the ColQ deficient mouse, a model of end-plate acetylcholinesterase deficiency. ColQ-/- mice received 7 weeks of daily salbutamol injection, and the effect on muscle strength and neuromuscular junction morphology was analysed. We show that salbutamol leads to a gradual improvement in muscle strength in ColQ-/- mice. In addition, the neuromuscular junctions of salbutamol treated mice showed significant improvements in several postsynaptic morphological defects, including increased synaptic area, acetylcholine receptor area and density, and extent of postjunctional folds. These changes occurred without alterations in skeletal muscle fibre size or type. These findings suggest that β-adrenergic agonists lead to functional benefit in the ColQ-/- mouse and to long-term structural changes at the neuromuscular junction. These effects are primarily at the postsynaptic membrane and may lead to enhanced neuromuscular transmission.
• dc.description.sponsorship Guarantors of Brain/Association of British Neurologists (Clinical Research Training Fellowship to G.M.); Wellcome Trust (Pathfinder Award, 201064/Z/16/Z; Investigator Award 109915/Z/15/Z to R.H.); the Medical Research Council (Confidence in Concept fund to R.H., H.L. and S.S.; MR/N025431/1 to R.H.); Canadian Institute of Health Research (PJT 162265 to S.S. and H.L.); Newton Fund UK/Turkey (MR/N027302/1 to R.H.); European Research Council (309548 to R.H.).
• dc.format.mimetype application/pdf
• dc.identifier.citation McMacken GM, Spendiff S, Whittaker RG, O'Connor E, Howarth RM, Boczonadi V, Horvath R, Slater CR, Lochmüller H. Salbutamol modifies the neuromuscular junction in a mouse model of ColQ myasthenic syndrome. Hum Mol Genet. 2019; 28(14):2339-2351. DOI 10.1093/hmg/ddz059
• dc.identifier.doi http://dx.doi.org/10.1093/hmg/ddz059
• dc.identifier.issn 0964-6906
• dc.identifier.uri http://hdl.handle.net/10230/42356
• dc.language.iso eng
• dc.publisher Oxford University Press
• dc.relation.ispartof Hum Mol Genet. 2019; 28(14):2339-2351
• dc.relation.projectID info:eu-repo/grantAgreement/EC/FP7/309548
• dc.rights © The Author(s) 2019. Published by Oxford University Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri http://creativecommons.org/licenses/by/4.0/
• dc.subject.keyword Albuterol
• dc.subject.keyword Neuromuscular junction
• dc.subject.keyword Cholinergic receptors
• dc.subject.keyword Mice
• dc.title Salbutamol modifies the neuromuscular junction in a mouse model of ColQ myasthenic syndrome
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion