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

Lookup NU author(s): Dr Grace McMacken, Dr Sally Spendiff, Dr Roger Whittaker, Emily O'Connor, Rachel Howarth, Dr Veronika Boczonadi, Professor Rita Horvath, Emeritus Professor Clarke Slater, Professor Hanns Lochmuller

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Abstract

© 2019 The Author(s).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.


Publication metadata

Author(s): McMacken GM, Spendiff S, Whittaker RG, O'Connor E, Howarth RM, Boczonadi V, Horvath R, Slater CR, Lochmuller H

Publication type: Article

Publication status: Published

Journal: Human Molecular Genetics

Year: 2019

Volume: 28

Issue: 14

Pages: 2339-2351

Online publication date: 01/04/2019

Acceptance date: 15/03/2019

Date deposited: 31/07/2019

ISSN (print): 0964-6906

ISSN (electronic): 1460-2083

Publisher: Oxford University Press

URL: https://doi.org/10.1093/hmg/ddz059

DOI: 10.1093/hmg/ddz059

PubMed id: 31220253


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