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.
Highlights
Motor neurons contact their target muscle fibres at highly specialised chemical synapses, neuromuscular junctions (NMJ)
Previous work has shown that ColQ−/− mice exhibit muscle weakness which is apparent from P5 [34]
We used forelimb grip strength to assess muscle strength at 3 time points (Fig. 1A) in wild type (WT), ColQ−/− mice treated with water and ColQ−/− mice treated with salbutamol
Summary
Motor neurons contact their target muscle fibres at highly specialised chemical synapses, neuromuscular junctions (NMJ). The NMJ is the pathogenic target in a wide range of human diseases, including those resulting from genetic defects affecting a diverse range of proteins which are critical for synaptic function, the Congenital Myasthenic Syndromes (CMS) [1,2]. CMS arise from mutations affecting presynaptic, synaptic or postsynaptic proteins at the NMJ, resulting in impairment of neuromuscular transmission by one or more mechanisms. Clinical benefit is gained from acetylcholinesterase (AChE) inhibitors, which augment the synaptic response to acetylcholine (ACh) [4]. AChE inhibitors are ineffective or even detrimental in Dok CMS, slowchannel CMS, end-plate AChE deficiency and MuSK CMS
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