Salbutamol modifies the neuromuscular junction in a mouse model of ColQ myasthenic syndrome
Salbutamol modifies the neuromuscular junction in a mouse model of ColQ myasthenic syndrome
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DOI：
10.1093/hmg/ddz059
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发表时间：
2019-07-15
影响因子：
3.5
通讯作者：
Lochmuller, Hanns
中科院分区：
文献类型：
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作者：
McMacken, Grace M.;Spendiff, Sally;Lochmuller, Hanns
β-肾上腺素能激动剂沙丁胺醇和麻黄碱已被证明可有效治疗人类神经肌肉接头疾病，特别是许多先天性肌无力综合征。然而，这种临床益处的机制尚不清楚，更好地了解肾上腺素信号对神经肌肉接头的影响对于促进更有针对性的疗法的开发至关重要。在这里，我们研究了沙丁胺醇治疗对 ColQ 缺陷小鼠（终板乙酰胆碱酯酶缺陷模型）神经肌肉接头的影响。 ColQ(-/-)小鼠每天注射沙丁胺醇7周，并分析其对肌肉力量和神经肌肉接头形态的影响。我们发现沙丁胺醇可以逐渐改善 ColQ(-/-) 小鼠的肌肉力量。此外，沙丁胺醇治疗小鼠的神经肌肉接头显示出几种突触后形态缺陷的显着改善，包括突触面积、乙酰胆碱受体面积和密度以及接头后褶皱范围的增加。这些变化的发生没有改变骨骼肌纤维的大小或类型。这些发现表明，β-肾上腺素能激动剂可改善 ColQ(-/-) 小鼠的功能，并导致神经肌肉接头处的长期结构变化。这些作用主要发生在突触后膜，可能导致神经肌肉传递增强。
The beta-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 beta-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.