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.

介绍：先天性肌无力综合征 (CMS) 是一组不同的遗传性神经肌肉疾病，其特征是神经肌肉接头 (NMJ) 的突触传递失败。CMS 通常在早期出现易疲劳的虚弱，并可能因呼吸系统并发症而致命。这AGRN基因是已知含有导致 CMS 的突变的 30 多种基因之一。在这项研究中，我们旨在确定一种用于刺激乙酰胆碱受体 (AChR) 聚集途径的化合物 (NT1654) 是否有益于由阿格恩(阿格恩^nmf380鼠标）。

方法：阿格恩^nmf380小鼠每天接受 NT1654 或载体化合物的注射，野生型同窝伴侣用于比较。每天对动物称重并进行握力评估。处理30天后处死动物，收集肌肉。对收集的组织进行了对 NMJ 和肌肉形态的调查。

结果： 虽然用电子显微镜观察到 NMJ 超微结构的最小改善，但使用荧光标记和共聚焦显微镜进行的总 NMJ 结构分析显示，在 阿格恩^{使用 NT1654 给药的nmf380}小鼠，变量经常恢复到野生型水平。肌肉重量和肌纤维特性的改善有助于增加前肢握力和体重。

结论：我们得出结论，NT1654 通过肌纤维成分的正常化和预防萎缩来恢复 NMJ 突触后结构并提高肌肉力量。我们假设这通过 AChR 聚类途径发生在阿格恩^nmf380小鼠。未来的研究应该调查这是否可能代表 CMS 患者的可行治疗选择，尤其是那些具有 AChR 聚集途径蛋白质突变的患者。