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BACKGROUND: Congenital myasthenic syndromes (CMS) are a group of inherited neuromuscular transmission disorders causing fatiguable muscle weakness. ADRB2 agonists have been observed to provide therapeutic benefit where destabilisation of NMJ structures is part of the underlying pathology, such as in DOK7, COLQ and MuSK CMS as well as in slow channel syndrome. However, very little is known about the molecular mechanisms underlying the effects of ADRB2 agonists in CMS. OBJECTIVE: In vitro investigation into whether an ADRB2 agonist affects the AChR clustering pathway and has the potential to increase the number and stability of AChR clusters. METHODS: Cultured C2C12 mouse myotubes overexpressing the common DOK7 frameshift mutation c.1124_1127dupTGCC were incubated with salbutamol sulphate and the effect on AChR cluster numbers were investigated. Moreover, agrin-induced AChR clusters in C2C12 WT cells were left to disperse after agrin-wash-off, and the effects of incubation with salbutamol sulphate on AChR cluster numbers were explored. RESULTS: Salbutamol sulphate induced a significant increase in the number of AChR clusters formed on C2C12 cells overexpressing c.1124_1127dupTGCC. Furthermore, significantly more clusters remained in C2C12 WT myotubes incubated with salbutamol sulphate following agrin wash-off. CONCLUSIONS: The results suggest that ADRB2 agonists directly affect proteins located at the neuromuscular junction and exert a stabilising effect on AChR clusters.

Original publication

DOI

10.3233/JND-170293

Type

Journal article

Journal

J Neuromuscul Dis

Publication Date

2018

Volume

5

Pages

231 - 240

Keywords

DOK7 protein, Myasthenic syndromes, adrenergic beta-2 receptor agonists, congenital, human, neuromuscular junction, Adrenergic beta-2 Receptor Agonists, Albuterol, Animals, Blotting, Western, Cell Line, Frameshift Mutation, In Vitro Techniques, Mice, Muscle Fibers, Skeletal, Muscle Proteins, Myasthenic Syndromes, Congenital, Neuromuscular Junction, Receptors, Cholinergic