Beta-2 Adrenergic Receptor Agonists Enhance AChR Clustering in C2C12 Myotubes: Implications for Therapy of Myasthenic Disorders.

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.