Effects of the ß2-Adrenoceptor Agonist, Albuterol, in a Mouse Model of Anti-MuSK Myasthenia Gravis

Abstract

The β2-adrenergic receptor agonist, albuterol, has been reported beneficial in treating several forms of congenital myasthenia. Here, for the first time, we examined the potential benefit of albuterol in a mouse model of anti-Muscle Specific Kinase (MuSK) myasthenia gravis. Mice received 15 daily injections of IgG from anti-MuSK positive patients, which resulted in whole-body weakness. At neuromuscular junctions in the tibialis anterior and diaphragm muscles the autoantibodies caused loss of postsynaptic acetylcholine receptors, and reduced the amplitudes of the endplate potential and spontaneous miniature endplate potential in the diaphragm muscle. Treatment with albuterol (8 mg/kg/day) during the two-week anti-MuSK injection series reduced the degree of weakness and weight loss, compared to vehicle-treated mice. However, the compound muscle action potential recorded from the gastrocnemius muscle displayed a decremental response in anti-MuSK-injected mice whether treated with albuterol or vehicle. Ongoing albuterol treatment did not increase endplate potential amplitudes compared to vehicle-treated mice nor did it prevent the loss of acetylcholine receptors from motor endplates. On the other hand, albuterol treatment significantly reduced the degree of fragmentation of endplate acetylcholine receptor clusters and increased the extent to which the remaining receptor clusters were covered by synaptophysin-stained nerve terminals. The results provide the first evidence that short-term albuterol treatment can ameliorate weakness in a robust mouse model of anti-MuSK myasthenia gravis. The results also demonstrate that it is possible for albuterol treatment to reduce whole-body weakness without necessarily reversing myasthenic impairment to the structure and function of the neuromuscular junction.

Characteristics of myasthenia gravis with antibodies to muscle‐specific kinase and low‐density lipoprotein‐related receptor protein 4

“…These findings add to previous reports on 3,4‐diaminopyridine effectiveness in experimental MuSK‐MG . Furthermore, treatment with the β2‐adrenergic agonist, albuterol, which is beneficial in congenital myasthenia caused by AChE deficiency or Dok‐7 mutations, reduced muscle weakness in mice injected with IgG from MuSK‐positive patients …”

Current Treatment, Emerging Translational Therapies, and New Therapeutic Targets for Autoimmune Myasthenia Gravis

“…The mechanism of action is not entirely clear but is believed to involve stabilization of AChRs at the postsynaptic membrane through protein kinase A (a downstream effector of β2 adrenergic receptors). Short-term treatment with the β2 adrenergic agonist albuterol was shown to improve weakness in a mouse model of anti-MuSK MG [151], suggesting that this class of agents might provide benefit in human MuSK MG. 3,4-Diaminopyridine is another symptomatic therapy with potential application in MuSK MG. Exploring use of this drug, which enhances AChR release at the motor nerve terminal, in MuSK MG is supported by preclinical models, experience with congenital MG with MuSK mutations, and case reports [152,153].…”

Salbutamol-responsive fetal acetylcholine receptor inactivation syndrome

“…1 Salbutamol, a b2-adrenergic agonist commenced in our patient considering its proven efficacy in various neuromuscular disorders and lack of response to other treatments, resulted in dramatic and sustained improvement. Salbutamol is highly effective in genetic CMS due to mutations in several genes, most notably DOK7 and COLQ, and has been demonstrated to improve AChR cluster assembly and NMJ architecture in a mouse model of anti-MuSK MG. 7 Our observations suggest that salbutamol is an effective therapy for a potentially severe condition for which there is currently no treatment.…”