title: 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.
authors: Physiology and Bosch Institute, University of Sydney, Sydney, New South Wales, Australia.
authors: Nazanin
authors: N
authors: Ghazanfari
authors: Physiology and Bosch Institute, University of Sydney, Sydney, New South Wales, Australia.
authors: Marco
authors: M
authors: Morsch
authors: Physiology and Bosch Institute, University of Sydney, Sydney, New South Wales, Australia.
authors: Nigel
authors: N
authors: Tse
authors: Department of Molecular Medicine, Concord Hospital, Concord, New South Wales, Australia.
authors: Stephen W
authors: SW
authors: Reddel
authors: Physiology and Bosch Institute, University of Sydney, Sydney, New South Wales, Australia.
authors: William D
authors: WD
authors: Phillips
mesh_terms: D058666:Adrenergic beta-2 Receptor Agonists / Q000494:pharmacology*; D000420:Albuterol / Q000494:pharmacology*; D000818:Animals; D001323:Autoantibodies / Q000276:immunology / Q000633:toxicity*; D005260:Female; D006801:Humans; D051379:Mice; D018482:Muscle, Skeletal / Q000276:immunology / Q000473:pathology; D020720:Myasthenia Gravis, Autoimmune, Experimental / Q000139:chemically induced / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D009469:Neuromuscular Junction / Q000276:immunology / Q000473:pathology; D020794:Receptor Protein-Tyrosine Kinases / Q000276:immunology
chemical_list: D058666:Adrenergic beta-2 Receptor Agonists; D001323:Autoantibodies; C511695:MuSK protein, mouse; D020794:Receptor Protein-Tyrosine Kinases; D000420:Albuterol