{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,11]],"date-time":"2026-10-11T02:24:23Z","timestamp":1791685463361,"version":"4.3.4"},"reference-count":44,"publisher":"Oxford University Press (OUP)","issue":"14","license":[{"start":{"date-parts":[[2020,6,16]],"date-time":"2020-06-16T00:00:00Z","timestamp":1592265600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000265","name":"Medical Research Council","doi-asserted-by":"publisher","award":["MR\/M006824\/1"],"award-info":[{"award-number":["MR\/M006824\/1"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010269","name":"Wellcome Trust","doi-asserted-by":"publisher","award":["103406\/Z\/13\/Z"],"award-info":[{"award-number":["103406\/Z\/13\/Z"]}],"id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2020,8,11]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Congenital myasthenic syndromes (CMS) are characterized by fatigable muscle weakness resulting from impaired neuromuscular transmission. \u03b22-adrenergic agonists are an effective treatment for DOK7-CMS. DOK7 is a component within the AGRN-LRP4-MUSK-DOK7 signalling pathway that is key for the formation and maintenance of the synaptic structure of the neuromuscular junction (NMJ). The precise mechanism of action of \u03b22-adrenergic agonists at the NMJ is not fully understood. In this study, we investigated whether \u03b22-adrenergic agonists improve both neurotransmission and structural integrity of the NMJ in a mouse model of DOK7-CMS. Ex-vivo electrophysiological techniques and microscopy of the NMJ were used to study the effect of salbutamol, a \u03b22-adrenergic agonist, on synaptic structure and function. DOK7-CMS model mice displayed a severe phenotype with reduced weight gain and perinatal lethality. Salbutamol treatment improved weight gain and survival in DOK7 myasthenic mice. Model animals had fewer active NMJs, detectable by endplate recordings, compared with age-matched wild-type littermates. Salbutamol treatment increased the number of detectable NMJs during endplate recording. Correspondingly, model mice had fewer acetylcholine receptor-stained NMJs detected by fluorescent labelling, but following salbutamol treatment an increased number were detectable. The data demonstrate that salbutamol can prolong survival and increase NMJ number in a severe model of DOK7-CMS.<\/jats:p>","DOI":"10.1093\/hmg\/ddaa116","type":"journal-article","created":{"date-parts":[[2020,6,11]],"date-time":"2020-06-11T19:10:39Z","timestamp":1591902639000},"page":"2325-2336","source":"Crossref","is-referenced-by-count":37,"title":["Effect of salbutamol on neuromuscular junction function and structure in a mouse model of DOK7 congenital myasthenia"],"prefix":"10.1093","volume":"29","author":[{"given":"Richard G","family":"Webster","sequence":"first","affiliation":[{"name":"Neurosciences Group, Nuffield Department of Clinical Neurosciences, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1721-6169","authenticated-orcid":false,"given":"An E","family":"Vanhaesebrouck","sequence":"additional","affiliation":[{"name":"Neurosciences Group, Nuffield Department of Clinical Neurosciences, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susan E","family":"Maxwell","sequence":"additional","affiliation":[{"name":"Neurosciences Group, Nuffield Department of Clinical Neurosciences, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Judith A","family":"Cossins","sequence":"additional","affiliation":[{"name":"Neurosciences Group, Nuffield Department of Clinical Neurosciences, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weiwei","family":"Liu","sequence":"additional","affiliation":[{"name":"Neurosciences Group, Nuffield Department of Clinical Neurosciences, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryo","family":"Ueta","sequence":"additional","affiliation":[{"name":"Division of Genetics, Department of Cancer Biology, Institute of Medical Science, The University of Tokyo, Tokyo 135-8550, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuji","family":"Yamanashi","sequence":"additional","affiliation":[{"name":"Division of Genetics, Department of Cancer Biology, Institute of Medical Science, The University of Tokyo, Tokyo 135-8550, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David M W","family":"Beeson","sequence":"additional","affiliation":[{"name":"Neurosciences Group, Nuffield Department of Clinical Neurosciences, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2020,6,16]]},"reference":[{"key":"2020081306365681300_ref1","doi-asserted-by":"crossref","first-page":"1677","DOI":"10.3390\/ijms19061677","article-title":"The neuromuscular junction and wide heterogeneity of congenital myasthenic syndromes","volume":"19","author":"Rodriguez Cruz","year":"2018","journal-title":"Int. J. Mol. Sci."},{"key":"2020081306365681300_ref2","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1111\/nyas.13538","article-title":"Therapeutic strategies for congenital myasthenic syndromes","volume":"1412","author":"Lee","year":"2018","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"2020081306365681300_ref3","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1007\/978-1-59745-156-7_15","volume-title":"Myasthenia Gravis and Related Disorders","author":"Beeson","year":"2009"},{"key":"2020081306365681300_ref4","doi-asserted-by":"crossref","first-page":"1507","DOI":"10.1093\/brain\/awm072","article-title":"Clinical features of the dok7 neuromuscular junction synaptopathy","volume":"130","author":"Palace","year":"2007","journal-title":"Brain"},{"key":"2020081306365681300_ref5","doi-asserted-by":"crossref","first-page":"889","DOI":"10.1001\/jamaneurol.2015.0853","article-title":"Impaired synaptic development, maintenance, and neuromuscular transmission in lrp4-related myasthenia","volume":"72","author":"Selcen","year":"2015","journal-title":"JAMA Neurol."},{"key":"2020081306365681300_ref6","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1186\/s13023-017-0732-z","article-title":"Novel sea and lg2 agrin mutations causing congenital myasthenic syndrome","volume":"12","author":"Xi","year":"2017","journal-title":"Orphanet. J. Rare Dis."},{"key":"2020081306365681300_ref7","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1016\/j.nmd.2013.08.002","article-title":"Salbutamol-responsive limb-girdle congenital myasthenic syndrome due to a novel missense mutation and heteroallelic deletion in musk","volume":"24","author":"Gallenmuller","year":"2014","journal-title":"Neuromuscul. Disord."},{"key":"2020081306365681300_ref8","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1016\/j.nmd.2012.11.004","article-title":"Salbutamol benefits children with congenital myasthenic syndrome due to dok7 mutations","volume":"23","author":"Burke","year":"2013","journal-title":"Neuromuscul. Disord."},{"key":"2020081306365681300_ref9","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1016\/j.jns.2013.05.017","article-title":"Salbutamol therapy in congenital myasthenic syndrome due to dok7 mutation","volume":"331","author":"Lorenzoni","year":"2013","journal-title":"J. Neurol. Sci."},{"key":"2020081306365681300_ref10","doi-asserted-by":"crossref","first-page":"144","DOI":"10.1212\/01.wnl.0000167132.35865.31","article-title":"Congenital endplate acetylcholinesterase deficiency responsive to ephedrine","volume":"65","author":"Bestue-Cardiel","year":"2005","journal-title":"Neurol."},{"key":"2020081306365681300_ref11","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1097\/CND.0000000000000160","article-title":"Colq-related congenital myasthenic syndrome and response to salbutamol therapy","volume":"18","author":"Padmanabha","year":"2017","journal-title":"J. Clin. Neuromuscul. Dis."},{"key":"2020081306365681300_ref12","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1002\/mus.23534","article-title":"Slow channel congenital myasthenic syndrome responsive to a combination of fluoxetine and salbutamol","volume":"47","author":"Finlayson","year":"2013","journal-title":"Muscle Nerve"},{"key":"2020081306365681300_ref13","doi-asserted-by":"crossref","first-page":"1517","DOI":"10.1212\/WNL.0b013e3181dd43bf","article-title":"Ephedrine treatment in congenital myasthenic syndrome due to mutations in dok7","volume":"74","author":"Lashley","year":"2010","journal-title":"Neurol."},{"key":"2020081306365681300_ref14","doi-asserted-by":"crossref","first-page":"828","DOI":"10.1016\/j.nmd.2009.09.008","article-title":"Ephedrine therapy in eight patients with congenital myasthenic syndrome due to dok7 mutations","volume":"19","author":"Schara","year":"2009","journal-title":"Neuromuscul. Disord."},{"key":"2020081306365681300_ref15","doi-asserted-by":"crossref","first-page":"789","DOI":"10.1002\/mus.22176","article-title":"Beneficial effects of albuterol in congenital endplate acetylcholinesterase deficiency and dok-7 myasthenia","volume":"44","author":"Liewluck","year":"2011","journal-title":"Muscle Nerve"},{"key":"2020081306365681300_ref16","doi-asserted-by":"crossref","first-page":"ra7","DOI":"10.1126\/scisignal.2000113","article-title":"Dok-7 activates the muscle receptor kinase musk and shapes synapse formation","volume":"2","author":"Inoue","year":"2009","journal-title":"Sci. Signal."},{"key":"2020081306365681300_ref17","first-page":"25","article-title":"Dok-7\/musk signaling and a congenital myasthenic syndrome","volume":"27","author":"Yamanashi","year":"2008","journal-title":"Acta Myol."},{"key":"2020081306365681300_ref18","doi-asserted-by":"crossref","first-page":"3765","DOI":"10.1093\/hmg\/dds198","article-title":"The spectrum of mutations that underlie the neuromuscular junction synaptopathy in dok7 congenital myasthenic syndrome","volume":"21","author":"Cossins","year":"2012","journal-title":"Hum. Mol. Genet."},{"key":"2020081306365681300_ref19","doi-asserted-by":"crossref","first-page":"1975","DOI":"10.1126\/science.1130837","article-title":"Dok-7 mutations underlie a neuromuscular junction synaptopathy","volume":"313","author":"Beeson","year":"2006","journal-title":"Science"},{"key":"2020081306365681300_ref20","first-page":"640","article-title":"Mutations in dok-7 underlie a congenital myasthenic syndrome with a limb girdle pattern of muscle weakness","volume":"60","author":"Beeson","year":"2006","journal-title":"Ann. Neurol."},{"key":"2020081306365681300_ref21","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1002\/ana.21408","article-title":"Dok-7 myasthenia: phenotypic and molecular genetic studies in 16 patients","volume":"64","author":"Selcen","year":"2008","journal-title":"Ann. Neurol."},{"key":"2020081306365681300_ref22","first-page":"269","article-title":"The carboxyl-terminal region of dok-7 plays a key, but not essential, role in activation of muscle-specific receptor kinase musk and neuromuscular synapse formation","volume":"161","author":"Ueta","year":"2017","journal-title":"J. Biochem."},{"key":"2020081306365681300_ref23","doi-asserted-by":"crossref","first-page":"5518","DOI":"10.1074\/jbc.M708607200","article-title":"Mutations causing dok7 congenital myasthenia ablate functional motifs in dok-7","volume":"283","author":"Hamuro","year":"2008","journal-title":"J. Biol. Chem."},{"key":"2020081306365681300_ref24","doi-asserted-by":"crossref","first-page":"1505","DOI":"10.1126\/science.1250744","article-title":"Neuromuscular disease. Dok7 gene therapy benefits mouse models of diseases characterized by defects in the neuromuscular junction","volume":"345","author":"Arimura","year":"2014","journal-title":"Science"},{"key":"2020081306365681300_ref25","doi-asserted-by":"crossref","first-page":"10302","DOI":"10.1073\/pnas.1107027108","article-title":"Mu-conotoxins that differentially block sodium channels nav1.1 through 1.8 identify those responsible for action potentials in sciatic nerve","volume":"108","author":"Wilson","year":"2011","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"2020081306365681300_ref26","doi-asserted-by":"crossref","first-page":"406","DOI":"10.1038\/321406a0","article-title":"Molecular distinction between fetal and adult forms of muscle acetylcholine receptor","volume":"321","author":"Mishina","year":"1986","journal-title":"Nature"},{"key":"2020081306365681300_ref27","doi-asserted-by":"crossref","first-page":"1522","DOI":"10.1016\/j.bbrc.2005.04.081","article-title":"The acetylcholine receptor gamma-to-epsilon switch occurs in individual endplates","volume":"331","author":"Yumoto","year":"2005","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"2020081306365681300_ref28","doi-asserted-by":"crossref","first-page":"e87840","DOI":"10.1371\/journal.pone.0087840","article-title":"Effects of the beta2-adrenoceptor agonist, albuterol, in a mouse model of anti-musk myasthenia gravis","volume":"9","author":"Ghazanfari","year":"2014","journal-title":"PLoS One"},{"key":"2020081306365681300_ref29","doi-asserted-by":"crossref","first-page":"1802","DOI":"10.1126\/science.1127142","article-title":"The muscle protein dok-7 is essential for neuromuscular synaptogenesis","volume":"312","author":"Okada","year":"2006","journal-title":"Science"},{"key":"2020081306365681300_ref30","doi-asserted-by":"crossref","first-page":"2061","DOI":"10.1093\/brain\/awl200","article-title":"Pre- and post-synaptic abnormalities associated with impaired neuromuscular transmission in a group of patients with 'limb-girdle myasthenia","volume":"129","author":"Slater","year":"2006","journal-title":"Brain"},{"key":"2020081306365681300_ref31","doi-asserted-by":"crossref","first-page":"448","DOI":"10.1002\/mus.20944","article-title":"Variable phenotypes associated with mutations in dok7","volume":"37","author":"Anderson","year":"2008","journal-title":"Muscle Nerve"},{"key":"2020081306365681300_ref32","doi-asserted-by":"crossref","first-page":"1556","DOI":"10.1093\/hmg\/ddy062","article-title":"The beta-adrenergic agonist salbutamol modulates neuromuscular junction formation in zebrafish models of human myasthenic syndromes","volume":"27","author":"McMacken","year":"2018","journal-title":"Hum. Mol. Genet."},{"key":"2020081306365681300_ref33","doi-asserted-by":"crossref","first-page":"231","DOI":"10.3233\/JND-170293","article-title":"Beta-2 adrenergic receptor agonists enhance achr clustering in c2c12 myotubes: implications for therapy of myasthenic disorders","volume":"5","author":"Clausen","year":"2018","journal-title":"J. Neuromuscul. Dis."},{"key":"2020081306365681300_ref34","doi-asserted-by":"crossref","first-page":"746","DOI":"10.1073\/pnas.1524272113","article-title":"Sympathetic innervation controls homeostasis of neuromuscular junctions in health and disease","volume":"113","author":"Khan","year":"2016","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"2020081306365681300_ref35","doi-asserted-by":"crossref","first-page":"2339","DOI":"10.1093\/hmg\/ddz059","article-title":"Salbutamol modifies the neuromuscular junction in a mouse model of colq myasthenic syndrome","volume":"28","author":"McMacken","year":"2019","journal-title":"Hum. Mol. Genet."},{"key":"2020081306365681300_ref36","doi-asserted-by":"crossref","first-page":"3713","DOI":"10.1093\/brain\/awz322","article-title":"Beta2-adrenergic receptor agonists ameliorate the adverse effect of long-term pyridostigmine on neuromuscular junction structure","volume":"142","author":"Vanhaesebrouck","year":"2019","journal-title":"Brain"},{"key":"2020081306365681300_ref37","doi-asserted-by":"crossref","first-page":"286","DOI":"10.1016\/j.expneurol.2013.06.012","article-title":"A mouse model of the slow channel myasthenic syndrome: neuromuscular physiology and effects of ephedrine treatment","volume":"248","author":"Webster","year":"2013","journal-title":"Exp. Neurol."},{"key":"2020081306365681300_ref38","doi-asserted-by":"crossref","first-page":"23871","DOI":"10.1074\/jbc.272.38.23871","article-title":"Beta2-adrenergic receptor desensitization, internalization, and phosphorylation in response to full and partial agonists","volume":"272","author":"January","year":"1997","journal-title":"J. Biol. Chem."},{"key":"2020081306365681300_ref39","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1111\/j.1749-6632.2012.06779.x","article-title":"Dok7 congenital myasthenic syndrome","volume":"1275","author":"Palace","year":"2012","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"2020081306365681300_ref40","doi-asserted-by":"crossref","first-page":"1935","DOI":"10.3390\/ijms19071935","article-title":"Postnatal development and distribution of sympathetic innervation in mouse skeletal muscle","volume":"19","author":"Straka","year":"2018","journal-title":"Int. J. Mol. Sci."},{"key":"2020081306365681300_ref41","doi-asserted-by":"crossref","first-page":"e13195","DOI":"10.1111\/apha.13195","article-title":"The sympathetic nervous system regulates skeletal muscle motor innervation and acetylcholine receptor stability","volume":"225","author":"Rodrigues","year":"2019","journal-title":"Acta Physiol."},{"key":"2020081306365681300_ref42","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1159\/000348677","article-title":"Novel pcr assay for determining the genetic sex of mice","volume":"7","author":"McFarlane","year":"2013","journal-title":"Sex. Dev."},{"key":"2020081306365681300_ref43","doi-asserted-by":"crossref","first-page":"2947","DOI":"10.1093\/hmg\/ddh320","article-title":"A mouse model of achr deficiency syndrome with a phenotype reflecting the human condition","volume":"13","author":"Cossins","year":"2004","journal-title":"Hum. Mol. Genet."},{"key":"2020081306365681300_ref44","doi-asserted-by":"crossref","first-page":"676","DOI":"10.1038\/nmeth.2019","article-title":"Fiji: an open-source platform for biological-image analysis","volume":"9","author":"Schindelin","year":"2012","journal-title":"Nat. Methods"}],"container-title":["Human Molecular Genetics"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/hmg\/advance-article-pdf\/doi\/10.1093\/hmg\/ddaa116\/33449494\/ddaa116.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/hmg\/article-pdf\/29\/14\/2325\/33637627\/ddaa116.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/hmg\/article-pdf\/29\/14\/2325\/33637627\/ddaa116.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2020,8,14]],"date-time":"2020-08-14T04:07:35Z","timestamp":1597378055000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/hmg\/article\/29\/14\/2325\/5857699"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,6,16]]},"references-count":44,"journal-issue":{"issue":"14","published-online":{"date-parts":[[2020,6,16]]},"published-print":{"date-parts":[[2020,8,11]]}},"URL":"https:\/\/doi.org\/10.1093\/hmg\/ddaa116","relation":{},"ISSN":["0964-6906","1460-2083"],"issn-type":[{"value":"0964-6906","type":"print"},{"value":"1460-2083","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2020,7,15]]},"published":{"date-parts":[[2020,6,16]]}}}