Recovery of respiratory function in mdx mice co-treated with neutralizing interleukin-6 receptor antibodies and Urocortin-2

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dc.check.date2019-08-30
dc.check.infoAccess to this article is restricted until 12 months after publication by request of the publisher.en
dc.contributor.authorBurns, David P.
dc.contributor.authorCanavan, Leonie
dc.contributor.authorRowland, Jane
dc.contributor.authorO'Flaherty, Robin
dc.contributor.authorBrannock, Molly
dc.contributor.authorDrummond, Sarah E.
dc.contributor.authorO'Malley, Dervla
dc.contributor.authorEdge, Deirdre
dc.contributor.authorO'Halloran, Ken D.
dc.contributor.funderUniversity College Corken
dc.contributor.funderTrinity College Dublinen
dc.date.accessioned2018-09-10T11:25:51Z
dc.date.available2018-09-10T11:25:51Z
dc.date.issued2018-08-30
dc.date.updated2018-09-07T09:02:34Z
dc.description.abstractThe mdx mouse model of Duchenne muscular dystrophy shows evidence of hypoventilation and pronounced diaphragm dysfunction. Six‐week‐old male mdx (n = 32) and wild‐type (WT; n = 32) mice received either saline (0.9% w/v) or a co‐administration of neutralizing interleukin‐6 receptor antibodies (xIL‐6R; 0.2 mg/kg) and corticotrophin‐releasing factor receptor 2 agonist (Urocortin‐2; 30 μg/kg), subcutaneously over 2 weeks. Breathing and diaphragm muscle contractile function (ex vivo) were examined. Diaphragm structure was assessed using histology and immunofluorescence. Muscle cytokine concentration was determined using a multiplex assay. Minute ventilation and diaphragm muscle peak force at 100 Hz were significantly depressed in mdx compared with WT. Drug treatment completely restored ventilation in mdx mice during normoxia and significantly increased mdx diaphragm force‐ and power‐generating capacity. The number of centrally‐nucleated muscle fibres and the areal density of infiltrates and collagen content were significantly increased in mdx diaphragm; all indices were unaffected by drug co‐treatment. The abundance of myosin heavy chain (MyHC) type IIx fibres was significantly decreased in mdx diaphragm; drug co‐treatment preserved MyHC type IIx complement in mdx muscle. Drug co‐treatment increased the cross‐sectional area of MyHC type I and IIx fibres in mdx diaphragm. The cytokines IL‐1β, IL‐6, KC/GRO and TNF‐α were significantly increased in mdx diaphragm compared with WT. Drug co‐treatment significantly decreased IL‐1β and increased IL‐10 in mdx diaphragm. Drug co‐treatment had no significant effect on WT diaphragm muscle structure, cytokine concentrations or function. Recovery of breathing and diaphragm force in mdx mice was impressive in our studies, with implication for human dystrophinopathies.en
dc.description.statusPeer revieweden
dc.description.versionAccepted Versionen
dc.format.mimetypeapplication/pdfen
dc.identifier.citationBurns, D. P., Canavan, L., Rowland, J., O'Flaherty, R., Brannock, M., Drummond, S. E., O'Malley, D., Edge, D. and O'Halloran, K. D. (2018) 'Recovery of respiratory function in mdx mice co-treated with neutralizing interleukin-6 receptor antibodies and Urocortin-2', Journal of Physiology. doi:10.1113/JP276954en
dc.identifier.doi10.1113/JP276954
dc.identifier.issn0022-3751
dc.identifier.issn1469-7793
dc.identifier.journaltitleJournal of Physiologyen
dc.identifier.urihttps://hdl.handle.net/10468/6742
dc.language.isoenen
dc.publisherJohn Wiley & Sons, Inc. on behalf of the Physiological Societyen
dc.rights© 2018, the Physiological Society. Published by John Wiley & Sons Inc. This is the peer reviewed version of the following article: Burns, D. P., Canavan, L., Rowland, J., O'Flaherty, R., Brannock, M., Drummond, S. E., O'Malley, D., Edge, D. and O'Halloran, K. D. (2018) 'Recovery of respiratory function in mdx mice co-treated with neutralizing interleukin-6 receptor antibodies and Urocortin-2', Journal of Physiology. doi:10.1113/JP276954, which has been published in final form at https://doi.org/10.1113/JP276954 . This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions.en
dc.subjectDMDen
dc.subjectmdxen
dc.subjectCorticotrophin releasing factoren
dc.subjectDiaphragm muscle ben
dc.subjectBreathingen
dc.subjectInterleukin-6en
dc.subjectUrocortin-2en
dc.titleRecovery of respiratory function in mdx mice co-treated with neutralizing interleukin-6 receptor antibodies and Urocortin-2en
dc.typeArticle (peer-reviewed)en
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