Access to this article is restricted until 12 months after publication by request of the publisher.. Restriction lift date: 2018-08-06
Restoration of pharyngeal dilator muscle force in dystrophin-deficient (mdx) mice following co-treatment with neutralizing interleukin-6 receptor antibodies and urocortin-2
| dc.check.date | 2018-08-06 | |
| dc.check.info | Access to this article is restricted until 12 months after publication by request of the publisher. | en |
| dc.contributor.author | Rowland, Jane | |
| dc.contributor.author | Burns, David P. | |
| dc.contributor.author | Canavan, Leonie | |
| dc.contributor.author | Murphy, Kevin H. | |
| dc.contributor.author | Brannock, Molly | |
| dc.contributor.author | O'Malley, Dervla | |
| dc.contributor.author | O'Halloran, Ken D. | |
| dc.contributor.author | Edge, Deirdre | |
| dc.contributor.funder | University College Cork | en |
| dc.date.accessioned | 2017-09-12T10:57:29Z | |
| dc.date.available | 2017-09-12T10:57:29Z | |
| dc.date.issued | 2017-08-06 | |
| dc.date.updated | 2017-09-12T10:43:28Z | |
| dc.description.abstract | New Findings: What is the central question of this study? We previously reported impaired upper airway dilator muscle function in the mdx mouse model of Duchenne muscular dystrophy (DMD). Our aim was to assess the effect of blocking interleukin-6 receptor signalling and stimulating corticotrophin-releasing factor receptor 2 signalling on mdx sternohyoid muscle structure and function. What is the main finding and its importance? The interventional treatment had a positive inotropic effect on sternohyoid muscle force, restoring mechanical work and power to wild-type values, reduced myofibre central nucleation and preserved the myosin heavy chain type IIb fibre complement of mdx sternohyoid muscle. These data might have implications for development of pharmacotherapies for DMD with relevance to respiratory muscle performance. The mdx mouse model of Duchenne muscular dystrophy shows evidence of impaired pharyngeal dilator muscle function. We hypothesized that inflammatory and stress-related factors are implicated in airway dilator muscle dysfunction. Six-week-old mdx (n = 26) and wild-type (WT; n = 26) mice received either saline (0.9% w/v) or a co-administration of neutralizing interleukin-6 receptor antibodies (0.2 mg kg−1) and corticotrophin-releasing factor receptor 2 agonist (urocortin 2; 30 μg kg−1) over 2 weeks. Sternohyoid muscle isometric and isotonic contractile function was examined ex vivo. Muscle fibre centronucleation and muscle cellular infiltration, collagen content, fibre-type distribution and fibre cross-sectional area were determined by histology and immunofluorescence. Muscle chemokine content was examined by use of a multiplex assay. Sternohyoid peak specific force at 100 Hz was significantly reduced in mdx compared with WT. Drug treatment completely restored force in mdx sternohyoid to WT levels. The percentage of centrally nucleated muscle fibres was significantly increased in mdx, and this was partly ameliorated after drug treatment. The areal density of infiltrates and collagen content were significantly increased in mdx sternohyoid; both indices were unaffected by drug treatment. The abundance of myosin heavy chain type IIb fibres was significantly decreased in mdx sternohyoid; drug treatment preserved myosin heavy chain type IIb complement in mdx muscle. The chemokines macrophage inflammatory protein 2, interferon-γ-induced protein 10 and macrophage inflammatory protein 3α were significantly increased in mdx sternohyoid compared with WT. Drug treatment significantly increased chemokine expression in mdx but not WT sternohyoid. Recovery of contractile function was impressive in our study, with implications for Duchenne muscular dystrophy. The precise molecular mechanisms by which the drug treatment exerts an inotropic effect on mdx sternohyoid muscle remain to be elucidated. | en |
| dc.description.sponsorship | University College Cork (Department of Physiology) | en |
| dc.description.status | Peer reviewed | en |
| dc.description.version | Accepted Version | en |
| dc.format.mimetype | application/pdf | en |
| dc.identifier.citation | Burns, D. P., Rowland, J., Canavan, L., Murphy, K. H., Brannock, M., O'Malley, D., O'Halloran, K. D. and Edge, D. (2017) 'Restoration of pharyngeal dilator muscle force in dystrophin-deficient (mdx) mice following co-treatment with neutralizing interleukin-6 receptor antibodies and urocortin 2', Experimental Physiology, 102(9), pp. 1177-1193. doi:10.1113/EP086232 | en |
| dc.identifier.doi | 10.1113/EP086232 | |
| dc.identifier.endpage | 1193 | en |
| dc.identifier.issn | 0958-0670 | |
| dc.identifier.issued | 9 | en |
| dc.identifier.journaltitle | Experimental Physiology | en |
| dc.identifier.startpage | 1177 | en |
| dc.identifier.uri | https://hdl.handle.net/10468/4686 | |
| dc.identifier.volume | 102 | en |
| dc.language.iso | en | en |
| dc.publisher | Wiley | en |
| dc.rights | © 2017 The Authors. Experimental Physiology © 2017 The Physiological Society. This is the peer reviewed version of the following article: Burns et al. (2017) Restoration of pharyngeal dilator muscle force in dystrophin-deficient (mdx) mice following co-treatment with neutralizing interleukin-6 receptor antibodies and urocortin 2. Exp Physiol, 102: 1177–1193., which has been published in final form at http://dx.doi.org/10.1113/EP086232. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving. | en |
| dc.subject | Corticotrophin releasing factor | en |
| dc.subject | DMD | en |
| dc.subject | Interleukin-6 | en |
| dc.subject | mdx | en |
| dc.subject | Sternohyoid muscle | en |
| dc.subject | Stress | en |
| dc.subject | Duchenne muscular dystrophy | en |
| dc.subject | Respiratory muscle | en |
| dc.subject | Interleukin-6 | en |
| dc.title | Restoration of pharyngeal dilator muscle force in dystrophin-deficient (mdx) mice following co-treatment with neutralizing interleukin-6 receptor antibodies and urocortin-2 | en |
| dc.type | Article (peer-reviewed) | en |
