Restoration of pharyngeal dilator muscle force in dystrophin-deficient (mdx) mice following co-treatment with neutralizing interleukin-6 receptor antibodies and urocortin 2

被引:11
作者
Burns, David P. [1 ]
Rowland, Jane [2 ]
Canavan, Leonie [2 ]
Murphy, Kevin H. [1 ]
Brannock, Molly [2 ]
O'Malley, Dervla [1 ]
O'Halloran, Ken D. [1 ]
Edge, Deirdre [2 ]
机构
[1] Univ Coll Cork, Sch Med, Dept Physiol, Cork, Ireland
[2] Univ Dublin, Trinity Coll Dublin, Trinity Biomed Sci Inst, Dept Physiol, Dublin, Ireland
关键词
DUCHENNE MUSCULAR-DYSTROPHY; CHRONIC SUSTAINED HYPOXIA; CC CLASS CHEMOKINES; UPPER AIRWAY MUSCLE; SKELETAL-MUSCLE; MOUSE DIAPHRAGM; THERAPEUTIC IMPLICATIONS; STERNOHYOID MUSCLE; GENE-EXPRESSION; SLEEP;
D O I
10.1113/EP086232
中图分类号
Q4 [生理学];
学科分类号
071003 ;
摘要
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 mu g 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-gamma-induced protein 10 and macrophage inflammatory protein 3 alpha 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.
引用
收藏
页码:1177 / 1193
页数:17
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