Restoration of pharyngeal dilator muscle force in dystrophin deficient (mdx) mice following co-treatment with neutralising IL-6 receptor antibodies and Urocortin-2

Abstract

The mdx mouse model of Duchenne muscular dystrophy (DMD) shows evidence of impaired pharyngeal dilator muscle function. We hypothesised 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⁻¹) or a co-administration of neutralising IL-6 receptor antibodies (xIL-6R; 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 partially ameliorated following 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 MHC type IIb fibres was significantly decreased in mdx sternohyoid; drug treatment preserved MHC type IIb complement in mdx muscle. The chemokines MIP-2, IP-10 and MIP-3α were significantly increased in mdx sternohyoid compared with WT. Drug treatment significantly increased chemokine expression in mdx but not WT. Recovery of contractile function was impressive in our study with implications for DMD. The precise molecular mechanisms by which the drug treatment exerts an inotropic effect on mdx sternohyoid muscle remains to be elucidated.

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