Early inhibition of tumor necrosis factor-α and interleukin-6 in muscle tissue as a therapy for dystrophinopathy in mdx mice

Abstract

Objective Pro-inflammatory cytokines can exacerbate muscle fiber damage in dystrophinopathy. The aim of the present study was to identify cytokine/chemokine alterations in the muscle tissues of mdx mice, a model of dystrophinopathy, and the beneficial effects of anti-proinflammatory cytokine therapy. Methods A total of 23 cytokines and chemokines were quantitatively measured in muscle tissues from mdx mice by fluorescent bead-based immunoassay. The mdx mice were treated with anti-tumor necrosis factor-α (TNF-α) and anti-interleukin-6 (IL-6) drugs, and their physical condition was evaluated by Rotarod and muscle damage by histopathological analysis. Results Levels of TNF-α and IL-6 were elevated at 14 days (P14), before a transient increase of macrophage and neutrophil-activating pro-inflammatory cytokines/chemokines, such as C-C motif ligand 2 (CCL2), CCL4 and KC (mouse C-X-C motif ligand 8 homolog), at P20. Administration of an anti-TNF-α drug (etanercept) and an anti-IL-6 receptor antibody (MR16-1) from P7 improved physical performance, and reduced both the area of basophilic fibers that indicated degenerating/regenerating fibers and CD68-positive macrophage infiltration. Initiating therapy at P7 inhibited the elevation of CCL2, CCL4 and KC more effectively than at P13. Conclusions The early administration of anti-TNF-α and anti-IL-6 drugs attenuated muscle fiber degeneration in a mouse model of dystrophinopathy.