Abstract
Duchenne muscular dystrophy (DMD) is an X-linked muscle disease caused by mutations in the dystrophin gene. The pathology of DMD manifests in patients with progressive muscle weakness, loss of ambulation and ultimately death. One of the characteristics of DMD is muscle inflammation, and dystrophin-deficient skeletal muscles produce higher levels of the pro-inflammatory cytokine interleukin 1β (IL-1β) in response to toll like receptor (TLR) stimulation compared to controls; therefore, blocking the IL-1β pathway could improve the disease phenotype in mdx mice, a mouse model of DMD. Kineret® or IL-1Ra is a recombinant IL-1 receptor antagonist approved by the FDA for treating rheumatoid arthritis. To determine the efficacy of IL-1Ra in a DMD model, we administered subcutaneous injections of saline control or IL-1Ra (25 mg/kg/day) to mdx mice daily for 45 days beginning at 5 weeks of age. Functional and histological parameters were measured at the conclusion of the study. IL-1Ra only partially inhibited this signaling pathway in this study; however, there were still interesting observations to be noted. For example, although not significantly changed, splenocytes from the IL-1Ra-treated group secreted less IL-1β after LPS stimulation compared to control mice indicating a blunted response and incomplete inhibition of the pathway (37% decrease). In addition, normalized forelimb grip strength was significantly increased in IL-1Ra-treated mice. There were no changes in EDL muscle-specific force measurements, histological parameters, or motor coordination assessments in the dystrophic mice after IL-1Ra treatment. There was a significant 27% decrease in the movement time and total distance traveled by the IL-1Ra treated mice, correlating with previous studies examining effects of IL-1 on behavior. Our studies indicate partial blocking of IL-1β with IL-1Ra significantly altered only a few behavioral and strength related disease parameters; however, treatment with inhibitors that completely block IL-1β, pathways upstream of IL-1β production or combining various inhibitors may produce more favorable outcomes.
Highlights
Duchenne muscular dystrophy (DMD) is an X-linked muscle disease characterized by inflammation and fibrosis in the skeletal muscles which results from constant cycles of muscle degeneration and regeneration [1,2,3]
To test whether interleukin 1 receptor antagonist (IL-1Ra) is effective in vivo in inhibiting IL-1 secretion, splenocytes from mdx mice treated with IL-1Ra or saline were stimulated with lipopolysaccharide (LPS)
The normalized forelimb and hindlimb grip strengths increased by approximately 11% (p
Summary
Duchenne muscular dystrophy (DMD) is an X-linked muscle disease characterized by inflammation and fibrosis in the skeletal muscles which results from constant cycles of muscle degeneration and regeneration [1,2,3]. Despite the severity of this disease, there are only limited treatment options for DMD patients with the current standard-of-care regimen being glucocorticoids (GCs) [4,5,6]. The mdx mouse model, identified via a spontaneous mutation in the dystrophin gene, exhibits some of the hallmark pathologies of DMD [3,7,8] In this model, inflammation develops in both the limbs and diaphragm at 3 weeks of age, with a peak at about age 8–10 weeks, before diminishing in the limbs but not the diaphragm [9]. Pre-clinical testing has demonstrated that anti-inflammatory drugs improve the mdx muscle phenotype and have the potential to alleviate inflammatory pathways in DMD patients [10,11,12,13]
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