Abstract

Duchenne muscular dystrophy (DMD) is a genetic muscle disease caused by the absence of a functional dystrophin protein. Lack of dystrophin protein disrupts the dystrophin-glycoprotein complex causing muscle membrane instability and degeneration. One of the secondary manifestations resulting from lack of functional dystrophin in muscle tissue is an increased level of cytokines that recruit inflammatory cells, leading to chronic upregulation of the nuclear factor (NF)-κB. Negative regulators of the classical NF-κB pathway improve muscle health in the mdx mouse model for DMD. We have previously shown in vitro that a negative regulator of the NF-κB pathway, A20, plays a role in muscle regeneration. Here, we show that overexpression of A20 by using a muscle-specific promoter delivered with an adeno-associated virus serotype 8 (AAV8) vector to the mdx mouse decreases activation of the NF-κB pathway in skeletal muscle. Recombinant A20 expression resulted in a reduction in number of fibers with centrally placed nuclei and a reduction in the number of T cells infiltrating muscle transduced with the AAV8-A20 vector. Taken together, we conclude that overexpression of A20 in mdx skeletal muscle provides improved muscle health by reduction of chronic inflammation and muscle degeneration. These results suggest A20 is a potential therapeutic target to ameliorate symptoms of DMD.

Highlights

  • Duchenne muscular dystrophy (DMD) is one of the most common muscle disorders, affecting about 1 in 3,500–6,000 males worldwide [1]

  • We have previously demonstrated that A20 plays a critical role in nuclear factor (NF)-κB pathway inhibition in skeletal muscle [22]

  • A20 Overexpression Driven by a Muscle-Specific Promoter Accomplished by associated virus serotype 8 (AAV8) Vector–Mediated Gene Transfer

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Summary

Introduction

Duchenne muscular dystrophy (DMD) is one of the most common muscle disorders, affecting about 1 in 3,500–6,000 males worldwide [1]. It is caused by mutations in the dystrophin gene, resulting in the absence of or a dysfunctional dystrophin protein [2], and disruption of the dystrophin-glycoprotein complex (DGC) required for muscle membrane stability [3]. The NF-κB pathway plays a role in inducing the ubiquitin-proteasome pathway in muscle [11], causing increased protein degradation [12,13]. Myogenic differentiation (MyoD) and myogenic factor-5 (Myf-5) are myogenic regulatory factors that play a role in normal murine muscle development and differentiation [14].

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