Molecular Medicine

, Volume 18, Issue 12, pp 1527–1535 | Cite as

Adeno-associated Virus Serotype 8 (AAV8) Delivery of Recombinant A20 to Skeletal Muscle Reduces Pathological Activation of Nuclear Factor (NF)-κB in Muscle of mdx Mice

  • Rakshita A Charan
  • Gabriela Niizawa
  • Hiroyuki Nakai
  • Paula R Clemens
Research Article


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.



The authors thank Daniel Reay and Aditee Shinde for technical assistance and advice. We also thank Bing Wang, PhD, for provision of the AAV-tMCK-GFP plasmid. This work was supported by a VA Merit Review grant and University of Pittsburgh departmental funds and in part was supported by grant DK078388 to H.N.

The authors take full responsibility for the contents of this paper, which do not represent the views of the Department of Veterans Affairs or the U.S. Government.

Supplementary material

10020_2012_18121527_MOESM1_ESM.pdf (934 kb)
Adeno-associated Virus Serotype 8 (AAV8) Delivery of Recombinant A20 to Skeletal Muscle Reduces Pathological Activation of Nuclear Factor (NF)-κB in Muscle of mdx Mice


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Authors and Affiliations

  • Rakshita A Charan
    • 1
    • 2
  • Gabriela Niizawa
    • 1
    • 2
  • Hiroyuki Nakai
    • 3
  • Paula R Clemens
    • 1
    • 2
  1. 1.Department of Veterans Affairs Medical CenterNeurology ServicePittsburghUSA
  2. 2.Department of Neurology, School of Medicine, S520 Biomedical Science TowerUniversity of PittsburghPittsburghUSA
  3. 3.Department of Molecular and Medical GeneticsOregon Health and Science UniversityPortlandUSA

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