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 output: Contribution to journalArticle

6 Citations (Scopus)

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 musclespecific 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.

Original languageEnglish (US)
Pages (from-to)1527-1535
Number of pages9
JournalMolecular Medicine
Volume18
Issue number12
DOIs
StatePublished - Nov 6 2012

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Inbred mdx Mouse
Dependovirus
Skeletal Muscle
Muscles
Dystrophin
Duchenne Muscular Dystrophy
Inborn Genetic Diseases
Serogroup
Health
Regeneration
Glycoproteins
Proteins
Up-Regulation
Cytokines
Inflammation
T-Lymphocytes
Membranes

ASJC Scopus subject areas

  • Genetics
  • Molecular Biology
  • Molecular Medicine
  • Genetics(clinical)

Cite this

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. / Charan, Rakshita A.; Niizawa, Gabriela; Nakai, Hiroyuki; Clemens, Paula R.

In: Molecular Medicine, Vol. 18, No. 12, 06.11.2012, p. 1527-1535.

Research output: Contribution to journalArticle

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