title: 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.
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.
authors.affiliation: Neurology Service, Department of Veterans Affairs Medical Center, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Rakshita A
authors.initials: RA
authors.lastname: Charan
authors.forename: Gabriela
authors.initials: G
authors.lastname: Niizawa
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Nakai
authors.forename: Paula R
authors.initials: PR
authors.lastname: Clemens
mesh_terms: D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism; D003546:Cysteine Endopeptidases; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000627:therapeutic use*; D000229:Dependovirus / Q000145:classification / Q000235:genetics*; D005260:Female; D015870:Gene Expression; D018014:Gene Transfer Techniques; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D018101:Mice, Inbred mdx; D018485:Muscle Fibers, Skeletal / Q000378:metabolism / Q000473:pathology; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D051787:Myogenic Regulatory Factor 5 / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D009336:Necrosis; D009928:Organ Specificity / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D011994:Recombinant Proteins / Q000235:genetics* / Q000627:therapeutic use; D012038:Regeneration; D012703:Serotyping; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000378:metabolism; D051841:Transcription Factor RelB / Q000378:metabolism; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; D044767:Ubiquitin-Protein Ligases / Q000235:genetics* / Q000627:therapeutic use*
chemical_list: D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; C497418:Myf5 protein, mouse; D051787:Myogenic Regulatory Factor 5; D016328:NF-kappa B; D011994:Recombinant Proteins; D051841:Transcription Factor RelB; D044767:Ubiquitin-Protein Ligases; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; D003546:Cysteine Endopeptidases; C513261:Tnfaip3 protein, mouse