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Inhibition of the IKK/NF-B pathway by AAV gene transfer improves muscle regeneration in older mdx mice

Tang, Y and Reay, DP and Salay, MN and Mi, MY and Clemens, PR and Guttridge, DC and Robbins, PD and Huard, J and Wang, B (2010) Inhibition of the IKK/NF-B pathway by AAV gene transfer improves muscle regeneration in older mdx mice. Gene Therapy, 17 (12). 1476 - 1483. ISSN 0969-7128

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Abstract

The IB kinase (IKKα, Β and the regulatory subunit IKKγ) complex regulates nuclear factor of B (NF-B) transcriptional activity, which is upregulated in many chronic inflammatory diseases. NF-B signaling promotes inflammation and limits muscle regeneration in Duchenne muscular dystrophy (DMD), resulting in fibrotic and fatty tissue replacement of muscle that exacerbates the wasting process in dystrophic muscles. Here, we examined whether dominant-negative forms of IKKα (IKKα-dn) and IKKΒ (IKKΒ-dn) delivered by adeno-associated viral (AAV) vectors to the gastrocnemius (GAS) and tibialis anterior (TA) muscles of 1, 2 and 11-month-old mdx mice, a murine DMD model, block NF-B activation and increase muscle regeneration. At 1 month post-treatment, the levels of nuclear NF-B in locally treated muscle were decreased by gene transfer with either AAV-CMV-IKKα-dn or AAV-CMV-IKKΒ-dn, but not by IKK wild-type controls (IKKα and Β) or phosphate-buffered saline (PBS). Although treatment with AAV-IKKα-dn or AAV-IKKΒ-dn vectors had no significant effect on muscle regeneration in young mdx mice treated at 1 and 2 months of age and collected 1 month later, treatment of old (11 months) mdx with AAV-CMV-IKKα-dn or AAV-CMV-IKKΒ-dn significantly increased levels of muscle regeneration. In addition, there was a significant decrease in myofiber necrosis in the AAV-IKKα-dn- and AAV-IKKΒ-dn-treated mdx muscle in both young and old mice. These results demonstrate that inhibition of IKKα or IKKΒ in dystrophic muscle reduces the adverse effects of NF-B signaling, resulting in a therapeutic effect. Moreover, these results clearly demonstrate the therapeutic benefits of inhibiting NF-B activation by AAV gene transfer in dystrophic muscle to promote regeneration, particularly in older mdx mice, and block necrosis. © 2010 Macmillan Publishers Limited All rights reserved.


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Details

Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Tang, Yyit3@pitt.eduYIT3
Reay, DPreayd@pitt.eduREAYD
Salay, MNmns31@pitt.eduMNS31
Mi, MY
Clemens, PRpclemens@pitt.eduPCLEMENS
Guttridge, DC
Robbins, PDprobb@pitt.eduPROBB
Huard, J
Wang, Bbingwang@pitt.eduBINGWANG
Date: 1 December 2010
Date Type: Publication
Journal or Publication Title: Gene Therapy
Volume: 17
Number: 12
Page Range: 1476 - 1483
DOI or Unique Handle: 10.1038/gt.2010.110
Schools and Programs: School of Medicine > Microbiology and Molecular Genetics
School of Medicine > Neurology
School of Medicine > Orthopaedic Surgery
Refereed: Yes
ISSN: 0969-7128
MeSH Headings: Animals; Cell Nucleus--enzymology; Dependovirus--genetics; Disease Models, Animal; Gene Transfer Techniques; Genetic Therapy; Genetic Vectors--genetics; Genetic Vectors--metabolism; I-kappa B Kinase--genetics; I-kappa B Kinase--metabolism; Mice; Mice, Inbred C57BL; Mice, Inbred mdx; Muscle, Skeletal--enzymology; Muscle, Skeletal--pathology; Muscle, Skeletal--physiology; Muscular Dystrophy, Duchenne--enzymology; Muscular Dystrophy, Duchenne--therapy; NF-kappa B--genetics; NF-kappa B--metabolism; Regeneration--physiology; Signal Transduction--genetics
Other ID: NLM NIHMS406792, NLM PMC3471137
PubMed Central ID: PMC3471137
PubMed ID: 20720575
Date Deposited: 04 Apr 2014 16:42
Last Modified: 09 Dec 2017 14:56
URI: http://d-scholarship.pitt.edu/id/eprint/20945

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