Journal
NEUROBIOLOGY OF DISEASE
Volume 43, Issue 3, Pages 598-608Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.nbd.2011.05.008
Keywords
Duchenne muscular dystrophy; mdx mouse; Histopathology; Muscle necrosis; Muscle regeneration; Specific force; Lengthening activation; Protein transduction domain; NEMO binding domain peptide; NF-kappa B
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Funding
- Department of Defense
- VA Merit Review grant
- Muscular Dystrophy Association [U54 AR50733, U01 NS069562]
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The activation of nuclear factor kappa B (NF-kappa B) contributes to muscle degeneration that results from dystrophin deficiency in human Duchenne muscular dystrophy (DMD) and in the mdx mouse. In dystrophic muscle, NF-kappa B participates in inflammation and failure of muscle regeneration. Peptides containing the NF-kappa B Essential Modulator (NEMO) binding domain (NBD) disrupt the I kappa B kinase complex, thus blocking NF-kappa B activation. The NBD peptide, which is linked to a protein transduction domain to achieve in vivo peptide delivery to muscle tissue, was systemically delivered to mdx mice for 4 or 7 weeks to study NF-kappa B activation, histological changes in hind limb and diaphragm muscle and ex vivo function of diaphragm muscle. Decreased NF-kappa B activation, decreased necrosis and increased regeneration were observed in hind limb and diaphragm muscle in mdx mice treated systemically with NBD peptide, as compared to control mdx mice. NBD peptide treatment resulted in improved generation of specific force and greater resistance to lengthening activations in diaphragm muscle ex vivo. Together these data support the potential of NBD peptides for the treatment of DMD by modulating dystrophic pathways in muscle that are downstream of dystrophin deficiency. Published by Elsevier Inc.
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