Systemic delivery of NEMO binding domain/IKKγ inhibitory peptide to young mdx mice improves dystrophic skeletal muscle histopathology

NEUROBIOLOGY OF DISEASE

卷:43

Article

Reay, Daniel P.¹  Yang, Michele^1,7  Watchko, Jon F.⁴  Daood, Molly⁴  O'Day, Terrence L.⁵  Rehman, Khaleel K.³  Guttridge, Denis C.⁶  Robbins, Paul D.³  Clemens, Paula R.^1,2,3 

[1] Univ Pittsburgh, Dept Neurol, Pittsburgh, PA 15213 USA

[2] Dept Vet Affairs Med Ctr, Neurol Serv, Pittsburgh, PA 15240 USA

[3] Univ Pittsburgh, Dept Microbiol & Mol Genet, Pittsburgh, PA 15213 USA

[4] Univ Pittsburgh, Dept Pediat, Magee Womens Res Inst, Pittsburgh, PA 15213 USA

[5] MedImmune Inc, Gaithersburg, MD 20878 USA

[6] Ohio State Univ, Dept Mol Virol Immunol & Med Genet, Columbus, OH 43210 USA

[7] Univ Colorado Denver, Neurol Sect, Dept Pediat, Aurora, CO 80045 USA

关键词: Duchenne muscular dystrophy;    mdx mouse;    Histopathology;    Muscle necrosis;    Muscle regeneration;    Specific force;    Lengthening activation;    Protein transduction domain;    NEMO binding domain peptide;    NF-kappa B;   

DOI  :  10.1016/j.nbd.2011.05.008

来源: Elsevier

【 摘 要 】

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.

【 授权许可】

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