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

Neurobiology of Disease

Jon F. Watchko¹  Paula R. Clemens²  Denis C. Guttridge²  Paul D. Robbins³  Daniel P. Reay⁴  Michele Yang⁴  Molly Daood⁵  Terrence L. O'Day⁵  Khaleel K. Rehman⁶ 

[1] Department of Pediatrics, Section of Neurology, University of Colorado Denver, Aurora, CO 80045, USA;Department of Microbiology and Molecular Genetics, University of Pittsburgh, Pittsburgh, PA 15213, USA;Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, Columbus, OH 43210, USA;Department of Neurology, University of Pittsburgh, Pittsburgh, PA 15213, USA;Department of Pediatrics, Magee-Women's Research Institute, University of Pittsburgh, Pittsburgh, PA 15213, USA;MedImmune, Inc., Gaithersburg, MD 20878, USA;

关键词: Duchenne muscular dystrophy;    mdx mouse;    Histopathology;    Muscle necrosis;    Muscle regeneration;    Specific force;   

DOI  :  

来源: DOAJ

【 摘 要 】

The activation of nuclear factor κB (NF-κB) contributes to muscle degeneration that results from dystrophin deficiency in human Duchenne muscular dystrophy (DMD) and in the mdx mouse. In dystrophic muscle, NF-κB participates in inflammation and failure of muscle regeneration. Peptides containing the NF-κB Essential Modulator (NEMO) binding domain (NBD) disrupt the IκB kinase complex, thus blocking NF-κB 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-κB activation, histological changes in hind limb and diaphragm muscle and ex vivo function of diaphragm muscle. Decreased NF-κB 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.

【 授权许可】

Unknown