Increases in nuclear p65 activation in dystrophic skeletal muscle are secondary to increases in the cellular expression of p65 and are not solely produced by increases in I[kappa]B- alpha kinase activity

• Published in: Journal of the neurological sciences Vol. 285; no. 1-2; pp. 159 - 171
• Main Authors: Singh, Rajvir, Millman, Gregory, Turin, Eric, Polisiakeiwicz, Lucasz, Lee, Brian, Gatti, Francesca, Berge, Jonas, Smith, Emily, Rutter, John, Sumski, Chris, Winders, WTyler, Samadi, Abbas, Carlson, CGeorge
• Format: Journal Article
• Language: English
• Published: 01.10.2009
• ISSN: 0022-510X
• DOI: 10.1016/j.jns.2009.06.030

Dystrophin-deficient muscle exhibits substantial increases in nuclear NF-[kappa]B activation. To examine potential mechanisms for this enhanced activation, the present study employs conventional Western blot techniques to provide the first determination of the relative expression of NF-[kappa]B signaling molecules in adult nondystrophic and dystrophic (mdx) skeletal muscle. The results indicate that dystrophic muscle is characterized by increases in the whole cell expression of I[kappa]B- alpha , p65, p50, RelB, p100, p52, IKK, and TRAF-3. The proportion of phosphorylated I[kappa]B- alpha , p65, NIK, and IKK beta , and the level of cytosolic I[kappa]B- alpha , were also increased in the mdx diaphragm. Proteasomal inhibition using MG-132 increased the proportion of phosphorylated I[kappa]B- alpha in nondystrophic diaphragm, but did not significantly increase this proportion in the mdx diaphragm. This result suggests that phosphorylated I[kappa]B- alpha accumulates in dystrophic cytosol because the rate of I[kappa]B- alpha degradation is lower than the effective rate of I[kappa]B- alpha synthesis and phosphorylation. Dystrophic increases in SUMO-1 (small ubiquitin modifier-1) protein and in Akt activation were also observed. The results indicate that increases in nuclear p65 activation in dystrophic muscle are not produced solely by increases in the activity of I[kappa]B- alpha kinase (IKK), but are due primarily to increases in the expression of p65 and other NF-[kappa]B signaling components.