title: 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 IkappaB-alpha kinase activity.
abstract: Dystrophin-deficient muscle exhibits substantial increases in nuclear NF-kappaB 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-kappaB 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 IkappaB-alpha, p65, p50, RelB, p100, p52, IKK, and TRAF-3. The proportion of phosphorylated IkappaB-alpha, p65, NIK, and IKKbeta, and the level of cytosolic IkappaB-alpha, were also increased in the mdx diaphragm. Proteasomal inhibition using MG-132 increased the proportion of phosphorylated IkappaB-alpha in nondystrophic diaphragm, but did not significantly increase this proportion in the mdx diaphragm. This result suggests that phosphorylated IkappaB-alpha accumulates in dystrophic cytosol because the rate of IkappaB-alpha degradation is lower than the effective rate of IkappaB-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 IkappaB-alpha kinase (IKK), but are due primarily to increases in the expression of p65 and other NF-kappaB signaling components.
authors.affiliation: Department of Physiology, Kirksville College of Osteopathic Medicine, AT Still University, Kirksville, MO 63501, USA.
authors.forename: Rajvir
authors.initials: R
authors.lastname: Singh
authors.forename: Gregory
authors.initials: G
authors.lastname: Millman
authors.forename: Eric
authors.initials: E
authors.lastname: Turin
authors.forename: Lucasz
authors.initials: L
authors.lastname: Polisiakeiwicz
authors.forename: Brian
authors.initials: B
authors.lastname: Lee
authors.forename: Francesca
authors.initials: F
authors.lastname: Gatti
authors.forename: Jonas
authors.initials: J
authors.lastname: Berge
authors.forename: Emily
authors.initials: E
authors.lastname: Smith
authors.forename: John
authors.initials: J
authors.lastname: Rutter
authors.forename: Chris
authors.initials: C
authors.lastname: Sumski
authors.forename: W Tyler
authors.initials: WT
authors.lastname: Winders
authors.forename: Abbas
authors.initials: A
authors.lastname: Samadi
authors.forename: C George
authors.initials: CG
authors.lastname: Carlson
mesh_terms: D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism*; D003600:Cytosol / Q000378:metabolism*; D003964:Diaphragm / Q000378:metabolism*; D005260:Female; D051550:I-kappa B Kinase / Q000378:metabolism*; D007700:Kinetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018101:Mice, Inbred mdx; D018482:Muscle, Skeletal / Q000378:metabolism*; D009136:Muscular Dystrophies / Q000378:metabolism*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D025842:SUMO-1 Protein / Q000378:metabolism; D051996:Transcription Factor RelA / Q000378:metabolism*
chemical_list: C498144:Rela protein, mouse; D025842:SUMO-1 Protein; D051996:Transcription Factor RelA; D051057:Proto-Oncogene Proteins c-akt; C496564:Chuk protein, mouse; D051550:I-kappa B Kinase