title: The IkappaB kinases IKKalpha and IKKbeta are necessary and sufficient for skeletal muscle atrophy.
abstract: Nuclear factor-kappaB (NF-kappaB) signaling is necessary for many types of muscle atrophy, yet only some of the required components have been identified. Gene transfer of a dominant negative (d.n.) IKKbeta into rat soleus muscles showed complete inhibition of 7-day disuse-induced activation of a kappaB reporter gene, while overexpression of wild-type (w.t.) IKKbeta did not. Overexpression of a d.n. IKKbeta-EGFP fusion protein showed that atrophy was inhibited by 50%, indicating that IKKbeta is required for the atrophy process. Overexpression of constitutively active (c.a.) IKKbeta-EGFP showed a marked increase in NF-kappaB activity and a decrease in fiber size of weight-bearing soleus muscles, while muscles overexpressing w.t. IKKbeta-HA had no effect. The same results were found for IKKalpha; overexpression of a d.n. form of the protein decreased unloading-induced NF-kappaB activation and inhibited atrophy by 50%, while overexpression of the w.t. protein had no effect. Overexpression of a c.a. IKKalpha-EGFP fusion protein showed that IKKalpha was sufficient to activate NF-kappaB activity and induce fiber atrophy in muscle. Overexpression of d.n. IKKbeta plus d.n. IKKalpha showed an additive effect on the inhibition of disuse atrophy (70%), suggesting that both kinases of the IKK complex are required for muscle atrophy. These data show that both IKKalpha and IKKbeta are necessary and sufficient for physiological muscle atrophy.
authors.affiliation: Boston University, Boston, MA 02215, USA.
authors.forename: Darin
authors.initials: D
authors.lastname: Van Gammeren
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Damrauer
authors.forename: Robert W
authors.initials: RW
authors.lastname: Jackman
authors.forename: Susan C
authors.initials: SC
authors.lastname: Kandarian
mesh_terms: D000818:Animals; D005260:Female; D017930:Genes, Reporter / Q000235:genetics; D051550:I-kappa B Kinase / Q000235:genetics / Q000378:metabolism*; D009133:Muscular Atrophy / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar
chemical_list: D016328:NF-kappa B; D051550:I-kappa B Kinase