The IkappaB kinases IKKalpha and IKKbeta are necessary and sufficient for skeletal muscle atrophy.
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.
Van Gammeren
Darin
D
Boston University, Boston, MA 02215, USA.
Damrauer
Jeffrey S
JS
Jackman
Robert W
RW
Kandarian
Susan C
SC
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
D016328:NF-kappa B; D051550:I-kappa B Kinase