The IκB kinases IKKα and IKKβ are necessary and sufficient for skeletal muscle atrophy

Nuclear factor-kappa B (NF-kappa B) 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.) IKK beta into rat soleus muscles showed complete inhibition of 7-day disuse-induced activation of a kappa B reporter gene, while overexpression of wild-type (w.t.) IKK beta did not. Overexpression of a d.n. IKK beta-EGFP fusion protein showed that atrophy was inhibited by 50%, indicating that IKK beta is required for the atrophy process. Overexpression of constitutively active (c.a.) IKK beta-EGFP showed a marked increase in NF-kappa B activity and a decrease in fiber size of weight-bearing soleus muscles, while muscles overexpressing w.t. IKK beta-HA had no effect. The same results were found for IKK alpha; overexpression of a d.n. form of the protein decreased unloading-induced NF-kappa B activation and inhibited atrophy by 50%, while overexpression of the w.t. protein had no effect. Overexpression of a c. a. IKK alpha-EGFP fusion protein showed that IKK alpha was sufficient to activate NF-kappa B activity and induce fiber atrophy in muscle. Overexpression of d.n. IKK beta plus d.n. IKK alpha 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 IKK alpha and IKK beta are necessary and sufficient for physiological muscle atrophy. - Van Gammeren, D., Damrauer, J.S., Jackman, R. W., Kandarian, S. C. The I kappa B kinases IKK alpha and IKK beta are necessary and sufficient for skeletal muscle atrophy. FASEB J. 23, 362-370 (2009)