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The IB kinases IKK and IKKβ are necessary and sufficient for skeletal muscle atrophy

Boston University, Boston, Massachusetts, USA

²Correspondence: Department of Health Sciences, 635 Commonwealth Ave., Rm 443, Boston University, Boston, MA 02215, USA. E-mail: skandar{at}bu.edu

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

Key Words: muscle wasting • inhibitor of B kinase • IKK complex • NF-B signaling

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