Nuclear Factor κB-inducing Kinase and IκB Kinase-α Signal Skeletal Muscle Cell Differentiation

Nuclear factor κB (NF-κB)-inducing kinase (NIK), IκB kinase (IKK)-α and -β, and IκBα are common elements that signal NF-κB activation in response to diverse stimuli. In this study, we analyzed the role of this pathway during insulin-like growth factor II (IGF-II)-induced myoblast differentiation. L6E9 myoblasts differentiated with IGF-II showed an induction of NF-κB DNA-binding activity that correlated in time with the activation of IKKα, IKKβ, and NIK. Moreover, the activation of IKKα, IKKβ, and NIK by IGF-II was dependent on phosphatidylinositol 3-kinase, a key regulator of myogenesis. Adenoviral transduction with the IκBα(S32A/S36A) mutant severely impaired both IGF-II-dependent NF-κB activation and myoblast differentiation, indicating that phosphorylation of IκBα at Ser-32 and Ser-36 is an essential myogenic step. Adenoviral transfer of wild-type or kinase-deficient forms of IKKα or IKKβ revealed that IKKα is required for IGF-II-dependent myoblast differentiation, whereas IKKβ is not essential for this process. Finally, overexpression of kinase-proficient wild-type NIK showed that the activation of NIK is sufficient to generate signals that trigger myogenin expression and multinucleated myotube formation in the absence of IGF-II.