IKK/NF-κB regulates skeletal myrogenesis via a signaling switch to inhibit differentiation and promote mitochondrial biogenesis

Nuclear factor kappa B (NF-kappa B) is involved in multiple skeletal muscle disorders, but how it functions in differentiation remains elusive given that both anti- and promyogenic activities have been described. In this study, we resolve this by showing that myogenesis is controlled by opposing NF-kappa B signaling pathways. We find that myogenesis is enhanced in MyoD-expressing fibroblasts deficient in classical pathway components RelA/p65, inhibitor of kappa B kinase beta (IKK beta), or IKK gamma. Similar increases occur in myoblasts lacking RelA/p65 or IKK beta, and muscles from RelA/p65 or IKK beta mutant mice also contain higher fiber numbers. Moreover, we show that during differentiation, classical NF-kappa B signaling decreases, whereas the induction of alternative members IKK alpha, RelB, and p52 occurs late in myogenesis. Myotube formation does not require alternative signaling, but it is important for myotube maintenance in response to metabolic stress. Furthermore, overexpression or knockdown of IKK alpha. regulates mitochondrial content and function, suggesting that alternative signaling stimulates mitochondrial biogenesis. Together, these data reveal a unique IKK/NF-kappa B signaling switch that functions to both inhibit differentiation and promote myotube homeostasis.