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IKK/NF-
B regulates skeletal myogenesis via a signaling switch to inhibit differentiation and promote mitochondrial biogenesis
Correspondence to Denis C. Guttridge: denis.guttridge{at}osumc.edu
Nuclear factor
B (NF-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-B signaling pathways. We find that myogenesis is enhanced in MyoD-expressing fibroblasts deficient in classical pathway components RelA/p65, inhibitor of B kinase β (IKKβ), or IKK
. Similar increases occur in myoblasts lacking RelA/p65 or IKKβ, and muscles from RelA/p65 or IKKβ mutant mice also contain higher fiber numbers. Moreover, we show that during differentiation, classical NF-B signaling decreases, whereas the induction of alternative members IKK
, 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 regulates mitochondrial content and function, suggesting that alternative signaling stimulates mitochondrial biogenesis. Together, these data reveal a unique IKK/NF-B signaling switch that functions to both inhibit differentiation and promote myotube homeostasis.
B kinase; MEF, mouse embryonic fibroblast; MSCV, murine stem cell virus; MyHC, myosin heavy chain; NF-B, nuclear factor B; NIK, NF-B–inducing kinase; Rb, retinoblastoma; SR, superrepressor; TA, transactivation domain; Tn, troponin.
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