Figure 4.

Roles of TNFα, TWEAK, cIAP1/2, and A20, in myogenesis in the regulation of switching from canonical to non-canonical NF-κB signaling. The transition from myoblast to myotube has been known for several years to involve a switch from canonical to non-canonical NF-κB signaling. More recently, several of the key players and the mechanisms of action for this switch have been identified. The promotion of TNFα-mediated canonical NF-κB signaling involves the positive regulation by the E3 ubiquitin ligase cIAP1/2 and the negative regulation by the deubiquitinase A20. The non-canonical pathway is oppositely controlled: it is negatively regulated by cIAP1/2 and positively regulated by A20. Interestingly, the cytokine TWEAK (a pathological factor in muscle atrophy) has been recently shown to stimulate non-canonical NF-κB signaling by removing the negative regulation of cIAP1/2 on that NF-κB pathway. Physiological levels of TWEAK, in fact, promote myogenesis through the enhancement of myoblast fusion amongst other things. The non-canonical NF-κB pathway has been shown previously to regulate mitochondrial biogenesis and to promote myotube maintenance, and recently shown to do so through the NF-κB-mediated induction of the mitochondrial regulator PPAR-γ co-activator 1β (PGC-1β). Figure adapted from Ref. (65).