Commun Biol . 2026 Apr 2;9(1):726. doi: 10.1038/s42003-026-09975-3. TWEAK-induced alternative NF-κB signaling regulates Cxcl10 and Mymx to promote myoblast-to-myotube fusion and muscle regeneration

Repair of adult skeletal muscle relies on molecular and cellular mechanisms that sustain tissue homeostasis during regeneration of injured myofibers. The NF-κB pathway has emerged as an important signaling network in skeletal muscle. Depending on the type of stimulus, activation of NF-κB signaling can occur through the classical or alternative pathway. TWEAK is a membrane bound and soluble cytokine that signals through Fn14, a highly inducible cell-surface receptor that is upstream of numerous signaling pathways including NF-κB. Upregulation of Fn14 signaling is associated with the progression of several chronic atrophic muscle disorders. In contrast, TWEAK/Fn14 signaling has also been suggested to play a beneficial role during muscle regeneration by promoting myoblast proliferation and fusion. In this study, we demonstrate that TWEAK promotes secondary fusion through direct transcriptional activation of Myomixer and CXCL10 by alternative NF-κB. Overall, our study demonstrates that TWEAK is beneficial for myoblast fusion and may be a potential approach to improve muscle regeneration in degenerative disorders.