The 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. In skeletal muscle, the classical pathway promotes myoblast proliferation and inhibits differentiation. In contrast, alternative NF-κB signaling is activated upon myoblast differentiation and required for myoblast fusion and promoting an oxidative metabolic phenotype. Furthermore, pathological NF-κB activation occurs in several muscle diseases, including Duchenne muscular dystrophy (DMD). TNF-like weak inducer of apoptosis (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 TWEAK signaling is seen in several chronic atrophic muscle disorders. In contrast, TWEAK signaling has also been suggested to play a beneficial role during muscle regeneration by promoting myoblast proliferation and fusion. In the present study, we examined the utility of recombinant TWEAK administration on muscle structure and function of D2.mdx mice. Preliminary results demonstrate that TWEAK improves muscle strength as seen by increased grip strength and increased holding time in a hanging wire test. Overall, our study demonstrates that TWEAK administration may be a potential approach to improve muscle regeneration in degenerative disorders such as DMD.