Investigating EDA2R-NIK signaling in denervation ınduced skeletal muscle response

Skeletal muscle atrophy following denervation is a hallmark of various neuromuscular diseases and decreases quality of life. Despite its clinical importance, the molecular mechanisms underlying denervation-induced atrophy are not completely understood. This study investigates the function of the EDA2R-NIK signaling pathway in regulating early and late responses to denervation-induced muscle atrophy. Our findings revealed that denervation upregulates EDA2R-NIK signaling, leading to muscle wasting. Short-term denervation (3 days) showed that both EDA2R-KO and muscle specific NIK-KO (Myo-NIK KO) mice exhibited preserved muscle mass, reduced non-canonical NF-κB signaling, with NIK-KO additionally preventing fiber area loss and lower expression of atrophy markers (Atrogin-1, MuRF1). This protective effect was lost by day 7, suggesting that EDA2R-NIK signaling may act mainly during early stress responses. Interestingly, EDA2R KO and Myo-NIK KO mice exhibited worsened neuromuscular junction (NMJ) morphology despite preserved muscle size, indicating a dual role for this pathway in both muscle wasting and synaptic maintenance. This study reveals a novel function of EDA2R-NIK signaling at the intersection of muscle atrophy and NMJ remodeling, proposing it as a key regulator of the denervation response. Targeting the EDA2R-NIK axis may provide a therapeutic strategy to mitigate early-stage denervation atrophy. However, weakened impact in longer denervation periods highlights the importance of combinatorial approaches for chronic denervation therapeutics.