The study investigates the role of NF-κB activation in muscle wasting, a condition that occurs in various pathological conditions such as cancer, cachexia, and diabetes. The researchers created transgenic mice with muscle-specific activation or inhibition of NF-κB by expressing either activated IκB kinase β (MIKK) or a dominant inhibitory form of IκBα (MISR). They found that MIKK mice exhibited severe muscle wasting, characterized by reduced muscle mass, smaller muscle fibers, and increased protein breakdown through ubiquitin-dependent proteolysis. In contrast, MISR mice, which had high levels of IκBα superrepressor, showed no overt phenotype despite high levels of IKKβ activity. Pharmacological inhibition of IKKβ and NF-κB using salicylate also reversed the muscle wasting phenotype in MIKK mice. The study further demonstrated that NF-κB activation increased the expression of the ubiquitin ligase MuRF1, a key mediator of muscle atrophy. In addition, NF-κB blockade reduced muscle loss in models of denervation and cancer cachexia. However, NF-κB activation did not induce typical cytokine production in muscle, suggesting that its role in muscle wasting is distinct from its function in inflammation and immunity. The findings suggest that NF-κB activation is a critical trigger for muscle atrophy and could be a potential therapeutic target for treating muscle wasting conditions.The study investigates the role of NF-κB activation in muscle wasting, a condition that occurs in various pathological conditions such as cancer, cachexia, and diabetes. The researchers created transgenic mice with muscle-specific activation or inhibition of NF-κB by expressing either activated IκB kinase β (MIKK) or a dominant inhibitory form of IκBα (MISR). They found that MIKK mice exhibited severe muscle wasting, characterized by reduced muscle mass, smaller muscle fibers, and increased protein breakdown through ubiquitin-dependent proteolysis. In contrast, MISR mice, which had high levels of IκBα superrepressor, showed no overt phenotype despite high levels of IKKβ activity. Pharmacological inhibition of IKKβ and NF-κB using salicylate also reversed the muscle wasting phenotype in MIKK mice. The study further demonstrated that NF-κB activation increased the expression of the ubiquitin ligase MuRF1, a key mediator of muscle atrophy. In addition, NF-κB blockade reduced muscle loss in models of denervation and cancer cachexia. However, NF-κB activation did not induce typical cytokine production in muscle, suggesting that its role in muscle wasting is distinct from its function in inflammation and immunity. The findings suggest that NF-κB activation is a critical trigger for muscle atrophy and could be a potential therapeutic target for treating muscle wasting conditions.