salicylates and Cachexia

Muscle wasting accompanies aging and pathological conditions ranging from cancer, cachexia, and diabetes to denervation and immobilization. We show that activation of NF-kappaB, through muscle-specific transgenic expression of activated IkappaB kinase beta (MIKK), causes profound muscle wasting that resembles clinical cachexia. In contrast, no overt phenotype was seen upon muscle-specific inhibition of NF-kappaB through expression of IkappaBalpha superrepressor (MISR). Muscle loss was due to accelerated protein breakdown through ubiquitin-dependent proteolysis. Expression of the E3 ligase MuRF1, a mediator of muscle atrophy, was increased in MIKK mice. Pharmacological or genetic inhibition of the IKKbeta/NF-kappaB/MuRF1 pathway reversed muscle atrophy. Denervation- and tumor-induced muscle loss were substantially reduced and survival rates improved by NF-kappaB inhibition in MISR mice, consistent with a critical role for NF-kappaB in the pathology of muscle wasting and establishing it as an important clinical target for the treatment of muscle atrophy.

Topics: Animals; Body Weight; Cachexia; Cell Line; Cytokines; Enzyme Activation; Enzyme Inhibitors; Female; Hindlimb; Humans; I-kappa B Kinase; Male; Mice; Mice, Transgenic; Muscle, Skeletal; Muscular Atrophy; Neoplasm Transplantation; NF-kappa B; Organ Size; Phenotype; Protein Serine-Threonine Kinases; Salicylates; Signal Transduction; Survival Rate; Ubiquitin