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      IKKbeta/NF-kappaB activation causes severe muscle wasting in mice.

      Cell

      Animals, Body Weight, Cachexia, metabolism, prevention & control, Cell Line, Cytokines, Enzyme Activation, Enzyme Inhibitors, administration & dosage, Female, Hindlimb, Humans, I-kappa B Kinase, Male, Mice, Mice, Transgenic, Muscle, Skeletal, innervation, pathology, Muscular Atrophy, NF-kappa B, genetics, Neoplasm Transplantation, Organ Size, Phenotype, Protein-Serine-Threonine Kinases, Salicylates, Signal Transduction, Survival Rate, Ubiquitin

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          Abstract

          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.

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          Journal
          15479644
          10.1016/j.cell.2004.09.027

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