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.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Body Weight
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Cachexia / metabolism*
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Cachexia / prevention & control
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Cell Line
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Cytokines / metabolism
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Enzyme Activation
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Enzyme Inhibitors / administration & dosage
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Enzyme Inhibitors / metabolism
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Female
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Hindlimb
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Humans
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I-kappa B Kinase
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Male
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Mice
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Mice, Transgenic
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Muscle, Skeletal / innervation
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Muscle, Skeletal / metabolism
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Muscle, Skeletal / pathology*
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Muscular Atrophy / metabolism*
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Muscular Atrophy / pathology
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NF-kappa B / genetics
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NF-kappa B / metabolism*
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Neoplasm Transplantation
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Organ Size
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Phenotype
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism*
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Salicylates / administration & dosage
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Salicylates / metabolism
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Signal Transduction
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Survival Rate
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Ubiquitin / metabolism
Substances
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Cytokines
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Enzyme Inhibitors
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NF-kappa B
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Salicylates
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Ubiquitin
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Protein Serine-Threonine Kinases
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CHUK protein, human
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Chuk protein, mouse
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I-kappa B Kinase
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IKBKB protein, human
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IKBKE protein, human
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Ikbkb protein, mouse
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Ikbke protein, mouse