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

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...

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Bibliographic Details
Published in:Cell 2004-10, Vol.119 (2), p.285-298
Main Authors: Cai, Dongsheng, Frantz, J Daniel, Tawa, Jr, Nicholas E, Melendez, Peter A, Oh, Byung-Chul, Lidov, Hart G W, Hasselgren, Per-Olof, Frontera, Walter R, Lee, Jongsoon, Glass, David J, Shoelson, Steven E
Format: Article
Language:English
Subjects:
Animals
Body Weight
Cachexia - metabolism
Cachexia - prevention & control
Cell Line
Cytokines - metabolism
Enzyme Activation
Enzyme Inhibitors - administration & dosage
Enzyme Inhibitors - metabolism
Female
Hindlimb
Humans
I-kappa B Kinase
Male
Mice
Mice, Transgenic
Muscle, Skeletal - innervation
Muscle, Skeletal - metabolism
Muscle, Skeletal - pathology
Muscular Atrophy - metabolism
Muscular Atrophy - pathology
Neoplasm Transplantation
NF-kappa B - genetics
NF-kappa B - metabolism
Organ Size
Phenotype
Protein-Serine-Threonine Kinases - genetics
Protein-Serine-Threonine Kinases - metabolism
Salicylates - administration & dosage
Salicylates - metabolism
Signal Transduction
Survival Rate
Ubiquitin - metabolism
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Summary: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.
ISSN:0092-8674