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. 2004 Oct 15;119(2):285-98.
doi: 10.1016/j.cell.2004.09.027.

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

Dongsheng Cai  1 , J Daniel Frantz, Nicholas E Tawa Jr, Peter A Melendez, Byung-Chul Oh, Hart G W Lidov, Per-Olof Hasselgren, Walter R Frontera, Jongsoon Lee, David J Glass, Steven E Shoelson
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Free article

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

Dongsheng Cai et al. Cell. .
Free article

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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