IKKβ/NF-κB activation causes severe muscle wasting in mice

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

Research output: Contribution to journalArticle

923 Scopus citations

Abstract

Muscle wasting accompanies aging and pathological conditions ranging from cancer, cachexia, and diabetes to denervation and immobilization. We show that activation of NF-κB, through muscle-specific transgenic expression of activated IκB kinase β (MIKK), causes profound muscle wasting that resembles clinical cachexia. In contrast, no overt phenotype was seen upon muscle-specific inhibition of NF-κB through expression of IκBα 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 IKKβ/NF-κB/MuRF1 pathway reversed muscle atrophy. Denervation- and tumor-induced muscle loss were substantially reduced and survival rates improved by NF-κB inhibition in MISR mice, consistent with a critical role for NF-κB in the pathology of muscle wasting and establishing it as an important clinical target for the treatment of muscle atrophy.

Original languageEnglish (US)
Pages (from-to)285-298
Number of pages14
JournalCell
Volume119
Issue number2
DOIs
StatePublished - Oct 15 2004
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Fingerprint Dive into the research topics of 'IKKβ/NF-κB activation causes severe muscle wasting in mice'. Together they form a unique fingerprint.

  • Cite this

    Cai, D., Frantz, J. D., Tawa, N. E., Melendez, P. A., Oh, B. C., Lidov, H. G. W., Hasselgren, P. O., Frontera, W. R., Lee, J., Glass, D. J., & Shoelson, S. E. (2004). IKKβ/NF-κB activation causes severe muscle wasting in mice. Cell, 119(2), 285-298. https://doi.org/10.1016/j.cell.2004.09.027