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

873 Citations (Scopus)

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

Fingerprint

Muscle
Chemical activation
Muscles
Muscular Atrophy
Cachexia
Denervation
Ubiquitin-Protein Ligases
Ubiquitin
Proteolysis
Immobilization
Neoplasms
Phosphotransferases
Pathology
Medical problems
Pharmacology
Phenotype
Tumors
Aging of materials
Proteins

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology

Cite this

Cai, D., Frantz, J. D., Tawa, N. E., Melendez, P. A., Oh, B. C., Lidov, H. G. W., ... 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

IKKβ/NF-κB activation causes severe muscle wasting in mice. / Cai, Dongsheng; Frantz, J. Daniel; Tawa, 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.

In: Cell, Vol. 119, No. 2, 15.10.2004, p. 285-298.

Research output: Contribution to journalArticle

Cai, D, Frantz, JD, Tawa, NE, Melendez, PA, Oh, BC, Lidov, HGW, Hasselgren, PO, Frontera, WR, Lee, J, Glass, DJ & Shoelson, SE 2004, 'IKKβ/NF-κB activation causes severe muscle wasting in mice', Cell, vol. 119, no. 2, pp. 285-298. https://doi.org/10.1016/j.cell.2004.09.027
Cai D, Frantz JD, Tawa NE, Melendez PA, Oh BC, Lidov HGW et al. IKKβ/NF-κB activation causes severe muscle wasting in mice. Cell. 2004 Oct 15;119(2):285-298. https://doi.org/10.1016/j.cell.2004.09.027
Cai, Dongsheng ; Frantz, J. Daniel ; Tawa, 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. / IKKβ/NF-κB activation causes severe muscle wasting in mice. In: Cell. 2004 ; Vol. 119, No. 2. pp. 285-298.
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