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

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

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

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 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
  • NF-kappa B / genetics
  • NF-kappa B / metabolism*
  • Neoplasm Transplantation
  • Organ Size
  • Phenotype
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism*
  • Salicylates / administration & dosage
  • Salicylates / metabolism
  • Signal Transduction
  • Survival Rate
  • Ubiquitin / metabolism

Substances

  • Cytokines
  • Enzyme Inhibitors
  • NF-kappa B
  • Salicylates
  • Ubiquitin
  • Protein-Serine-Threonine Kinases
  • CHUK protein, human
  • Chuk protein, mouse
  • I-kappa B Kinase
  • IKBKB protein, human
  • IKBKE protein, human
  • Ikbkb protein, mouse
  • Ikbke protein, mouse