Nrf2 protects against TWEAK-mediated skeletal muscle wasting

Sci Rep. 2014 Jan 10;4:3625. doi: 10.1038/srep03625.


Skeletal muscle (SM) regeneration after injury is impaired by excessive inflammation. Particularly, the inflammatory cytokine tumour necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) is a potent inducer of skeletal muscle wasting and fibrosis. In this study we investigated the role of Nrf2, a major regulator of oxidative stress defence, in SM ischemia/reperfusion (I/R) injury and TWEAK induced atrophy. We explored the time-dependent expression of TWEAK after I/R in SM of Nrf2-wildtype (WT) and knockout (KO) mice. Nrf2-KO mice expressed significant higher levels of TWEAK as compared to WT mice. Consequently, Nrf2-KO mice present an insufficient regeneration as compared to Nrf2-WT mice. Moreover, TWEAK stimulation activates Nrf2 in the mouse myoblast cell line C2C12. This Nrf2 activation inhibits TWEAK induced atrophy in C2C12 differentiated myotubes. In summary, we show that Nrf2 protects SM from TWEAK-induced cell death in vitro and that Nrf2-deficient mice therefore have poorer muscle regeneration.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • Base Sequence
  • Cell Line
  • Cytokine TWEAK
  • DNA Primers
  • Enzyme-Linked Immunosorbent Assay
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Muscle, Skeletal / pathology*
  • Muscular Atrophy / prevention & control*
  • NF-E2-Related Factor 2 / physiology*
  • Polymerase Chain Reaction
  • Tumor Necrosis Factors / physiology*


  • Cytokine TWEAK
  • DNA Primers
  • NF-E2-Related Factor 2
  • Nfe2l2 protein, mouse
  • Tnfsf12 protein, mouse
  • Tumor Necrosis Factors