Mechanical stress activates the nuclear factor-kappaB pathway in skeletal muscle fibers: a possible role in Duchenne muscular dystrophy

FASEB J. 2003 Mar;17(3):386-96. doi: 10.1096/fj.02-0542com.

Abstract

The ex vivo effects of passive mechanical stretch on the activation of nuclear factor-kappaB (NF-kappaB) pathways in skeletal muscles from normal and mdx mouse, a model of Duchenne muscular dystrophy (DMD), were investigated. The NF-kappaB/DNA binding activity of the diaphragm muscle was increased by the application of axial mechanical stretch in a time-dependent manner. The increased activation of NF-kappaB was associated with a concomitant increase in I-kappaB (IkappaB) kinase activity and the degradation of IkappaBalpha protein. Pretreatment of the muscles with nifedipine (a Ca2+ channel blocker) and gadolinium(III) chloride (a stretch-activated channel blocker) did not alter the level of activation of NF-kappaB, ruling out involvement of Ca2+ influx through these channels. Furthermore, N-acetyl cysteine, a free radical inhibitor, blocked the mechanical stretch-induced NF-kappaB activation, suggesting the involvement of free radicals. Compared with normal diaphragm, the basal level of NF-kappaB activity was higher in muscles from mdx mice, and it was further enhanced in mechanically stretched muscles. Furthermore, activation of NF-kappaB and increased expression of inflammatory cytokines IL-1beta and tumor necrosis factor alpha in the mdx mouse precede the onset of muscular dystrophy. Our results show that mechanical stretch activates the classical NF-kappaB pathway and this pathway could be predominately active in DMD.

Publication types

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

MeSH terms

  • Acetylcysteine / pharmacology
  • Animals
  • Calcium Signaling
  • Culture Techniques
  • Diaphragm
  • Free Radical Scavengers / pharmacology
  • I-kappa B Kinase
  • I-kappa B Proteins / metabolism
  • Interleukin-1 / biosynthesis
  • Interleukin-1 / genetics
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred mdx
  • Muscle Fibers, Skeletal / metabolism*
  • Muscle, Skeletal / metabolism*
  • Muscular Dystrophy, Duchenne / etiology
  • Muscular Dystrophy, Duchenne / metabolism*
  • NF-KappaB Inhibitor alpha
  • NF-kappa B / metabolism*
  • NF-kappa B / physiology
  • Protein-Serine-Threonine Kinases / metabolism
  • RNA, Messenger / biosynthesis
  • Signal Transduction*
  • Stress, Mechanical
  • Tumor Necrosis Factor-alpha / biosynthesis
  • Tumor Necrosis Factor-alpha / genetics

Substances

  • Free Radical Scavengers
  • I-kappa B Proteins
  • Interleukin-1
  • NF-kappa B
  • Nfkbia protein, mouse
  • RNA, Messenger
  • Tumor Necrosis Factor-alpha
  • NF-KappaB Inhibitor alpha
  • Protein-Serine-Threonine Kinases
  • Chuk protein, mouse
  • I-kappa B Kinase
  • Ikbkb protein, mouse
  • Ikbke protein, mouse
  • Acetylcysteine