Mechanical stress activates the nuclear factor-kappaB pathway in skeletal muscle fibers: a possible role in Duchenne muscular dystrophy.
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.
Kumar
Ashok
A
Department of Medicine, Baylor College of Medicine, Houston, Texas 77030, USA.
Boriek
Aladin M
AM
D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D020013:Calcium Signaling; D046508:Culture Techniques; D003964:Diaphragm; D016166:Free Radical Scavengers / Q000494:pharmacology; D051550:I-kappa B Kinase; D020672:I-kappa B Proteins / Q000378:metabolism; D007375:Interleukin-1 / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018101:Mice, Inbred mdx; D018485:Muscle Fibers, Skeletal / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000378:metabolism*; D020388:Muscular Dystrophy, Duchenne / Q000209:etiology / Q000378:metabolism*; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism* / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis; D015398:Signal Transduction; D013314:Stress, Mechanical; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics
D016166:Free Radical Scavengers; D020672:I-kappa B Proteins; D007375:Interleukin-1; D016328:NF-kappa B; C000606205:Nfkbia protein, mouse; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D000072000:NF-KappaB Inhibitor alpha; D017346:Protein Serine-Threonine Kinases; C496564:Chuk protein, mouse; D051550:I-kappa B Kinase; C496562:Ikbkb protein, mouse; C496566:Ikbke protein, mouse; D000111:Acetylcysteine