Use of pifithrin to inhibit p53-mediated signalling of TNF in dystrophic muscles of mdx mice.
Tumour Necrosis Factor (TNF) plays a major role in exacerbating necrosis of dystrophic muscle; however, the precise molecular mechanism underlying this effect of TNF is unknown. This study investigates the role that p53 plays in TNF-mediated necrosis of dystrophic myofibres by inhibiting p53 using pifithrin-alpha and three pifithrin-beta analogues. Tissue culture studies using C2C12 myoblasts established that pifithrin-alpha was toxic to differentiating myoblasts at concentrations greater than 10 muM. While non-toxic concentrations of pifithrin-alpha did not prevent the TNF-mediated inhibition of myoblast differentiation, Western blots indicated that nuclear levels of p53 were higher in TNF-treated myoblasts indicating that TNF does elevate p53. In contrast, in vivo studies in adult mdx mice showed that pifithrin-alpha significantly reduced myofibre necrosis that resulted from voluntary wheel running over 48 h. These results support the hypothesis that p53 plays some role in TNF-mediated necrosis of dystrophic muscle and present a potential new target for therapeutic interventions.
School of Anatomy and Human Biology, University of Western Australia, Crawley, WA, Australia.
Felicity J
FJ
Waters
Thea
T
Shavlakadze
Matthew J
MJ
McIldowie
Matthew J
MJ
Piggott
Miranda D
MD
Grounds
D000818:Animals; D052160:Benzothiazoles / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects / Q000528:radiation effects; D002454:Cell Differentiation / Q000187:drug effects / Q000528:radiation effects; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D005260:Female; D051379:Mice; D008810:Mice, Inbred C57BL; D018101:Mice, Inbred mdx; D008954:Models, Biological; D009137:Muscular Dystrophy, Animal / Q000378:metabolism / Q000473:pathology*; D032448:Myoblasts, Skeletal / Q000187:drug effects / Q000473:pathology / Q000502:physiology / Q000528:radiation effects; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D014050:Toluene / Q000031:analogs & derivatives* / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism / Q000502:physiology*; D014466:Ultraviolet Rays
D052160:Benzothiazoles; D014409:Tumor Necrosis Factor-alpha; D016159:Tumor Suppressor Protein p53; D014050:Toluene; C121565:pifithrin