Use of pifithrin to inhibit p53-mediated signalling of TNF in dystrophic muscles of mdx mice

• Published in: Molecular and cellular biochemistry Vol. 337; no. 1-2; pp. 119 - 131
• Main Authors: Waters, Felicity J, Shavlakadze, Thea, McIldowie, Matthew J, Piggott, Matthew J, Grounds, Miranda D
• Format: Journal Article
• Language: English
• Published: Boston Boston : Springer US 01-04-2010; Springer US; Springer; Springer Nature B.V
• Subjects: Animals; Benzothiazoles - pharmacology; Biochemistry; Biomedical and Life Sciences; Cardiology; Cell Death - drug effects; Cell Death - radiation effects; Cell Differentiation - drug effects; Cell Differentiation - radiation effects; Cell Nucleus - drug effects; Cell Nucleus - metabolism; Cells, Cultured; Female; Immunology; Life Sciences; Medical Biochemistry; Mice; Mice, Inbred C57BL; Mice, Inbred mdx; Models, Biological; Molecular biology; Muscles; Muscular dystrophy; Muscular Dystrophy, Animal - metabolism; Muscular Dystrophy, Animal - pathology; Myoblasts, Skeletal - drug effects; Myoblasts, Skeletal - pathology; Myoblasts, Skeletal - physiology; Myoblasts, Skeletal - radiation effects; Oncology; Proteins; Rodents; Signal Transduction - drug effects; Signal Transduction - physiology; Toluene - analogs & derivatives; Toluene - pharmacology; Tumor necrosis factor; Tumor Necrosis Factor-alpha - antagonists & inhibitors; Tumor Necrosis Factor-alpha - pharmacology; Tumor proteins; Tumor Suppressor Protein p53 - metabolism; Tumor Suppressor Protein p53 - physiology; Ultraviolet Rays; mdx; Pifithrin; TNF; Muscular dystrophy; p53; Necrosis
• ISSN: 0300-8177; 1573-4919
• DOI: 10.1007/s11010-009-0291-2

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-α and three pifithrin-β analogues. Tissue culture studies using C2C12 myoblasts established that pifithrin-α was toxic to differentiating myoblasts at concentrations greater than 10 μM. While non-toxic concentrations of pifithrin-α 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-α 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.