Muscle cachexia is regulated by a p53-PW1/Peg3-dependent pathway.
Muscle wasting (cachexia) is an incurable complication associated with chronic infection and cancers that leads to an overall poor prognosis for recovery. Tumor necrosis factor-alpha (TNFalpha) is a key inflammatory cytokine associated with cachexia. TNFalpha inhibits myogenic differentiation and skeletal muscle regeneration through downstream effectors of the p53 cell death pathway including PW1/Peg3, bax, and caspases. We report that p53 is required for the TNFalpha-mediated inhibition of myogenesis in vitro and contributes to muscle wasting in response to tumor load in vivo. We further demonstrate that PW1 and p53 participate in a positive feedback regulatory loop in vitro. Consistent with this observation, we find that the number of PW1-expressing stem cells in skeletal muscle declines significantly in p53 nullizygous mice. Furthermore, gene transfer of a dominant-negative form of PW1 into muscle tissue in vivo blocks myofiber atrophy in response to tumor load. Taken together, these results show a novel role for p53 in mediating muscle stem cell behavior and muscle atrophy, and point to new targets for the therapeutic treatment of muscle wasting.
Schwarzkopf
Martina
M
Brookdale Department of Molecular, Cell, and Developmental Biology, Mount Sinai Medical School, New York, New York 10029, USA.
Coletti
Dario
D
Sassoon
David
D
Marazzi
Giovanna
G
D000818:Animals; D002100:Cachexia / Q000378:metabolism*; D002469:Cell Separation; D002478:Cells, Cultured; D049452:Green Fluorescent Proteins / Q000235:genetics; D006801:Humans; D051741:Kruppel-Like Transcription Factors; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009124:Muscle Proteins / Q000378:metabolism; D018482:Muscle, Skeletal / Q000166:cytology / Q000378:metabolism*; D009133:Muscular Atrophy / Q000378:metabolism; D009374:Neoplasms, Experimental / Q000378:metabolism / Q000473:pathology; D011494:Protein Kinases / Q000378:metabolism*; D032496:Satellite Cells, Skeletal Muscle / Q000166:cytology / Q000378:metabolism; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism*; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
D051741:Kruppel-Like Transcription Factors; D009124:Muscle Proteins; C097901:Peg3 protein, mouse; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D016159:Tumor Suppressor Protein p53; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; D011494:Protein Kinases