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Muscle cachexia is regulated by a p53–PW1/Peg3-dependent pathway

¹ Brookdale Department of Molecular, Cell, and Developmental Biology, Mount Sinai Medical School, New York, New York 10029, USA; ² Department of Histology and Medical Embryology and Interuniversity Institute of Myology, University of Rome La Sapienza, Rome 00161, Italy; ³ Myology Group, Institut national de la santé et de la recherche médicale (INSERM) U787, Paris 75634, France; ⁴ Université Pierre et Marie Curie-Paris6, UMR S 787, 75634 Paris, France

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- (TNF) is a key inflammatory cytokine associated with cachexia. TNF 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 TNF-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.

[Keywords: Skeletal muscle; muscle differentiation; cancer cachexia; p53; PW1/Peg3; Pax7]

Received May 18, 2006; revised version accepted October 25, 2006.

⁶ Corresponding author.

E-MAIL david.sassoon{at}mssm.edu; FAX 33-01-53-60-08-02.

Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.412606

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