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
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↵5 Both authors contributed equally to this work.
Abstract
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-α (TNFα) is a key inflammatory cytokine associated with cachexia. TNFα 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 TNFα-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.
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Footnotes
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↵6 Corresponding author.
↵6 E-MAIL david.sassoon{at}mssm.edu; FAX 33-01-53-60-08-02.
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Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.412606
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- Received May 18, 2006.
- Accepted October 25, 2006.
- Copyright © 2006, Cold Spring Harbor Laboratory Press
