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

作者：Schwarzkopf Martina; Coletti Dario; Sassoon David^*; Marazzi Giovanna

来源：Genes & Development, 2006, 20(24): 3440-3452.

DOI：10.1101/gad.412606

• skeletal muscle
• muscle differentiation
• cancer cachexia
• p53
• PW1/Peg3
• Pax7

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

• 出版日期2006-12-15