Tumor necrosis factor-α gene transfer induces cachexia and inhibits muscle regeneration

Authors

  • Dario Coletti,

    1. Brookdale Department of Molecular, Cell and Developmental Biology, Mount Sinai Medical School, New York, New York
    2. Department of Histology and Medical Embryology and Interuniversity Institute of Myology, University of Rome “La Sapienza,” Rome, Italy
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  • Viviana Moresi,

    1. Department of Histology and Medical Embryology and Interuniversity Institute of Myology, University of Rome “La Sapienza,” Rome, Italy
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  • Sergio Adamo,

    1. Department of Histology and Medical Embryology and Interuniversity Institute of Myology, University of Rome “La Sapienza,” Rome, Italy
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  • Mario Molinaro,

    1. Department of Histology and Medical Embryology and Interuniversity Institute of Myology, University of Rome “La Sapienza,” Rome, Italy
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  • David Sassoon

    Corresponding author
    1. Brookdale Department of Molecular, Cell and Developmental Biology, Mount Sinai Medical School, New York, New York
    2. Inserm Unité “Muscle Biology and Stem Cells” UPMC Faculté de Médecine Pitié-Salpétrière, Paris, France
    • Department of Molecular, Cell & Developmental Biology, Mount Sinai School of Medicine, Box 1020, One Gustave L. Levy Place, New York, NY 10029
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Abstract

Chronic disease states are associated with elevated levels of inflammatory cytokines that have been demonstrated to lead to severe muscle wasting. A mechanistic understanding of muscle wasting is hampered by limited in vivo cytokine models which can be applied to emerging mouse mutants as they are generated. We developed a simple and novel approach to induce adult mouse skeletal muscle wasting based on direct gene transfer of an expression vector encoding the secreted form of the murine tumor necrosis factor-α (mTNFα). This procedure results in the production of elevated levels of circulating mTNFα followed by body weight loss, upregulation of Atrogin1, and muscle atrophy, including muscles distant from the site of gene transfer. We also found that mTNFα gene transfer resulted in a significant inhibition of regeneration following muscle injury. We conclude that in addition to being a potent inducer of cachexia, TNFα is a potent inhibitor of myogenesis in vivo. genesis 43:120–128, 2005. © 2005 Wiley-Liss, Inc.

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