title: Tumor necrosis factor-alpha gene transfer induces cachexia and inhibits muscle regeneration.
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-alpha (mTNFalpha). This procedure results in the production of elevated levels of circulating mTNFalpha followed by body weight loss, upregulation of Atrogin1, and muscle atrophy, including muscles distant from the site of gene transfer. We also found that mTNFalpha gene transfer resulted in a significant inhibition of regeneration following muscle injury. We conclude that in addition to being a potent inducer of cachexia, TNFalpha is a potent inhibitor of myogenesis in vivo.
authors.affiliation: Brookdale Department of Molecular, Cell and Developmental Biology, Mount Sinai Medical School, New York, New York 10029, USA.
authors.forename: Dario
authors.initials: D
authors.lastname: Coletti
authors.forename: Viviana
authors.initials: V
authors.lastname: Moresi
authors.forename: Sergio
authors.initials: S
authors.lastname: Adamo
authors.forename: Mario
authors.initials: M
authors.lastname: Molinaro
authors.forename: David
authors.initials: D
authors.lastname: Sassoon
mesh_terms: D000818:Animals; D018274:Electroporation; D018014:Gene Transfer Techniques; D008297:Male; D051379:Mice; D009124:Muscle Proteins / Q000378:metabolism; D018482:Muscle, Skeletal / Q000502:physiology*; D009133:Muscular Atrophy / Q000235:genetics* / Q000378:metabolism; D032446:Myoblasts / Q000378:metabolism; D012038:Regeneration / Q000502:physiology*; D044843:SKP Cullin F-Box Protein Ligases / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics* / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D009124:Muscle Proteins; D014409:Tumor Necrosis Factor-alpha; C486691:Fbxo32 protein, mouse; D044843:SKP Cullin F-Box Protein Ligases