Tumor necrosis factor-alpha gene transfer induces cachexia and inhibits muscle regeneration.
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.
Coletti
Dario
D
Brookdale Department of Molecular, Cell and Developmental Biology, Mount Sinai Medical School, New York, New York 10029, USA.
Moresi
Viviana
V
Adamo
Sergio
S
Molinaro
Mario
M
Sassoon
David
D
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
D009124:Muscle Proteins; D014409:Tumor Necrosis Factor-alpha; C486691:Fbxo32 protein, mouse; D044843:SKP Cullin F-Box Protein Ligases