Tumor necrosis factor-alpha-induced apoptosis is associated with suppression of insulin-like growth factor binding protein-5 secretion in differentiating murine skeletal myoblasts.
Wasting of muscle and fat during cachexia exceeds that explained by reduced food intake alone. This wasting may result from an imbalanced cytokine environment, which could lead to increased protein catabolism. Supporting this, tumor necrosis factor-alpha (TNF-alpha) is raised in several animal models of cachectic muscle wasting. Therefore, we assessed the effects of TNF-alpha and its second messenger, ceramide, on the proliferation, differentiation, and survival of murine C2 skeletal myoblasts. Because insulin-like growth factor binding protein-5 (IGFBP-5) and insulin-like growth factor-II (IGF-II) are potent regulators of myoblast proliferation and differentiation, we monitored the ability of exogenous TNF-alpha to manipulate this system. Fibroblast growth factor (FGF) ceramide, or TNF-alpha suppressed differentiation of C2 cells compared with controls. All treatments suppressed IGF-II production but only TNF-alpha blocked IGFBP-5 secretion. TNF-alpha increased apoptotic cell death, which otherwise remained basal (low serum differentiation medium (LSM), FGF) or low (ceramide). Suppression of both IGFBP-5 and IGF-II secretion may explain why of all triggers tested, only TNF-alpha not only blocked differentiation, but also promoted cell death. This suggests a fundamental role of IGFBP-5 for maintaining muscle survival. Supporting this hypothesis, no increase in apoptosis was seen in IGFBP-5 cDNA tranfected C2 cells after TNF-alpha treatment. In summary, the IGF system is essential for maintaining skeletal muscle cell survival and differentiation, and its suppression by TNF-alpha is fundamental regarding muscle wasting, and may be associated in vivo with cancer cachexia.
Meadows
K A
KA
University Department of Surgery, Bristol Royal Infirmary, Bristol, England.
Holly
J M
JM
Stewart
C E
CE
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D002453:Cell Cycle / Q000187:drug effects / Q000502:physiology; D002460:Cell Line; D003402:Creatine Kinase / Q000032:analysis; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology; D006801:Humans; D018975:Insulin-Like Growth Factor Binding Protein 5 / Q000096:biosynthesis* / Q000378:metabolism; D007335:Insulin-Like Growth Factor II / Q000096:biosynthesis / Q000378:metabolism; D051379:Mice; D018482:Muscle, Skeletal / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000494:pharmacology; D015290:Second Messenger Systems; D013110:Sphingosine / Q000031:analogs & derivatives / Q000494:pharmacology; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D018975:Insulin-Like Growth Factor Binding Protein 5; C064769:N-acetylsphingosine; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D016222:Fibroblast Growth Factor 2; D007335:Insulin-Like Growth Factor II; D003402:Creatine Kinase; D013110:Sphingosine