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 env ironment, which could lead to increased protein catabolism. Supporting this , tumor necrosis factor-alpha (TNF-alpha) is raised in several animal model s of cachectic muscle wasting. Therefore, we assessed the effects of TNF-al pha and its second messenger, ceramide, on the proliferation, differentiati on, and survival of murine C2 skeletal myoblasts. Because insulin-like grow th factor binding protein-5 (IGFBP-5) and insulin-like growth factor-II (IG F-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 differenti ation of C2 cells compared with controls. All treatments suppressed ICF-II production but only TNF-alpha blocked IGFBP-5 secretion. TNF-alpha increase d apoptotic cell death, which otherwise remained basal (low serum different iation medium (LSM), FGF) or low (ceramide). Suppression of both IGFBP-5 an d IGF-II secretion may explain why of all triggers tested, only TNF-alpha n ot only blocked differentiation, but also promoted cell death. This suggest s a fundamental role of IGFBP-5 for maintaining muscle survival. Supporting this hypothesis, no increase in apoptosis was seen in IGFBP-5 cDNA transfe cted C2 cells after TNF-alpha treatment. In summary, the IGF system is esse ntial for maintaining skeletal muscle cell survival and differentiation, an d its suppression by TNF-alpha is fundamental regarding muscle wasting, and may be associated in vivo with cancer cachexia. J. Cell. Physiol. 183:330- 337, 2000. (C) 2000 Wiley-Liss, Inc.