Cachexia or muscle wasting is a common condition that occurs in many chronic diseases. The wasting conditions are characterized by increased levels of TNF-alpha which was also known as cachectin in the past. But how TNF-alpha exerts its cachetic effects remains controversial. To clarify this issue, we investigated the impact of TNF-alpha on C2C12 cell myogenic differentiation. Our results demonstrate that myotube formation was completely inhibited by TNF-alpha when added to differentiating C2C12 myoblasts. The inhibitory effect of TNF-alpha on differentiation was accompanied by activation of NF-kappa B and down regulation of myogenin and Akt. Importantly, TNF-alpha's effect on differentiation was abolished when IGF-1 was added to the culture. IGF-1 treatment also inhibited NF-kappa B reporter activity and restored Akt levels. Our data suggest that TNF-alpha inhibits myogenic differentiation through NF-kappa B activation and impairment of IGF-1 signaling pathway. The reversal of TNF-alpha induced inhibition of myogenesis by IGF-1 may have significant therapeutic potential. (C) 2015 Elsevier Inc. All rights reserved.