Suppressor of cytokine signaling (SOCS) I was initially identified as an intracellular negative feedback regulator of the JAK-STAT signal pathway. Recently, it has been Suggested that SOCS1 affects signals of growth factors and hormones. One of them, SOCS 1, is also known to be involved in auto-regulation of IRS-1-mediated signaling. However, the mechanism(s) of SOCS1 induction by insulin-like growth factor (IGF)-1 and a role of SOCS1 on IGF-1 receptor-mediated signaling are not clarified. Here, we investigate SOCS1 on muscle differentiation. We found that muscle differentiation was Suppressed in SOCS] stable transformant C2C12 myoblasts, while it was promoted in SOCS1-deficient myoblasts. Additionally, SOCS1 augmented MEK phosphorylation and reduced Akt phosphorylation induced by IGF-1. Then, SOCS1 stable transformant C2C12 myoblasts, infected with adenovirus bearing constitutively active Akt, have the ability to differentiate again. Collectively, these findings suggest that SOCS1 suppresses muscle differentiation through negative feedback regulation of IGF-1 receptor-mediated signaling. (C) 2005 Elsevier Inc. All rights reserved.