INHIBITORS OF THE PROTEASOME BLOCK THE MYOGENIC DIFFERENTIATION OF RAT L6 MYOBLASTS

Myogenesis is characterized by membrane fusion and accumulation of mus cle specific proteins. We have previously shown that nitric oxide acts as a messenger for membrane fusion. Here we show that inhibitors of t he proteasome, such as lactacystin, reversibly block both the fusion o f L6 myoblasts and the accumulation of muscle specific proteins, such as myosin heavy chain (MHC). The inhibitors also reversibly prevented the induction of the NF-kappa B activity, which is required for the ex pression of nitric oxide synthase (NOS). Moreover, the inhibition of t he NF-kappa B activity occurred in parallel with that of the NOS activ ity upon treatment with increasing concentrations of lactacystin, Whil e pyrrolidine dithiocarbamate, an inhibitor of NF-kappa B, blocked bot h membrane fusion and accumulation of MHC, N-G-monomethyl-L-arginine, a specific inhibitor of NOS, inhibited only the fusion. These results suggest that the proteasome plays an essential role in the regulation of myogenic differentiation through the activation of NF-kappa B and t hat the target of NF-kappa B for the expression of muscle specific pro teins is distinct from that for myoblast fusion, (C) 1998 Federation o f European Biochemical Societies.