Inhibition of NFkappaB by activated c-Jun NH2 terminal kinase 1 acts as a switch for C2C12 cell death under excessive stretch

Abstract

Mechanical stimuli play an important role in adaptive response of skeletal muscles, while inappropriate stretches result in apoptosis. In this study, we investigated the contribution of cyclic stretches to apoptosis of myoblast C2C12 cells. A 24-h cyclic stretch at an extension level of over 15%/10 cycles/min produced abundant reactive oxygen species, leading to significant apoptosis. Under such stretches, JNK1 phosphorylation increased while NFkappaB activity decreased. Inhibition of JNK by a specific chemical inhibitor or RNAi increased cell survival, which was blocked by additional NFkappaB inhibition. Furthermore, inhibition of JNK rescued the transcriptional activity of NFkappaB and upregulated the expression of Bcl2 through NFkappaB nuclear localization, suggesting the existence of inhibition of NFkappaB by activated JNK pathway. Taken together, our study suggests that excessive ROS induced by undue stretch favor the activation of JNK1, which in turn inhibit the activity of NFkappaB, resulting in significant apoptosis.