Myoblasts Stressed by Differentiating

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Nakanishi et al. provide evidence that during muscle fiber formation, both in culture (C2C12 cells) and in mouse embryos, the endoplasmic reticulum (ER) stress response is activated, resulting in activation of caspase-12 and apoptosis of a fraction of the cells. When cultured C2C12 cells were transferred to differentiation medium, a fraction of the cells underwent apoptosis (active caspase-12). ER stress was detected (as an increased abundance of the transcription factor CHOP and of the ER chaperone BiP) in most of the myoblasts after 24 hours in differentiation medium. Although the percentage of apoptotic cells was decreased in cells transfected with the caspase-12-suppressor MAGE-3, the ER stress response was not inhibited. The ER stress appeared to be different in the surviving differentiating cells than in the cells destined for apoptosis. The transcription factor ATF6 was activated only in the dying cells, whereas the phosphorylated form of the kinase PERK, also associated with ER stress, was present only in the surviving cells. ATF6 is a transcription factor activated in response to ER stress by transit to the Golgi and subsequent cleavage that releases it in a transcriptionally active form. Although inhibition of the enzymes that activate ATF6 decreased the number of apoptotic cells, overexpression of active ATF6 did not increase the number of apoptotic cells, which suggests that additional signaling processes contribute to caspase-12 activation and apoptosis. This report represents a physiological role for caspase-12-mediated cell death in development, whereas previously it had only been associated with pathological conditions. K. Nakanishi, T. Sudo, N. Morishima, Endoplasmic reticulum stress response signaling transmitted by ATF6 mediates apoptosis during muscle development. J. Cell Biol. 169 , 555-560 (2005). [Abstract] [Full Text]