On page 555, Nakanishi et al. show that ER stress triggers apoptosis during muscle development. It is the ER stress pathway's first appearance in a nonpathological context.

As muscle precursor cells called myoblasts differentiate, they fuse into multinucleated myotubes. This process is accompanied by a considerable amount of apoptosis—up to 20% of the myoblasts die. The new results show that markers of the ER stress-signaling pathway are up-regulated during this process.

ER stress-induced apoptosis is preceded by the unfolded protein response (UPR), which up-regulates ER chaperones such as BiP. The authors found BiP and ER stress-specific caspase-12 in differentiating myoblasts, including the survivors. In dying myoblasts, death effector caspases such as caspase-9 and -3 were also activated. Survival versus death might depend on the relative amounts of caspases versus antiapoptotic proteins such as XIAPs. Apoptosis might thereby eliminate cells that cannot keep up with the demands of differentiation.

Developing muscle cells undergo dramatic ER expansion and morphological changes, which might initiate the ER stress, perhaps by disrupting calcium homeostasis. ER stress was sensed by ATF6, a transcription factor that is inhibited by ER chaperones until the chaperones are called away for folding duties. The inhibition of ATF6 activation blocked myoblast apoptosis, and new evidence suggests it also blocks myotube formation in vitro.