Even the mightiest individuals are vulnerable to muscle loss, whether from severe injury, old age, or as a byproduct of disease, and many scientists see the engineering of replacement muscle as a promising solution. Current methods involve the culture of progenitor stem cells, known as myoblasts, for transplantation. These cells in turn fuse and differentiate to form myofibers—mature muscle fibers capable of contraction.
Myoblasts show promise for muscle replacement, but cultured myofibers may be superior for clinical use, and could reduce the risk of tumor formation—a potential hazard with undifferentiated myoblasts. Unfortunately, current strategies for myofiber production have proven inadequate, and myofibers produced from cultured myoblasts tend to be poorly differentiated. “Myoblast transplantation is far ahead of myofiber transplantation,” explains Nobuhiro Morishima, of the RIKEN Discovery Research Institute in Wako. “And one of the reasons for the slow progress of cultured myofiber transplantation is the inefficiency of myofiber formation in culture.”
Previous work by Morishima’s team revealed that differentiation of myoblasts appears to correlate with functional disruption of the endoplasmic reticulum (ER), the cellular organelle responsible for protein folding and processing1. Now the team has used chemicals that directly trigger this condition, known as ‘ER stress’, in cultured myoblasts to better understand the role of this process in muscle development2.
Surprisingly, treated cells responded in different ways; nearly half the treated cells died, via a process known as apoptosis, while the other cells survived and differentiated to form fully functional myofibers (Fig. 1 - Click on link below). Closer examination revealed that the ‘survivors’ were expressing higher levels of Bcl-xL, a protein known to block apoptosis. Morishima suggests that this process of stress-mediated death may be a means for preventing ‘weak’ cells from forming myofibers, as muscle tissue is routinely exposed to stressful physiological conditions. What remains unclear is how otherwise identical cells end up choosing between two different pathways during differentiation, and Morishima hopes to examine this further in the future.
For now, however, his team is encouraged by the high yield of functioning myofibers that can be generated through this culture method, and they are now attempting to better understand the differentiation process and how to exploit it for biomedical applications. “We would like to answer the question of how the myoblast-differentiating ER stress conditions naturally occur in the body,” he says, “and hopefully we will be able to show the merit of ER stress for myofiber formation in vivo for the advancement of both basic biology and clinical research.”
Reference
1. Nakanishi, K., Sudo, T. & Morishima, N. Endoplasmic reticulum stress signaling transmitted by ATF6 mediates apoptosis during muscle development. Journal of Cell Biology 169, 555–560 (2005).
2. Nakanishi, K., Dohmae, N. & Morishima, N. Endoplasmic reticulum stress increases myofiber formation in vitro. FASEB Journal, published online, 13 April 2007 (doi: 10.1096/fj06-6408com).
