MyoD (red) is gained and then lost to maintain a pool of muscle stem cells, which express Pax7 (green).

Muscle stem cells called satellite cells can pull back from the brink, according to Zammit et al. (page 347). When activated by muscle damage, the cells divide and start uniformly down a differentiation path. Only at the last minute do some of the cells split off to revert to a quiescent, stem cell phenotype.

Satellite cells sit quietly underneath the basal lamina of myofibers until a muscle is damaged. Either mitogens leaking into a damaged muscle or signals from a deinnervated muscle may wake up the satellite cells, which then divide and supply new cells that fuse to repair or replace damaged myofibers.

Zammit et al. isolated intact myofibers and placed them in mitogen-laden cultures to activate the satellite cells. The activated cells, which when quiescent make the transcription factor Pax7 but not the muscle determinant MyoD, turned on MyoD. Most of the doubly positive cells then turned off Pax7 and differentiated, but some turned off MyoD instead and reverted to a quiescent phenotype.

The Pax7+, MyoD cells could not have arisen from a persistent, fast-dividing pool of Pax7+, MyoD cells because at intermediate times such cells were found on only a few myofibers. The authors also noted that recently replicated cell pairs may have provided evidence for a recent switch, as in some cases only one of the daughter cells expressed MyoD.

Thus, the cells are capable of shutting off MyoD, which was thought to mark an irreversible commitment to the skeletal muscle lineage. Using this divergent pathway, satellite cells can replenish themselves, with no need to invoke an outside supply of new stem cells. Heterogeneity may still exist in the starting population of satellite cells, predisposing some cells to the eventual loss of MyoD. Alternatively, the satellite cells may progress to the MyoD+ state as a truly homogenous population, with loss of MyoD in certain cells relying on communication both with the myofiber and between multiplying satellite cells. ▪