Inhibition of skeletal muscle development: less differentiation gives more muscle.

The fact that stem cells have to be protected from premature differentiation is true for many organs in the developing embryo and the adult organism. However, there are several arguments that this is particularly important for (skeletal) muscle. There are some evolutionary arguments that muscle is a "default" pathway for mesodermal cells, which has to be actively prevented in order to allow cells to differentiate into other tissues. Myogenic cells originate from very small areas of the embryo where only a minor portion of these cells is supposed to differentiate. Differentiated muscle fibres are unconditionally post-mitotic, leaving undifferentiated stem cells as the only source of regeneration. The mechanical usage of muscle and its superficial location in the vertebrate body makes regeneration a frequently used mechanism. Looking at the different inhibitory mechanisms that have been found within the past 10 or so years, it appears as if evolution has taken this issue very serious. At all possible levels we find regulatory mechanisms that help to fine tune the differentiation of myogenic cells. Secreted molecules specifying different populations of somitic cells, diffusing or membrane-bound signals among fellow myoblasts, modulating molecules within the extracellular matrix and last, but not least, a changing set of activating and repressing cofactors. We have come a long way from the simple model of MyoD just to be turned on at the right time in the right cell.