Reflections on lineage potential of skeletal muscle satellite cells: Do they sometimes go MAD?

Postnatal muscle growth and repair is supported by satellite cells-myogenic progenitors positioned between the myofiber basal lamina and plasma membrane. In adult muscles, satellite cells are quiescent but become activated and contribute differentiated progeny when myofiber repair is needed. The development of cells expressing osteogenic and adipogenic genes alongside myoblasts in myofiber cultures raised the hypothesis that satellite cells possess mesenchymal plasticity. Clonal studies of myofiber-associated cells further suggest that satellite cell myogeneity and diversion into Mesenchymal Alternative Differentiation (MAD) occur in vitro by a stochastic mechanism. However, in vivo this potential may be executed only when myogenic signals are impaired and the muscle tissue is compromised. Such a mechanism may contribute to the increased adiposity of aging muscles. Alternatively, it is possible that mesenchymal interstitial cells (sometimes co-isolated with myofibers), rather than satellite cells, account for the nonmyogenic cells observed in myogenic cultures. Herein, we first elaborate on the myogenic potential of satellite cells. We then introduce definitions of adult stem-cell unipotency, multipotency, and plasticity as well as elaborate on recent studies that established the status of satellite cells as myogenic stem cells. Last, we highlight evidence in favor of satellite cell plasticity and emerging hurdles restraining this hypothesis.