Molecular regulation of muscle stem cell asymmetric division

Satellite cells located beneath the basal lamina of myofibers are required for the growth and regeneration of skeletal muscle. Molecular genetic studies in mice have established that a small subset of the satellite cell population comprises stem cells that are capable of reconstituting the satellite cell population following transplantation. Satellite stem cells are capable of long-term self-renewal and of giving rise to committed myogenic progenitors through asymmetric apical–basal cell divisions. The regulation of asymmetric division is a key mechanism to regulate muscle stem cell homeostasis and hence the regenerative capacity of muscle tissue. Stem cell polarity is established by the PAR complex, comprised of PAR3/PAR6/aPKC, to regulate self-renewal and expansion. We have discovered that full-length dystrophin is expressed in satellite stem cells in skeletal muscle. We have made the seminal discovery that dystrophin regulates the establishment of PAR-mediated polarity in satellite cells. In the absence of dystrophin, the polarity effector Par1b is dysregulated, leading to the failure of Par3 to become localized to the cortex associated with the basal lamina. Importantly, this results in an abnormal increase in centrosome number, a 10-fold reduction in the numbers of satellite stem cells undergoing asymmetric divisions, and a marked decrease in the generation of myogenin-expressing progenitors. Accordingly, our data suggest that the failure of regenerative myogenesis to keep pace with disease progression in DMD is not due to muscle stem cell exhaustion, but rather due to a cell-autonomous deficiency in asymmetric division. Our findings have important implications for therapeutic interventions, such as gene therapy or exon skipping, and suggest that in addition to differentiated myofibers, muscle stem cells must be a therapeutic target.