Contribution of Retinoid X Receptor Signaling to the Specification of Skeletal Muscle Lineage

Pluripotent stem cells possess a tremendous potential for the\ud treatment of many diseases because of their capacity to differentiate\ud into a variety of cell lineages. However, they provide little\ud promise for muscle-related diseases, mainly because of the lack\ud of small molecule inducers to efficiently direct myogenic conversion.\ud Retinoic acid, acting through the retinoic acid receptor\ud (RAR) and retinoid X receptor (RXR), affects stem cell fate\ud determination in a concentration-dependent manner, but it\ud only has a modest efficacy on the commitment of ES cells into\ud skeletal muscle lineage. The RXR is very important for embryonic\ud development but is generally considered to act as a silent\ud partner of RAR in a non-permissive mode. In this study, we have\ud examined whether activation of the RXR by rexinoid or RXRspecific\ud signaling play a role in the specification of stem cells\ud into muscle lineage. Our findings demonstrate that mouse ES\ud cells generate skeletal myocytes effectively upon treatment\ud with rexinoid at the early stage of differentiation and that on\ud a molecular level, rexinoid-enhanced myogenesis simulates\ud the sequential events observed in vivo. Moreover, RXR-mediated\ud myogenic conversion requires the function of -catenin\ud but not RAR. Our studies establish the feasibility of applying\ud the RXR agonist in cell-based therapies to treat muscle-related\ud diseases. The aptitude of mouse ES cells to generate\ud skeletal myocytes following rexinoid induction also provides\ud a model system to study the convergence of different signaling\ud pathways in myogenesis.This work was supported by an operating grant from the Natural Sciences and Engineering Research Council of Canada and by a graduate scholarship award from the Canadian Institutes of Health Research (to M. L.); and by a grant from the University of Ottawa Author Fund in support of Open Access Publishin