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Pluripotent stem cells have the capacity to develop into different cell lineages, and can be promoted into skeletal muscle lineage through the use of small molecule inducers. Retinoic acid (RA) signaling through the retinoic acid receptor (RAR) and retinoid X receptor (RXR), is important for embryonic development, and is able to enhance myogenic differentiation in vitro if used in combination with other small molecule inducers. Nevertheless, it only yields moderate results in promoting the differentiation of embryonic stem (ES) cells into skeletal myocytes. RXR is also known to be essential for embryonic development, but it is generally considered to act as a silent partner for other nuclear receptors such as RAR. We recently discovered that RXR selective ligand efficiently induces myogenic differentiation in mouse ES cells which respond poorly to RA. In addition, myogenic differentiation, enhanced by the RXR ligand, is mediated through a RAR independent mechanism, and recapitulates closely the sequential events observed in vivo. Since ES cell differentiation represents the properties of early developing embryo, efficiently generating skeletal myocytes with RXR selective ligand provides means to further scrutinize signaling pathways in skeletal myogenesis, in view of developing cell-based therapies for skeletal muscle-related diseases. In this chapter, we attempt to provide an in-depth analysis of recent research findings and the current stage of knowledge in the field of skeletal myogenesis.

Retinoid X Receptor Signalling in the Specification of Skeletal Muscle Lineage