Roles of peroxisome proliferator-activated receptors delta and gamma in myoblast transdifferentiation

Dietary long chain fatty acids and thiazolidinediones act as potent activators of adipogenesis in established preadipose cell lines. High concentrations of thiazolidinediones have also been shown to induce terminal differentiation of non-preadipose cells, such as fibroblasts and myoblasts, into adipose-like cells. This transdifferentiation was observed in both rodent and human myoblasts. In this report, we show that PPARδ mediates some of the effects exerted by long chain fatty acids on myogenesis and adipogenesis. Activation of PPARδ by long chain fatty acids impairs the expression of the determination factor MyoD1 and α-actin, abolishes the development of multinucleated myotubes, and in parallel induces the expression of PPARγ gene, a master regulator of adipogenesis. Ectopic expression of PPARδ in C2C12 myoblasts potentiated the fatty acid-induced expression of adipogenic markers, while expression of a dominant negative PPARδ mutant exerted opposite effects. Furthermore, a sequential activation of first PPARδ with long chain fatty acids and then PPARγ with thiazolidinediones is required for adipogenesis in C2C12 myoblasts. This study demonstrates that PPARδ, at least in part, is responsible for the dual effects of long chain fatty acids as inhibitors of myogenesis and inducers of transdifferentiation into preadipose-like cells.