The muscle phenotypes described here are remarkably similar to those of transgenic mice expressing either calcineurin, calmodulin-dependent kinase, or PGC-1α (Naya et al. 2000; Lin et al. 2002; Wu et al. 2002), indicating that PPARδ could be one of the hypothetical downstream transcription factors of these pathways. It is important to note that, from our ligand and gain-of-function transgenic studies, PPARδ needs to be activated in order to direct the muscle fiber switch. Indeed, in a recent report by Luquet et al. (2003), simple overexpression of wild-type PPARδ in muscle was found not to be sufficient to promote a fiber switch or obesity resistance, although certain oxidation enzymes were increased. This supports the model in Figure 6C that the activating signal or ligand, but not the receptor, is limiting. Thus, PPARδ activation, rather than merely an increase of PPARδ levels, is an essential element for fiber switching and its associated functional manifestations. How might endogenous PPARδ become activated naturally by exercise training? First, it is possible that exercise generates or increases endogenous ligands for PPARδ as tissues are undergoing substantial increases in fatty-acid internalization and burning. Fatty acids and their metabolites can activate PPARδ. A second model is that exercise may induce expression of PGC-1α (Goto et al. 2000) and thereby activate PPARδ. This is consistent with previous work in which we have shown that PGC-1α physically associates with PPARδ in muscle tissue and can powerfully activate it even in the absence of ligands (Wang et al. 2003). Alternatively, PPARδ may be activated by a distal upstream signaling component such as a kinase cascade. Further dissecting the interactions between PPARδ and its regulatory components will be necessary to fully understand the molecular basis of muscle fiber determination pertinent to exercise training.