Discussion
Our data reveal that a PPARδ-mediated transcriptional pathway can regulate muscle fiber specification, enabling the generation of a strain of mice with a “long-distance running” phenotype. We show that targeted expression of an activated form of PPARδ produces profound and coordinated increases in oxidation enzymes, mitochondrial biogenesis, and production of specialized type I fiber contractile proteins—the three hallmarks for muscle fiber type switching (Figure 6C). While induction of muscle oxidation enzymes by PPARδ has been seen both in vivo and in vitro (Muoio et al. 2002; Dressel et al. 2003; Luquet et al. 2003; Tanaka et al. 2003; Wang et al. 2003), its effects shown here on muscle fiber switching are unexpected. These progressive changes in oxidative capacity in conjunction with eventual changes in type I muscle fiber lead to a dramatically improved exercise profile and protection against obesity. This does not solely depend on achieving a directed muscle fiber type switch but also requires all the associated changes in neural innervation, motor neuron function, and peripheral metabolic adaptation to enable a new integrated physiological response. Accordingly, activation of muscle PPARδ essentially recapitulates the effects of exercise training even in the absence of training itself. To our knowledge, this has not been directly described for any other transcriptional factor.
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.
Skeletal muscle is a major site to regulate whole-body fatty-acid and glucose metabolism. We show that mice with increased oxidative fibers are resistant to high-fat-induced obesity and glucose intolerance. Moreover, ligand studies provide compelling evidence that activation of endogenous PPARδ can produce similar effects. Might PPARδ have any beneficial effects on glucose metabolism in the lean condition? This has not been explored; however, insulin resistance in the elderly is confined mostly to skeletal muscle and may be due to reduction of mitochondrial number and/or function (Petersen et al. 2003). The ability of PPARδ to stimulate mitochondrial biogenesis and oxidative function suggests that PPARδ could be important for control of insulin resistance during normal aging. Together, these data indicate that PPARδ and its ligands comprise a key molecular switch to regulate muscle fiber specification, obesity resistance, insulin sensitivity, and, most surprisingly, physical endurance. This work demonstrates that complex physiologic properties such as fatigue, endurance, and running capacity can be genetically manipulated.