PPARδ Promotes Running Endurance by Preserving Glucose

Management of energy stores is critical during endurance exercise; a shift in substrate utilization from glucose toward fat is a hallmark of trained muscle. Here we show that this key metabolic adaptation is both dependent on muscle PPAR delta and stimulated by PPAR delta ligand. Furthermore, we find that muscle PPAR delta expression positively correlates with endurance performance in BXD mouse reference populations. In addition to stimulating fatty acid metabolism in sedentary mice, PPAR delta activation potently suppresses glucose catabolism and does so without affecting either muscle fiber type or mitochondrial content. By preserving systemic glucose levels, PPAR delta acts to delay the onset of hypoglycemia and extends running time by similar to 100 min in treated mice. Collectively, these results identify a bifurcated PPAR delta program that underlies glucose sparing and highlight the potential of PPAR delta-targeted exercise mimetics in the treatment of metabolic disease, dystrophies, and, unavoidably, the enhancement of athletic performance.