Response to “PPARδ Modulation by GW501516: An Unsuccessful Exercise Mimetic”
In 2008, Narkar et al. indicated that GW501516 and exercise acted synergistically to enhance endurance capacity in mice, and proposed the molecule as an exercise‐mimetic.2 Moreover, a recent study indicates that GW501516 treatment for 3 weeks promotes running performance in trained and untrained mice.3 Although both GW501516 and exercise increase the proportion of slow‐twitch skeletal muscle fibers and improve running endurance, the mechanisms for these actions are not identical. Exercise increases energy availability by promoting catabolism of proteins, glycolysis, and glycogenesis from amino acids, whereas GW501516 enhanced fatty acid oxidation through branched chain amino acid and ketone body pathways, and reduced glucose utilization3 (Figure1).
Unfortunately, GW501516 was withdrawn from research by GlaxoSmithKline, which originally developed the drug; this was prompted by findings of rapidly developing cancers in a number of organs when animals were treated with GW501516. However, some clinical trials reported that the drug has no significant adverse effects4 and one study even reported that GW501516 induced apoptosis in invasive bladder cancer cells.5
It is clear that GW501516 has potential for doping in sports, as a number of athletes have tested positive for GW501516 since the World Anti‐Doping Agency (WADA) added the drug to its prohibited list of drugs in 2009. Nevertheless, currently available data are insufficient to determine whether GW501516 is a useful candidate as an exercise‐mimetic.