“Hitting the wall” is a familiar experience to people who push their bodies to the limit during a marathon or even in an unexpected bout of prolonged exertion. Biochemically speaking, this means the body’s tissues have used up their reserves of glucose. Exercise typically improves performance by teaching the body to oxidize fat for energy and to preserve glucose. But how that process works has remained unclear. A team of researchers led by Michael Downes and Ronald M. Evans of the Salk Institute for Biological Studies has now determined that one of the proteins in muscle that orchestrates this improved endurance is a transcription factor called PPARδ (Cell Metab. 2017, DOI: 10.1016/j.cmet.2017.04.006). The team also found that activating PPARδ with a compound called GW501516 enhanced endurance in mice without any training. Even “couch-potato” mice were able to run an additional 100 minutes before they hit the wall if they were given a dose of GW501516. Whether the drug-induced enhancement occurs in humans is still to be determined, but the compound has already been touted on the black market as a performance enhancer and it was banned by the World Anti-Doping Agency in 2013.