Runners, swimmers, and cyclists are familiar with the phenomenon of "hitting the wall" when the connection between brain and body feels like it's been lost: You know that you're still trying to move, but doing it feels more conceptual than physical. In Cell Metabolism, researchers show in mice the physiological basis for why this phenomenon occurs. Their research also found that training is not the only way to enhance endurance - it can also be achieved using a small molecule to stimulate a pathway that was already known to be activated by training.

"It turns out that 'hitting the wall' happens when your brain can no longer get enough glucose. At that point, you're toast," says co-corresponding author Ronald Evans, a Howard Hughes Medical Institute Investigator and Director of the Gene Expression Laboratory at the Salk Institute. "We previously believed that training improves endurance because it allows the muscles to more effectively burn fat as an energy source."

But in this study, they show that it's the other side of this dual metabolic program that may be more important: training progressively reprograms muscle to burn less glucose, thereby preserving it as an energy source for your brain. Muscle can use either fat or glucose as its energy source, but the brain relies solely on glucose.

Research over the past two decades from Evans and the study's co-corresponding author, Michael Downes, a Senior Staff Scientist in the lab, has focused on a transcription factor called PPARδ, which activates pathways involved when athletes train to increase their endurance. Here, the researchers demonstrate that this metabolic adaptation both is dependent on PPARδ and can be stimulated by molecularly activating PPARδ.

In the first set of experiments, they genetically knocked out PPARδ in the muscles of mice and studied the effects. "When we did this and then ran those animals on a treadmill, we found that the genes that are normally induced by exercise failed to be induced," Downes says. "This indicates that PPARδ plays a central role in exercise, and that it's an important molecular switch gating energy entry into the muscle."

In the next part, they used a small-molecule drug to activate PPARδ in the muscles of sedentary mice. They found that the drug not only increased fat oxidation in muscle, but it also forestalled the effects of hypoglycemia, or loss of blood glucose, on the brain. As a result, the mice who had been given the drug were able to increase the length of time they could run before "hitting the wall" - from 160 to 270 minutes - despite having no training to improve their endurance.

"What we illustrate in this paper is that if you want to move the wall, there is more than one way to do so," Evans says. "The standard method is to train; you will improve a bit with each run. But we've shown improvement can happen without expending the energy that otherwise would be needed to get to this point."

While the researchers recognize that these discoveries could be exploited by athletes wanting to gain a competitive advantage, the greatest promise lies in improving endurance in people who are unable to exercise due to health problems. This could include the frail, the elderly, and people who are confined to bed after injuries or surgery, as well as those affected by conditions like Duchenne muscular dystrophy, cystic fibrosis, cachexia (wasting syndrome), and chronic obstructive pulmonary disease.

"Exercise is valuable for many different kinds of problems," Evans says. "With this research, you can begin to think about how a therapeutic that confers the advantages of fitness could help people gain health benefits. The greater potential is essentially unlimited."

This research was primarily funded by the National Institutes of Health and the National Health and Medical Research Council of Australia.

Article: PPARδ Promotes Running Endurance by Preserving Glucose, Fan et al, Cell Metabolism, doi: 10.1016/j.cmet.2017.04.006, published 2 May 2017.