Boosting athletic endurance by 70 percent.

Every week, there seems to be another story about the health benefits of running. That’s great – but what if you can’t run? For the elderly, obese or otherwise mobility-limited, the rewards of aerobic exercise have long been out of reach.

Salk Institute scientists, building on earlier work that identified a gene pathway triggered by running, have discovered how to fully activate that pathway in sedentary mice with a chemical compound, mimicking the beneficial effects of exercise such as increased fat burning and stamina. The study, which appeared in Cell Metabolism in May 2017, not only deepens our understanding of aerobic endurance, but also offers people with heart conditions, pulmonary disease, type 2 diabetes or other health limitations the hope of achieving its benefits pharmacologically.

“It is well known that people can improve their aerobic endurance through training,” senior author Ronald Evans, Howard Hughes Medical Institute investigator and holder of Salk’s March of Dimes Chair in Molecular and Developmental Biology shared with Giving Back Magazine. “The question for us was: how does endurance work? And if we really understand the science, can we replace training with a drug?”

Activating fat burning takes longer than burning sugar, which is why the body generally uses sugar (glucose) for its fuel. And although muscles can burn either fat or sugar, the brain prefers the latter, which explains why runners who “hit the wall” experience both physical and mental fatigue when they use up their supply of glucose. Developing endurance – becoming more fit – prompts a person’s muscles to shift from burning carbohydrates and sugars to burning fat, allowing one to sustain aerobic activity for longer periods of time.

The Salk researchers showed how a dose of the chemical compound they had been investigating, called GW1516 (or GW for short), leads the body to make this switch from using sugar to using fat without endurance training. In mouse studies, GW not only helped sedentary, “couch potato” mice resist weight gain, but also prompted them to run much longer than a control group of sedentary mice. Mice in the control group could run about 160 minutes before exhaustion. Mice on the drug, however, could run about 270 minutes – about 70 percent longer. For both groups, exhaustion set in when blood sugar dropped, suggesting that low glucose levels are responsible for fatigue.

GW works by activating a gene called PPARD, which, it turns out, leads to changes in gene expression that prevent sugar from being an energy source for muscles during exercise, possibly to preserve sugar for the brain.

“This study suggests that burning fat is less a driver of endurance than a compensatory mechanism to conserve glucose,” says Michael Downes, a Salk senior scientist and co¬-senior author of the paper. “PPARD is suppressing all the points that are involved in sugar metabolism in the muscle so glucose can be redirected to the brain, thereby preserving brain function.”

“Exercise activates PPARD, but we are showing that you can do the same thing without mechanical training. It means you can improve endurance to the equivalent level as someone in training, without all of the physical effort,” adds Weiwei Fan, a Salk research associate and the paper’s first author.

Although the lab’s studies have been in mice, pharmaceutical companies are interested in using the research to develop clinical trials for humans. The team can envision a number of therapeutic applications for a prescription drug at based on GW, from increasing fat-burning in people suffering from obesity or type 2 diabetes to improving patients’ fitness before and after surgery.