'Exercise-In-A-Pill' Boosts Athletic Endurance by 70%
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, including increased fat burning and stamina.
Salk Institute scientists build on earlier work that identified a gene pathway triggered by running, finding pathway conserves glucose and encourages fat-burning and endurance.
Credit: Salk Institute
“It’s well known that people can improve their aerobic endurance through training,” says senior author Ronald Evans, Howard Hughes Medical Institute investigator and holder of Salk’s March of Dimes Chair in Molecular and Developmental Biology. “The question for us was: how does endurance work? And if we really understand the science, can we replace training with a drug?”
In the current study, the Salk team gave normal mice a higher dose of GW, for a longer period of time (8 weeks instead of 4). Both the mice that received the compound and mice that did not were typically sedentary, but all were subjected to treadmill tests to see how long they could run until exhausted.
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 (glucose) dropped to around 70 mg/dl, suggesting that low glucose levels (hypoglycemia) are responsible for fatigue.
Credit: Salk Institute
To understand what was happening at the molecular level, the team compared gene expression in a major muscle of mice. They found 975 genes whose expression changed in response to the drug, either becoming suppressed or increased. Genes whose expression increased were ones that regulate breaking down and burning fat. Surprisingly, genes that were suppressed were related to breaking down carbohydrates for energy. This means that the PPARD pathway prevents sugar from being an energy source in muscle 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.”
Interestingly, the muscles of mice that took the exercise drug did not exhibit the kinds of physiological changes that typically accompany aerobic fitness: additional mitochondria, more blood vessels and a shift toward the type of muscle fibers that burn fat rather than sugar. This shows that these changes are not exclusively driving aerobic endurance; it can also be accomplished by chemically activating a genetic pathway.
“Exercise activates PPARD, but we’re 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,” says 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 based on GW, from increasing fat-burning in people suffering from obesity or type 2 diabetes to improving patients’ fitness before and after surgery.
Other authors included Wanda Waizenegger, Chun Shi Lin, Ming-Xiao He, Christopher E. Wall, Ruth T. Yu, Annette R. Atkins of Salk; Vincenzo Sorrentino, Hao Li and Johan Auwerx of the Ecole Polytechnique Federale de Lausanne; and Christopher Liddle of the University of Sydney.
The work was funded by the National Institutes of Health, the National Health and Medical Research Council of Australia, The Leona M. and Harry B. Helmsley Charitable Trust, the Samuel Waxman Cancer Research Foundation, Stand Up to Cancer and Ipsen Bioscience, Inc.
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