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Chemical activation of a PPAR genetic pathway shifts muscle metabolism away from glucose and toward fat, presenting an alternative path to fitness. In this image, which shows a partial view of a mouse calf muscle, staining is used to distinguish different types of muscle fibers: oxidative slow-twitch (blue), oxidative fast-twitch (green), glycolytic fast-twitch (red). [Waitt Center/Salk Institute]If you live a sedentary life, you may be resigned to doing without the benefits of aerobic exercise. You may even fear that if you were to start exercising, you would soon find yourself “hitting the wall.” But what if you could obtain some of the benefits of exercise without having to run, swim, or cycle? This question has been raised by a new study that suggests the path between exercise and fitness is not as straightforward as we might have guessed. In fact, there may be a shortcut—an exercise pill.
Building on earlier work that identified a gene pathway triggered by running, Salk Institute scientists 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. The scientists presented their findings May 2 in the journal Cell Metabolism, in an article entitled “PPARδ Promotes Running Endurance by Preserving Glucose.”
PPARδ, a peroxisome proliferator-activated receptor, is one of a group of nuclear receptor proteins that function as transcription factors regulating the expression of genes. When it is activated, whether by exercise or chemical stimulation, PPARδ shifts metabolism in muscle cells. Instead of relying on glucose, the muscle cells burn more fat, leaving more glucose for brain cells.
“It turns out that ‘hitting the wall’ happens when your brain can no longer get enough glucose. At that point, you’re toast,” said co-corresponding author Ronald Evans, Ph.D., director of the Salk Institute’s Gene Expression Laboratory. “We previously believed that training improves endurance because it allows the muscles to more effectively burn fat as an energy source.”
But in the current study, the Salk Institute scientists 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.
Previous work by the Evans lab into PPARδ offered intriguing clues: mice genetically engineered to have a permanently activated PPARD gene became long-distance runners who were resistant to weight gain and highly responsive to insulin—all qualities associated with physical fitness. The team found that a chemical compound called GW1516 (GW) similarly activated PPARδ, replicating the weight control and insulin responsiveness in normal mice that had been seen in the engineered ones. However, GW did not affect endurance (how long the mice could run) unless coupled with daily exercise, which defeated the purpose of using it to replace exercise.
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.
“By preserving systemic glucose levels, PPARδ acts to delay the onset of hypoglycemia and extends running time by ∼100 min in treated mice,” wrote the authors of the Cell Metabolism article. “Collectively, these results identify a bifurcated PPARδ program that underlies glucose sparing and highlight the potential of PPARδ-targeted exercise mimetics in the treatment of metabolic disease, dystrophies, and, unavoidably, the enhancement of athletic performance.”
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. Activating fat burning takes longer than burning sugar, which is why the body generally uses glucose unless it has a compelling reason not to—like maintaining brain function during periods of high energy expenditure. Although muscles can burn either sugar or fat, the brain prefers sugar, which explains why runners who “hit the wall” experience both physical and mental fatigue when they use up their supply of glucose.
“This study suggests that burning fat is less a driver of endurance than a compensatory mechanism to conserve glucose,” says Michael Downes, Ph.D., 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. In addition to having increased endurance, mice who were given the drug were also resistant to weight gain and more responsive to insulin than the mice who were not on the drug.
“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, Ph.D., 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.