Researchers from the Salk Institute for Biological Studies in La Jolla, CA, have discovered a chemical compound that can activate a gene normally stimulated by running.
By activating this gene - called PPAR delta (PPARD) - in sedentary mice, the researchers were able to mimic the beneficial effects of aerobic exercise, such as increased endurance and fat burning.
Senior author Ronald Evans - of the Gene Expression Laboratory at Salk and the Howard Hughes Medical Institute in Chevy Chase, MD - and colleagues say that their findings advance the possibility of "exercise-in-a-pill" - that is, a drug that can simulate the benefits of exercise.
Evans and colleagues recently reported their findings in the journal Cell Metabolism.
Current guidelines recommend that adults engage in at least 150 minutes of moderate-intensity aerobic activity or 75 minutes of vigorous-intensity aerobic activity every week in order to improve overall health and fitness.
According to the Centers for Disease Control and Prevention (CDC), however, only 49 percent of adults in the United States meet these recommendations.
While much of this failure may be down to a lack of motivation, for some individuals - such as elderly adults or individuals with mobility problems - the exercise recommendations are simply unachievable.
The new study, however, sheds light on the physiological mechanisms that underly the benefits of aerobic activity, and it suggests that these can be activated without actually having to exercise.
Boosting exercise endurance with a chemical compound
In previous research, Evans and colleagues discovered that the gene PPARD plays a role in the body's response to aerobic exercise.
The team found that mice that had a permanently activated PPARD gene ran longer distances and demonstrated increased aerobic endurance - that is, the ability to sustain aerobic activity for longer periods before becoming exhausted. The rodents also demonstrated resistance to weight gain, as well as a higher response to insulin, which are both indicators of physical fitness.
Additionally, the researchers found that a chemical compound called GW1516 (GW) activated PPARD in normal mice.
However, while the compound - administered to the rodents over a 4-week period - simulated the weight maintenance and insulin responsiveness seen in mice with a permanently activated PPARD gene, it did not boost endurance.
For the new study, Evans and team set out to investigate whether higher doses of GW administered over a longer period might boost aerobic endurance and physical fitness.
Aerobic endurance increased by 70 percent with GW
The researchers gave an increased dose of GW to sedentary mice for 8 weeks and subjected them to a treadmill test. Their aerobic endurance was compared with that of sedentary mice that did not receive the compound (the controls).
The researchers found that mice that received GW were able to exercise for around 70 percent longer than the controls before becoming exhausted, at 270 minutes versus 160 minutes.
The team found that both groups became exhausted when their blood sugar levels fell to around 70 milligrams per deciliter. As well as suggesting that low blood sugar levels play a role in exercise-induced fatigue, these findings suggest that GW might protect against such an effect.
Next, the researchers looked at the gene expression in the muscles of mice in response to GW.
They found that the compound either increased or suppressed expression in 975 genes. Genes that showed an increase in expression included those related to the breakdown and burning of fat.
Findings explain why some athletes 'hit the wall'
The team was surprised to find that genes suppressed in response to GW included those associated with the breakdown of carbohydrates for energy.
According to the researchers, this indicates that the PPARD pathway stops sugar from being a source of energy in muscle during physical activity, possibly to safeguard sugar for the brain.
The researchers explain that burning sugar is a faster process than fat-burning, so the body tends to use glucose as its primary energy source. However, during physical activity, the body needs to preserve some glucose to help maintain brain function.
The new findings suggest that the PPARD pathway aids this process, and it helps to explain why some athletes "hit the wall" - their brain is not getting enough glucose.
"This study suggests that burning fat is less a driver of endurance than a compensatory mechanism to conserve glucose," says co-senior author Michael Downes, of the Gene Expression Laboratory at Salk. "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."
Reaping the rewards of exercise 'without the physical effort'
While further studies are needed to determine the safety and efficacy of PPARD activation in humans, the researchers believe that their findings could pave the way for drugs that can mimic the effects of physical activity.
"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."
First author Weiwei Fan, Gene Expression Laboratory, Salk Institute
The researchers are well aware that their findings could be exploited by athletes who wish to boost their aerobic endurance, but they say that they could also bring benefits for individuals who are unable to exercise, reducing their risk of chronic illnesses associated with lack of physical activity.
"Exercise is valuable for many different kinds of problems," says Evans. "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."