The elusive exercise pill just took a step closer to becoming a reality. Scientists have found that two compounds can boost endurance in mice by changing the metabolic properties of the animals’ muscle. One of the drugs appears to mimic some of the benefits of exercise even in sedentary mice. But the most dramatic benefit comes from combining one of the drugs with exercise, enabling mice to run 60 to 75 percent longer.

In previous research, Ronald Evans and his colleagues from the Salk Institute, in La Jolla, CA, genetically engineered so-called marathon mice, animals with double the running endurance of their normal counterparts. The mice gained their superstamina with a boost in the expression of a gene called PPARδ. Evans’s team has now found a way to trigger the same effect using drugs, a development that could potentially make the result applicable to humans.

In research published today in the journal Cell, the scientists tested two compounds that crank up the PPARδ pathway, with slightly different effects. One drug, which acts upstream of PPARδ, enhances running endurance by 44 percent. “It’s tricking the muscle into believing it’s been exercised daily,” said Evans in a statement released by the Salk Institute. “It proves you can have a pharmacological equivalent to exercise.”

A drug that directly activates PPARδ was even more effective, but only when combined with exercise. It had no effect on sedentary mice, but it allowed active mice to run 60 to 75 percent longer. The drugs work differently than anabolic steroids or other muscle-building drugs currently in development, which increase muscle mass but not endurance.

If the findings hold true in humans, the drugs could provide a new way to induce the health benefits of exercise, especially in people who find it difficult but are most in need, such as those who are obese or at high risk of diabetes. “Why don’t people exercise when they know it’s good for them? Because it’s hard; you feel fatigued,” says William Evans, director of the Nutrition, Metabolism, and Exercise Laboratory at the University of Arkansas for Medical Sciences, in Little Rock. “Perhaps a product like this might help people who have a hard time initiating an exercise program.” William Evans was not involved in the research.

Muscle is made up of two types of fibers: fast-twitch fibers, which generate power and speed, and slow-twitch or fatigue-resistant fibers, responsible for endurance. Endurance training triggers genetic changes that shift muscle metabolism toward the slow-twitch type of muscle, which burns fat. (Fast-twitch fibers burn carbohydrates.)

The most effective treatment–the drug and exercise combination–seems to work by reprogramming muscle metabolism. Mice that ran and took the PPARδ-activator compound gained 38 percent more slow-twitch muscle fibers than their sedentary counterparts, which were comparable to control mice, and showed a unique pattern of gene expression that partially mimicked that of exercise. “It looks like they’ve been able to make fast muscle fibers act more like slow muscle fibers, which have a greater capacity to use fats as fuel,” says William Evans.

Scientists don’t yet know if the drugs will have the same effects in humans. (The PPARδ activator has been in clinical trials for obesity and cholesterol regulation, but results have not yet been released.) If the drugs are successful, William Evans says, these compounds might be most useful for someone “who needs to lose a lot of weight or who is at risk of diabetes. It may make doing regular submaximal endurance exercise seem easier to people who don’t do exercise.” However, he says, “if, as I suspect, people look at it as a substitute for exercise, that would be bad news indeed.”

With their endurance-enhancing properties, the compounds also have a high potential for abuse by athletes. Ronald Evans and his team are already working with the World Anti-Doping Agency to develop tests to detect one of the drugs. However, it’s unclear whether such drugs would boost performance in a well-conditioned long-distant runner. “Endurance runners already have 80 to 90 percent slow-twitch fibers,” says William Evans, who biopsied world-class endurance runners several years ago. “So if this drug makes fast-twitch fibers behave like slow-twitch fibers, it’s unclear if it would have any effects.”