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.)