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Evans's group has delved into a more practical way of toying with PPARdelta. In earlier studies, the animals' muscles luxuriated in activated PPARdelta their whole lives because they had been genetically altered from birth. Could the same feat be reproduced in normal mice not carrying the long-distance-running gene? Would tinkering with PPARdelta in adulthood boost performance in the absence of exercise? Evans and his team have probed these questions in new work.
Instead of altering the genome of mice, they gave the mice a drug that switches on PPARdelta. (The drug is currently being tested as a cholesterol-lowering drug in human studies.) Unexpectedly, when the researchers put the animals on the treadmill after a steady diet of the PPARdelta-activating drug, they ran no farther than normal mice. "By itself, it's not an exercise pill," concludes Evans. "Obviously, changing adult muscle with a drug is a very different undertaking than creating a permanent change in its genes."
Still, Evans remains hopeful. To better understand why the pill didn't work on its own, he and his team determined which genes cranked up in animals that took the drug and in animals that exercised. While half the genes overlapped, exercise triggered a set of genes that the pill did not. Evans thinks that, even though the drug apparently missed some key elements along the way, the pill clearly shows promise.
Given the gene overlap, Evans now wonders whether the pill might augment exercise, if not replace it. To address this question, he and his colleagues are putting two groups of mouse runners in a head-to-head training program. One group will run several days a week at a steady but not all-out effort—the equivalent of a brisk middistance run. The other group will get the same training but will also receive the PPARdelta pill. "With the exact same training, we hope the mice with the drug will run longer," says Evans. Indeed, preliminary studies look very promising.
Even if it works, the pill shouldn't put any gyms out of business. "You can't get away with doing nothing," says Evans. "Our idea is that the pill could make exercise more beneficial by revving up metabolism." It might also give overweight people an endurance boost to get through those painful first workouts.
By contrast, "a lot of the drugs being developed try to alter appetite, but it is very difficult to change appetite," Evans adds. Plus a side effect of changing appetite can sabotage the weight-loss strategy. "Your metabolism slows down during a diet, which makes it even harder to lose weight and easier to gain weight." A PPARdelta drug "does not require the willful reduction in eating," he points out, although exercise is still a must.
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