Exercise in a Pill

Move over, steroids. Take a hike, human growth hormone. If scientists are right, a simple pill can enhance and even mimic the beneficial effects of exercise. At least in mice. But some people may not be waiting for research to show that the compounds work in people as well. The scientist who discovered the drugs, which are a cinch for chemists to synthesize, believes they may already be in athletes’ equipment bags—since anti-doping agencies had no idea they should even be on the lookout for them.

The drugs, called AICAR and GW1516, work by genetically reprogramming muscle fibers. The result is that the fibers use energy more efficiently, allowing them to contract repeatedly without tiring. Mice given the drugs ran faster and—this is where marathoners should prick up their ears—44 percent longer on the treadmill than un-drugged mice without flagging, Ronald Evans, a Howard Hughes Medical Institute investigator at the Salk Institute for Biological Studies in La Jolla, and colleagues are reporting today in an advance online publication in the journal Cell. The drugs also retool the muscles, with the result that there are more slow-twitch fibers (the kind used for endurance exercises) and fewer fast-twitch fibers (which let you put on bursts of speed, as in a sprint).

The drugs differ in just how much you—by which I mean a mouse, of course—can get away with. GW1516 had a dramatic impact on endurance, but to get the benefit the mice had to exercise. AICAR, on the other hand, really does seem like the proverbial exercise in a pill: no exertion required.

The work builds on research that Evans reported in 2004, when he created genetically-engineered “marathon mice” that had altered muscle composition and enough physical endurance to run twice as far as normal mice. The genetic engineering basically flipped a switch so that a gene called PPAR-delta was permanently “on.” PPAR-delta is more prevalent in slow-twitch muscle fibers than in fast-twitch ones, so keeping the gene turned on “increase[d] the amount of non-fatiguing muscle fibers,” Evans said. The result was a mouse able to run up to twice the distance of a normal littermate without training.

Despite whisperings that genetic engineering will be the next Olympic doping scandal, it’s obviously easier to get the benefits of the marathon mouse through a pill rather than gene splicing. But this genetic switch was flipped when the animals were still embryos. That raised the question, “what about reprogramming in an adult?” Evans said. “When all the muscles are in place, can you give a drug that washes over the muscle for a few hours at a time and reprograms existing muscle fibers? That’s a very different question.”

And it’s the question the new study answers with a resounding “yes.” GW1516 acts in concert with exercise: Evans had two groups of mice run on a treadmill for 30 minutes five days a week for a total of four weeks. All of the mice, as expected, became more fit, able to run longer and faster than when they were couch potatoes. But the animals that also got GW1516 ran 68 percent longer than un-drugged mice. “The dramatic effect of the drug was stunning,” Evans said.

The second drug, AICAR, wowed them even more: even in the absence of exercise, it activated many of the genes in muscle that are turned on by exercise. After four weeks of swallowing the drug, mice were able to run 44 percent longer than un-drugged mice—despite never having set paw into the treadmill. “The mice were behaving as if they’d exercised,” said Evans. Even better, actually: mice on the drug ran longer and farther than mice that had dutifully taken to the treadmill every day. Who said life was fair?

Both drugs trigger a suite of changes that underlie the improved endurance. They increase the number of mitochondria (structures that produce energy) in muscle cells, and increase blood flow. Evans suspects there were also beneficial changes to the heart and lungs. That suggests that the drugs could give even sedentary people the benefits of exercise. “Almost no one gets the recommended 40 minutes to an hour per day of exercise,” Evans says. “If there was a way to mimic exercise, it would make the quality of exercise that they do much more efficient.”

And for people who already walk, jog or run? “If you like exercise, you like the idea of getting more bang for your buck,” which GW1516 can provide, he says. “If you don’t like exercise, you love the idea of getting the benefits from a pill,” as with AICAR.

Which brings us back to sports. Evans says that the sports world has known about his work on PPAR-delta since at least his creation of the marathon mouse in 2004. GW1516 has a relatively simple, easy-to-synthesize chemical structure. Evans has therefore developed a test based on mass spectrometry that can detect the drugs and their metabolic by-products in blood or urine. He knows the test works in mice; its accuracy in humans needs to be road-tested. But he, HHMI and the World Anti-Doping Agency are currently working to certify the test and make it available in time to test this year’s Olympians—but only retroactively: urine and blood samples will be stored and tested when the technique is ready for prime time.
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