"Exercise in a pill."

That's how researchers are describing two drugs that apparently mimic the effects of physical exercise on the body, raising prospects of new treatments against diseases, new ways to cheat at sports, and new rationalizations for couch potatoes to stuff themselves at brunch.

In a series of startling experiments in mice, the drugs improved the ability of cells to burn fat and retain muscle mass, and they substantially prolonged endurance during exercise. Using one of the compounds for just a month, even sedentary, couch-potato mice improved their endurance running by a staggering 44%. Some mice that combined a month of exercise with the other drug bolstered their long-distance running by about 70% over untreated mice.

One of the drugs is already in late-stage human trials for other purposes, and the mouse experiments raise hopes for new strategies to protect people against obesity, diabetes and muscle-wasting diseases such as muscular dystrophy.

But underscoring the risks, one of the compounds has been withdrawn from human trials because of toxic side effects, and researchers said that the drugs could easily be abused by competitive athletes to enhance their performance. Researchers have already devised a test to detect them in blood and urine.

A spokesman for the World Anti-Doping Agency said in a written statement that, following policy, it wouldn't say when the test would go into use. But the statement noted that "a number of anti-doping organizations, including the International Olympic Committee, store doping control samples of their events for eight years for potential future retesting." A spokeswoman at GlaxoSmithKline, which developed one of the drugs, said that if athletes get their hands on the drug, "they won't be getting it from us."

The exercise-pill study, published Friday in the journal Cell, was conducted on mice, and it is possible that the drugs may show less benefit, or even none at all, when applied to humans. Still, the underlying genetic switches activated by the drugs appear to be the same in humans and mice.

The researchers examined how the drugs acted on the cellular and molecular level, but they also evaluated the simple ability of mice to run on a treadmill. Unlike humans who may suffer a motivational issue before exercise, "mice are very good at running as far as they can," said principal investigator Ronald Evans, a researcher at the Salk Institute for Biological Sciences, La Jolla, Calif., and the Howard Hughes Medical Institute. "When they get exhausted they just stop running. They can't run any more."

First, Dr. Evans and his team gave the mice a drug known as GW1516, which used to be under development by GlaxoSmithKline as a drug against dyslipidemia, a disorder affecting cholesterol. Side effects forced the company to scuttle it, a Glaxo representative said.

Still, the drug enabled mice to run for more than three hours, compared with less than two hours for untreated control mice. But this drug's effect occurred only when the mice also got regular exercise; sedentary mice got no benefit from the drug. "This is the no-pain, no-gain drug," said Dr. Evans.

Based on research into the genetic switches that control endurance muscle cells, Dr. Evans and his team decided to give the mice a second drug: AICAR, or acadesine, which was recently licensed by Schering-Plough Corp. and is in late-stage trials for the prevention of problems that can occur during coronary surgery. This drug enabled even sedentary mice to run longer, as if they were in good physical condition. "That is the true couch-potato experiment," Dr. Evans said.

Anabolic steroids, often abused by athletes, enhance the performance of fast-twitch muscle cells -- those that provide power and speed. The two drugs being researched are among the first compounds shown clearly to improve the slow-twitch muscle cells used in endurance activities. Whereas fast-twitch muscle cells burn sugar, slow-twitch cells primarily burn fat, which means they could help combat obesity. Previously, resveratrol, found in red wine, was shown to enable mice to run farther, but exactly how it works on slow-twitch muscles isn't clear. A person would also have to drink "hundreds of bottles" of wine to get enough resveratrol to improve athletic performance, said Dr. Evans.

Patients who are bedridden or wheelchair-bound "can't exercise, and this would give them some of the benefits," said Joseph Hornyak, associate professor of physical medicine and rehabilitation at the University of Michigan at Ann Arbor. But the pills would be unlikely to provide all the benefits of real exercise. "People who exercise have lower levels of depression and higher bone density," said Prof. Hornyak. "Whether or not this pill would confer those benefits, we don't know."

The broadest appeal of the drugs may be for gain-without-pain preeners who would sooner pop a pill than strain themselves or a hamstring. Such "off-label" use is "not only a real possibility but a probability," said Dr. Evans.

If the medicine "results in better-looking people, that would be good," said comedian Fran Lebowitz. "All I have right now is a vision of slim, vain, lazy mice."

Write to Mark Schoofs at mark.schoofs@wsj.com and Ron Winslow at ron.winslow@wsj.com

Corrections & Amplifications- AICAR, or acadesine, is injected. This Currents article Friday about two experimental medicines that mimic the effects of endurance exercise in mice incorrectly referred to AICAR as a pill.

RESOURCE/SOURCE: http://online.wsj.com/public/article/SB121751115798400781-E9ZVWh5UWyU4_ayM1_h7u_1d3nA_20080831.html?mod=tff_main_tff_top on Friday, August 1, 2008.