01 Aug 2008

Exercise in a pill?

Researchers who genetically engineered "marathon mice" that could run for hours have found two drugs that can mimic the effects - and they have already developed a test for the drugs in case athletes try to cheat with them.

The drugs reproduce many of the biological benefits of exercise, helping cells burn fat better and boosting endurance, said Ronald Evans, a Howard Hughes Medical Institute researcher at the Salk Institute for Biological Studies in California.

One of the pills may some day help people enhance their exercise or training, while the other might be more suited for couch potatoes who need to kick-start themselves, Evans and colleagues reported in the journal Cell.

"If you like exercise, you like the idea of getting more bang for your buck," Evans said in a statement. "If you don't like exercise, you love the idea of getting the benefits from a pill."

Astonishing results
In 2004, Evans and his colleagues genetically manipulated a gene in the mice called PPAR-delta, a master regulator of different genes. The genetically engineered mice could run twice as far as normal mice and stayed lean even when fed a high-fat diet.

The next step was to find a drug that might mimic these effects.

Evans tested a compound called GW1516, one of a family of compounds that researchers are looking at as obesity and diabetes drugs. But even though it affected the genes of the mice, it did not affect their metabolism. "There was no change at all in running performance. Nothing - not even a percent," Evans said in a statement.

Mimicking life
Then the researchers thought about what happens in real life.

"If you're out of shape - and most of us are - and you want to change, you have to do some exercise. The way we reprogram muscle in adults is by training."

So they trained the mice while some were on the drug and others were not.

All the mice became more athletic, but those given GW1516 ran 68 percent longer than those that had only done the exercise training. "The dramatic effect of the drug was stunning," Evans said.

Help for muscle-wasting diseases?
But that does not help people who might have muscle-wasting diseases, fatigue, or who are too overweight to exercise.

They went back to see if there was a different way to affect PPAR-delta. One compound that is well understood already is AMP-activate protein kinase or AMPK, "a master regulator of cellular and organismal metabolism", they wrote.

"We think AMPK activity is the secret to allowing PPAR-delta drugs to work," Evans said.

A drug called AICAR mimics AMP, Evans said, "so muscle thinks it's burning fat."

Mice given AICAR ran 44 percent longer than untreated animals, the researchers found.

"This is a drug that is like pharmacological exercise," Evans says. "After four weeks of receiving the drug, the mice were behaving as if they'd been exercised."

Treated mice could outrun mice given traditional exercise training, Evans said.

"Almost no one gets the recommended 40 minutes to an hour per day of exercise," Evans said. "For this group of people, if there was a way to mimic exercise, it would make the quality of exercise that they do much more efficient."

Pill not available commercially yet
The pills are only available experimentally now and Evans is not working with any drug company. But GW1516 has a relatively simple chemical structure and can be synthesized easily, Evans said.

His team created a mass spectrometry test to detect the two drugs and their metabolic by-products in the blood or urine. They are working with the World Anti-Doping Agency to develop the test, perhaps in time to retroactively test 2008 Olympic athletes. - (Maggie Fox/Reuters Health)