Drugs mimic exercise benefits in mice

Affect gene for muscles, metabolism

Four years ago, Ronald M. Evans used genetic engineering to create super mice that ran twice as far as normal rodents.

In a discovery that reads like a couch potato's fantasy, California researchers report that they have pinpointed two drugs that mimic many of the beneficial effects of exercise. The compounds increase fat-burning ability and dramatically boost endurance - tantalizing possibilities for athletes and even weekend warriors who one day might be able to short-cut workouts by popping a pill.

While the drugs have only been shown to work in mice and aren't on the market, researchers are worried competitive athletes might get a laboratory to reproduce the chemicals. With the Olympics starting in just over a week, the scientists have already worked with the World Anti-Doping Agency to develop a test that screens athletes' blood and urine for even the tiniest traces of the two substances.

Their study, published online yesterday in the journal Cell, showed that the drugs can increase the activity of a master gene that controls metabolism and muscle fibers, reprogramming muscles to burn fat and produce dramatically more endurance.

Four years ago, Ronald M. Evans, a Howard Hughes Medical Institute investigator, used genetic engineering to create super mice that ran twice as far as normal rodents and ate ravenously without gaining weight.

"That led us to wonder if we could flip this same [genetic] switch with a drug," said Evans, who has been besieged by coaches and athletes looking for a competitive edge since his earlier mice studies.

Now, Evans and his colleagues at the Salk Institute in California think they have found the key. Their new results indicate that animals receiving one of the two drugs ran 80 percent farther than those that did not.

The drugs were initially developed for other uses, and Evans believes they could eventually be used to treat obesity and diabetes and help frail people who are unable to exercise.

Other researchers not involved in the study describe it as a breakthrough, but they also raised concerns about the drugs' safety and effectiveness in humans.

"While an almost Pavlovian reflex is: 'Can I get on the waiting list or on the clinical trial?', it is still quite the waiting game until the approach as a whole, and the specific drugs in question, can be proven safe in patients and consumers," molecular biologist Yaacov Barak, of the Jackson Laboratory in Bar Harbor, Maine, said in an e-mail interview.

Noting serious side effects that prompted federal regulators to pull diet drugs such as Fen-Phen and Ephedra off the market, Barak said scientists still do not know enough about the long-term effects of stimulating such a key gene, known as PPAR-delta, in humans.

One of the drugs Evans' team used is called GW1516. In monkeys it has shown promise in increasing levels of HDL, the good cholesterol. They gave GW1516 to a group of young mice for five weeks, noted encouraging genetic and muscle changes, and then set the animals loose on a treadmill.

There was no athletic improvement.

Puzzled, the researchers realized muscles needed something else to reprogram them. Realizing exercise changes muscles, they returned to the treadmill and subjected two groups of mice to 30 minutes of slow daily exercise for a month. One group received the drug, the other did not.

At the end, both groups showed improved performance, but there was "an explosion of activity" among the GW1516 bunch, Evans said, with those mice running about an hour and a half longer on the treadmill and 80 percent farther than their non-drugged counterparts. Unlike steroids that build muscles, or blood doping that brings more oxygen to the blood, the GW1516 triggered genetic changes that altered the animals' metabolism.

Intrigued, the researchers next studied the elaborate chain of events unleashed in the body during exercise to understand how that process kick-started the GW1516. They zeroed in on an enzyme activated during exercise that helps lower blood sugar and aids cells to burn fat and respond to insulin.

Then they searched for a drug that might turn on the enzyme without exercise. They chose AICAR, a substance scientists have studied for more than a decade in diabetes and heart disease trials. They gave one group of "couch potato" mice the drug for a month, and then put them on a treadmill and discovered, without any prior exercise, they could run 44 percent longer than untreated mice.

"By genetically tuning up the muscle [with this drug] you can dramatically bypass exercise," said Evans.

So far, he said, the researchers have noticed no side effects from either drug in mice. Much more testing needs to be done to show the drugs are safe, however.

Translating the correct dosages from mice to man could be tricky, said Chih-Hao Lee, an assistant professor of genetics at the Harvard School of Public Health. He said the dosages given to mice in the month-long trials would correspond to about three years in humans. "How long will you have to take the drug to show benefits in humans?" he said.

AICAR, one of the two drugs Evans used, is being studied in humans now to help control bleeding during open heart surgery. A spokesman for Schering-Plough, the company that has licensed it, declined to comment on Evans' work.

The World Anti-Doping Agency, a Canadian-based organization that develops policies for many sports and the Olympics, acknowledged in a statement that it has worked with Evans to track the chemicals in athletes. It declined to say whether the test would be used during the Olympics, but noted that specimens from athletes are stored for eight years for retesting as science advances.

"Thanks to the much appreciated cooperation of Ron Evans and his team at the Salk Institute, WADA received key information in advance in order to develop and implement ways to detect these molecules," the statement said.

Kay Lazar can be reached at klazar@globe.com.