Pill may boost endurance without exercise

By Kay Lazar, Globe Staff

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 may be able to short-cut workouts by popping a pill.

While the findings have only been shown in mice, and the drugs aren't even on the market yet, researchers are worried competitive athletes might find 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 today in the journal Cell, is the first to show that a master gene, known as PPAR-delta, that controls metabolism and muscle fibers can be reprogrammed, using only drugs, to burn fat and produce dramaticallly more exercise endurance.

Four years ago, Ronald M. Evans, a Howard Hughes Medical Institute investigator, used genetic tinkering 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 beseiged by coaches and athletes looking for a competitive edge ever since his earlier mice studies.

Now, Evans and his colleagues at the Salk Institute in California think they've found the key. Their new results indicate that animals receiving one of the two drugs ran 80 percent farther than ones who didn't.

Other researchers not involved in the study describe it as a breakthrough -- a first to show that drugs can reprogram a key gene to produce such dramatic endurance results. But they also raised several 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 don't know enough about the long-term effects of stimulating such a key gene in humans.

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

There was zero athletic improvement.

Puzzled, the researchers went back to the drawing board and realized muscles needed something else to unlock them. They figured exercise changes muscles, so they returned to the treadmill and subjected two groups of mice to 30 minutes of slow daily exercise for a month. One group also received the drug, the other didn't.

At the end, both groups improved performance, but there was "an explosion of activity" among the GW1516 bunch, Evans said, with the critters 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 then studied the elaborate chain of events unleashed in a body during exercise to understand how that process kick-started the GW1516. They zeroed in on AMPK, 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, then popped 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, who envisions both AICAR and GW1516 being used one day to help treat obesity, and boost overall cardiovascular fitness of patients with illnesses that leave them largely immobilized.

So far, he said, the researchers have noticed no ill side effects from the drugs in mice.

But translating the correct dosages from mice to man could be tricky, said Harvard School of Public Health assistant professor of genetics Chih-Hao Lee. He said the dosages given to mice in the month-long trials would correlate to about three years in humans.

"How long will you have to take the drug to show benefits in humans?" he said.

Lee Sweeney, chairman of physiology at the University of Pennsylvania School of Medicine, said it would likely be several years before Evans' mice breakthrough might be ready for clinical trials in humans.

"This has much greater promise for people than anything I am aware of," 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 licened it, declined comment on Evans' work.

The World Anti-Doping Agency, a Canadian-based organization that develops anti-doping policies for many sports and the Olympics, acknowledged in a written statement that it has worked with Evans to track the chemicals in athletes.

"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," it said.