Scientists say they've put exercise in a pill

Researchers experiment with a chemical compound that they say can produce the benefits of aerobic activity without the work.

Ronald Evans holds a vial of a drug that boosts the effects of exercise in mice. Evans works at the Salk Institute for Biological Studies in La Jolla, Calif.

In AICAR, scientists say they've found exercise in a pill

1:07 PM PDT, July 31, 2008

Scientists have discovered what could be the ultimate workout for couch potatoes: exercise in a pill.

In experiments on mice that did no exercise, the chemical compound, known as AICAR, allowed them to run 44% farther on a treadmill than those that did not receive the drug.


The drug appeared to change the physical composition of muscle, essentially transforming the tissue from sugar-burning fast-twitch fibers to fat-burning slow-twitch ones -- the same change that occurs in distance runners and cyclists through training.


"You're getting the benefits of exercise without having to do any work," said David Mangelsdorf, a pharmacologist at University of Texas Southwestern Medical Center in Dallas, who was not connected with the research.It is unknown if the drug has any benefit for athletes who actually work out -- or any human for that matter, since the research has so far only involved mice.


"The mouse doctors and cell biologists are of course quite enthusiastic about these things, but the human doctors are a little more reticent," said Dr. Benjamin Levine, a cardiologist who leads the Institute for Exercise and Environmental Medicine at Presbyterian Hospital of Dallas and who was not involved in the study.


The chemical pathways that transform muscle cells appear to be the same in mice and humans. But because their metabolisms are vastly different, nobody knows what dosage would be required to achieve an effect in people and whether it would be safe.


Nonetheless, lead researcher Ronald Evans, a molecular physiologist at the Salk Institute for Biological Studies in La Jolla, said he has already been contacted by dozens of athletes and overweight people who have heard about his research from previous lectures.


"Anything that could provide half of a quarter of one percent is attractive," said Dr. Don Catlin, a professor emeritus of molecular and medical pharmacology at UCLA and a top anti-doping expert. "The athlete who can find a way to get an edge is one up on his competitors."


One request came from a horse trainer he met on an airplane who was interested in trying it out on a thoroughbred, he said. Evans declined.


He said he has notified world anti-doping officials, who are now scrambling to implement a test for it before the Beijing Olympics start next week.The compound, which is naturally produced in tiny amounts in human muscle cells and has been studied for decades, is readily available through scientific supply companies.


One company was offering AICAR for $120 a gram. At that price, giving a person the drug in the same concentration as the mice would cost thousands of dollars a day.Evans predicted that in the wake of his study, published today in the journal Cell, the drug will "fly off the shelves."


The drug has been tested in humans for a variety of conditions related to the heart and repeatedly passed basic safety tests."It was found to be a quite safe drug, at least at the doses we were using," said chemist Paul Laikind, who patented the compound in the 1980s and began testing it as a means of preserving blood flow to the heart during surgery.


The compound is now owned by drug maker Schering-Plough Corp., which is trying to develop it as an intravenous infusion for the prevention of ischemia-reperfusion injury, a complication of bypass surgery.


With more research, scientists said, the drug's fat-burning properties could also help reduce weight, ward off diabetes, prevent heart disease and help bedridden patients become fit.The discovery of AICAR as a potential couch-potato exercise pill grew out of Evans' continuing research on creating super mice.


In 2004, he made headlines for engineering "marathon mice." By injecting a single gene into the nucleus of a fertilized egg, he created mice born with more efficient muscles, faster metabolisms and stronger hearts.Evans wanted to know if it was possible to achieve the same effect using a drug.


His team didn't start with AICAR, but another compound known as GW1516, which drug maker GlaxoSmithKline is trying to develop as a drug to raise levels of HDL, or good cholesterol. The drug is known to stimulate the production of a protein known as PPARd, which in turn activates the genes that boost endurance in muscle cells.


In sedentary mice, the drug had no effect on endurance. Only when the drug was combined with exercise did it give the mice an advantage. After five weeks of training, mice that got the drug were able to run for an average of three hours and 24 minutes, a 68% improvement over mice that received only training.


When the researchers dissected the test mice, they found that the number of high-efficiency muscle fibers had increased 29%.


"That's a huge increase," Evans said. "That's the kind of stuff that Lance Armstrong and endurance athletes aim for."The experiment might have ended there, but after Evans submitted the paper for publication last year, one academic reviewer wanted to know why the drug had transformed the fiber only with exercise.

The reviewer surmised that the answer could be found somewhere in the complex chain of chemical reactions that energize muscle cells during exercise.Evans decided to try AICAR because it closely resembles a nucleotide that prompts the production of an enzyme that activates the high-endurance genes.


To Evans' surprise, the experiment worked. When sedentary mice were fed the drug daily for four weeks, they were able to run an average of 547 meters on a treadmill, 44% farther than mice that had received a placebo.

The researchers now plan to test whether AICAR or GW1516 can increase endurance beyond what can be achieved by intensive training alone, a key question for athletes.


In the meantime, Evans said that his team has developed detection protocols for both compounds and their breakdown products and turned them over to the World Anti-Doping Assn. in Montreal.


He said it is unclear whether the tests will be in place for the Olympics.Frederic Donze, a spokesman for the association, said in an e-mail that the organization "does not indicate when it implements new detection means or methods."


But he added it is not crucial for the test to be in place now.


"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 and detection as anti-doping science advances," he said.

By Alan Zarembo - alan.zarembo@latimes.com