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Can Exercise Come in a Pill?

A new drug works at the genetic level to change metabolism. But how effective is it? And is it safe?
 
 
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The timing couldn't have been better.

Salk Institute molecular biologist Ronald Evans debuted the results of a metabolic wonder drug that could mimic exercise, increase endurance and double fat-burning muscle just in time for the Olympics.

Exercisers could lose their treadmills, predicted health reporters, couch potatoes could lose their guilt -- and Olympic athletes could, well, cheat.

In an article in the journal Cell titled AMPK and PPAR Agonists Are Exercise Mimetics, Evans, a professor at the Howard Hughes Medical Institute, and 12 colleagues write that they have identified the "muscle endurance gene signature" and "molecular crosstalk" of two drugs that can actually reprogram muscle, in some cases, without exercise.

One drug, GW1516, developed but abandoned by GlaxoSmithKline because of toxic side effects, improved the endurance of mice that exercised by 77 percent and increased fat-burning "slow twitch" muscle fibers by 38 percent.

The other drug, AICAR, similar to the body's food energy nucleotide, adenosine monophosphate (AMP), and licensed by Schering-Plough Corp. for prevention of a surgical complication (at least until this month's stock bounce anticipating new "uses"), improved endurance in mice that did not exercise by 44 percent.

The changes seen in the lab were not "cosmetic," like the muscle building of steroids.

Rather, both drugs alter metabolism at the genetic level by acting upon PPAR-delta, a gene-controlling protein that produces the slow-twitch, fat-burning muscle fibers associated with endurance athletes, versus fast-twitch, sugar-burning fibers.

"This is not just a free lunch," Evans told the New York Times. "It's pushing your genome toward a more enhanced genetic tone that impacts metabolism and muscle function. So instead of inheriting a great set-point, you are using a drug to move your own genetics to a more activated metabolic state."

Happy Abs Forever?

While the promise of an Ectomorph Nation filled with lean, muscular bodies always opens Wall Street ears and wallets, the 46-year-old La Jolla, Calif.-based Salk Institute for Biological Sciences is not as enamored with lab-to-commercialization "technology transfer" as many pharma-supported institutions are.

Two-thirds of its approximately $90 million annual budget comes from federal funds -- the study published in Cell was supported by the Howard Hughes Medical Institute, the Hillblom Foundation and the National Institutes of Health -- and it penned its first partnership with a for-profit company, Paris-based Ipsen, only this year.

Nor is Evans likely a pharma favorite after publishing the results of a Salk mice study in Nature Medicine last year that found that long-term use of GlaxoSmithKline's Avandia in the treatment of type 2 diabetes "may cause osteoporosis due to both increased bone resorption and decreased bone formation." Oops.

And questions remain about the mice breakthroughs -- like what, exactly, the definition of exercise is.

Evans and the study's other authors report that sedentary mice treated with AICAR had a decreased ratio of fat mass to body weight and increased oxygen consumption. But, asks Frank Booth, a professor at the University of Missouri School of Medicine, did they have a slower resting heart rate and greater cardiac output (the amount of blood the heart pumps per minute) following exercise? Lower blood pressure and decreased arterial stiffness?

Besides increasing endurance in the mice trials, did the drugs show other exercise benefits? For example, were new blood vessels created to carry oxygen to new muscle cells, asks David L. Katz in the New Haven Register? Was red blood cell production increased in bone marrow? Were mood and hormone levels altered favorably?

Was the "exercise" even of the kind that builds strength needed by bedridden people and the elderly, or did it just mimic aerobic exercise, asks Eric Hoffman of the Children's National Medical Center in Washington, D.C., in an Associated Press article.

Humans would have to take AICAR and GW1516 for a long time to see results, other skeptics say. And by altering the expression of genes, the drugs could increase cancer risk or pose a threat of injury to the heart, like other colossal laboratory failures have.

Then there's the slippery slope of animal research.

Are results from genetically engineered animal "models" -- possibly electric-shocked or faced with drowning to "run" -- even applicable to humans?

"Extrapolation from rodent research to outcomes in people is notoriously uncertain and fraught with danger," writes Katz. "Basic science studies and animal experiments have resulted over the years in headlines about cures for cancer, a definitive obesity gene and effective AIDS vaccines, to name a few. None of these has yet to materialize, and early hyperbole in each case gave way to disappointment."

Even if these drugs do, in fact, work for humans, there is a question of prioritizing users.

Sure, the effortless exercise is intended for people with muscle-wasting diseases like diabetes and obesity. But if a feeder frenzy of Lance Armstrong and Angelina Jolie wannabes starts, and money and glamour kick in, those with the greatest need will not likely be at the front of the line.
Martha Rosenberg is a columnist and cartoonist who frequently writes about the impact of the pharmaceutical, food and gun industries on public health. A former medical copywriter, her work has appeared in the Boston Globe, San Francisco Chronicle, Los Angeles Times, Chicago Tribune, on the BBC and in the original National Lampoon.
 
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