Drugs turn 'couch potato' mice into long-distance runners

Just in time for the Olympics, scientists say they have discovered drugs that could cause the next athletic doping scandal.

In a study published today in the journal Cell1, scientists say they have found the first targeted drugs that boost endurance. They are already working with the World Anti-Doping Agency (WADA) to develop tests to expose would-be cheats who use the drugs.

The ultimate test of murine endurance.
Courtesy of the Salk Institute for Biological Studies

The scientists examined the effects of two compounds, called GW1516 and AICAR, on endurance in mice. When dosed with GW1516 and exercised on a treadmill every day for five weeks, the mice could run about 68% longer and 70% farther than mice that underwent the same training programme but didn't receive the drug, the scientists found. When given daily doses of AICAR, but no exercise training, another set of mice could run 23% longer and 44% farther than untreated mice.

The AICAR-treated mice also lost fat and had boosted expression of genes involved in making energy — similar to the beneficial effects induced by exercise, according to Ronald Evans of the Howard Hughes Medical Institute in La Jolla, California, who led the work.

The compound resveratrol, found in red wine, also boosts endurance in mice, but acts on many molecules and therefore has many other effects. Evans says his work is the first to target a specific molecular pathway to mimic the effects of endurance exercise. “We have discovered that there’s a switch that can be flipped to unlock a little bit more potential out of your muscles and give yourself a chance to be in a much more healthy state,” Evans says, calling the study “the true couch potato experiment”.

Feel the burn Evans’s group has found that the drugs work by stimulating certain enzymes that sense energy levels in cells.

AICAR, for instance, activates an enzyme that prompts the body to burn fats and sugars when energy levels are low. So by giving mice AICAR, “you’ve fooled the muscle into thinking you just did a huge amount of exercise, when all you really did is activate the enzyme that’s normally activated due to exercise,” says Lewis Cantley, a cancer and endocrinology researcher at Harvard Medical School in Boston, Massachusetts. “It’s really quite cute.”

Evans hopes that the drugs will be used to improve the health of people who can’t exercise, such as the bedridden or very obese. He contacted WADA about his findings, he says, because “we realized that as soon as the paper comes out there’s a good chance that athletes will start experimenting”.

All-new drugs of abuse Frédéric Donzé, a spokesman at WADA’s headquarters in Montreal, Canada, says the agency does not reveal when it rolls out new tests. But, he adds, “Thanks to the much appreciated cooperation of Ron Evans and his team, WADA received key information in advance in order to develop and implement ways to detect these molecules.” The agency stores samples for up to 8 years after they are taken, so the tests could be used retroactively to catch cheaters if they are not deployed in time for this year’s Olympics.

Neither of the drugs tested in Evans’ study have been approved for use in humans. GW1516 has been tested by the drug firm Ligand in San Diego, California, and UK-based GlaxoSmithKline in trials to cut levels of high-density lipoprotein, or ‘bad’ cholesterol. Meanwhile, the drug-maker Schering Plough of Kenilworth, New Jersey, is running phase III trials of AICAR (also known as acadesine) to treat ischaemic reperfusion, a complication that can develop after heart attacks.

However, other drugs that are already approved by regulators for human use act in similar ways to the two tested in the study. For instance, the diabetes drug metformin activates the same enzyme activated by AICAR. A similar drug, fenformin, is more potent than metformin, but is banned in the United States because of serious side effects in people with kidney problems.

As Cantley notes, endurance athletes such as long-distance runners will probably be the first to experiment with these and other related drugs. “This will fly through that community like crazy,” he says. “You’re going to get a new set of drugs of abuse.”

I don’t want something that designed for the mental aspect. I want something purely to ramp up my respiratory and muscular systems in a safe way.

Heck, if I know I’d have a sprint to do, and I anticipate it, I’d try to get my heart started by breathing deep and quickly. Just doing that made me tired.

I’m sick of it.

This study, it should be noted, was performed on a series of 10 vermincycles aka “rodent wheels” constructed out of passivated high-strength aircraft aluminum alloy machined to tolerances of +/- .0001 mm at a cost of $837,300.

So? Custom-built research equipment is never cheap and if you want accurate data, your equipment needs materials with appropriate properties and low tolerances.

In that case, I’ll be sure to check my tire inflation carefully, and to do that, I think I’ll need a $439,500. combination pressure gauge and interferometer, plus I will need to check the isotopis proportions of each of the nitrogen, oxygen, and argon contained within my tires, because those factors affect the angular velocity of the gases acting on the inside walls of the tires, as well as the balance of the cetifugal and centripedal forces acting on my 20” rims.

Only if you need to measure your car's performance mileage within milliliter. You'd also need to account (and preferably measure the effect of) other variables like ambient temperature, road structure, etc...

Funny thing: Many car manufacturers run these sorts of expensive tests when testing their products. They don't do these expensive tests for fun.

Another thing: Mice and rats are rather small creatures with small bodymass and minuscule muscles. A Few-milligram systemic flaw can easily skew the entire experiment...

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