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This series of studies and the Mighty Mouse study, taken together, demonstrate that strength training and aerobic training are tremendously helpful in making and keeping us lean, fit, and healthy.      

Drugs Produce Marathon Mice—With Exercise (and Without)

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Creatine on Steroids

A few months back I wrote about a mouse study where conversion of slow-twitch endurance muscle fibers to fast-twitch strength fibers transformed obese mice into lean and muscular “Mighty Mouse” types. Enduring, fat mice became lean and powerful sprinters or weight lifters. This was accomplished without exercise and no change in diet.

The point was that metabolically active fast fibers burn calories without an increase in physical activity, suggesting that strength training may be as effective as endurance training for losing fat and controlling weight—perhaps more effective. (See article 207 in our Strength Training category)

Now we have new mouse studies going in the opposite direction. Drugs transformed sugar-burning fast fibers into fat-burning slow fibers, the same change that occurs in marathon runners and cyclists through training. The transformed mice were able to run 44% farther on a treadmill without exercise, and 70% farther with interval training.

The two drugs involved have potential for fat burning and weight control, say the researchers, along with possible health benefits for people who are bedridden or unable to do much exercise. (They also note the opportunity for abuse by athletes.)

Interestingly, a central action of the drugs is production of ATP for the cells to burn—the same benefit provided by creatine. Creatine supplementation helps replenish ATP, a chemical which is the immediate source of energy for all muscle contractions. The more creatine in the muscle, the more times ATP can be quickly regenerated. (For more about creatine, see article 7 in our Diet & Nutrition category.)

The gene based action of the drugs is more powerful than creatine, however. Think creatine on steroids.

The latest study is reported in the August 8, 2008, issue of the research journal Cell.

Both drugs tap into the molecular mechanisms that “reprogram” muscle genes in response to exercise. They trick the muscle into believing it’s been exercising, explained Ronald M. Evans, who led the study. (He's a researcher at the Salk Institute for Biological Sciences and Howard Hughes Medical Institute.) The drugs boost the activity of a master gene called PPARd, which is known to control other genes important to muscle metabolism.

Evans and his colleagues began by giving mice a PPARd enhancing drug known as GW1516 for five weeks. They hoped that would reprogram their muscles for endurance. “It was a spectacular failure.” Evans said. “[It] had no impact on running ability” even though there were changes in muscle gene activity. Something was missing.

So they tried again—adding exercise. That did it.

Two groups of mice were put on a regimen of interval training. (Mice can't be persuaded to lift weights, but they are willing to run on little treadmills.) Both groups ran on a treadmill for 30 minutes five days a week for four weeks. One group got GW1516 and the other didn’t. The group receiving the drug increased their running time by 68 percent and their running distance by 70 percent over the other trained mice.

Now it really gets interesting.

Evans and his team were still looking for the magic pill that would work without exercise. They decided to try another drug called AICAR, or acadesine. It worked—almost as well as GW1516 and exercise combined.

Four weeks of AICAR allowed the mice to run 44% farther—without exercise. After four weeks on the drug, the mice were behaving as if they’d been exercising, Evans said. In fact, those that got the drug actually ran longer than untreated mice who exercised.

“The animals receiving AICAR improved their running performance and their ability to burn fat,” reported Howard Hughes Medical Institute (HHMI) Research News. “None of these effects, however, were as strong as they were in animals that received both exercise and activation of PPAR-delta via GW1516.” Again, mice taking GW1516—and exercising—ran 70% farther than other trained mice.

What does exercise add? And what’s the role of ATP?

Exercise activates AMPK, an enzyme which triggers the release of ATP for muscle cells to burn. “We think AMPK activity is the secret to allowing PPAR-delta drugs to work,” Ronald Evans explained. That’s the bottom line, the short answer.

Here are the technical details from HHMI News: “During exercise, cells burn ATP as their primary source of energy. In the process, they create a by-product called AMP. When cells sense the presence of AMP, they activate AMPK. Activation of AMPK creates more ATP for the cell to burn. AMPK also triggers changes that lower blood sugar, sensitize cells to insulin, enable cells to burn more fat, suppress inflammation, and otherwise influence metabolic pathways. This is one reason that exercise is so beneficial.” (Emphasis mine.)

What Does This Mean to You?

Don’t burn your gym membership card or throw away you running flats just yet.

First, we don’t know if the ‘exercise pills’ will work on humans. If they do—Evans says GW1516 has a relatively simple chemical structure that can be easily synthesized—the pills would be unlikely to provide all the benefits of real exercise.

Patients who are bedridden or wheelchair-bound “can’t exercise, and this would give them some of the benefits,” said Professor Joseph Hornyak, an expert on rehabilitative medicine at the University of Michigan at Ann Arbor. “People who exercise have lower levels of depression and higher bone density,” he noted. (The Wall Street Journal, August 1, 2008)

On the other end of the spectrum, Dr. Evans says it’s not certain that athletes could get a boost from the drugs. The effects in mice might not work as well in highly trained people who may be “pushing the limits” already.

Evans is clearly hopeful, however. For example, he and his team say in the study that the drugs have "therapeutic potential in treating certain muscle diseases such as wasting and frailty as well as obesity where exercise is known to be beneficial."

More broadly, the drugs could help people who don’t get enough exercise. Evans says: Almost no one gets the recommended 40 minutes a day. For this group of people, if there was a way to mimic exercise, it would make the quality of exercise that much more efficient. This might be enough to move people out of the “danger zone” toward a lower risk, healthier set point.

A final note of caution from The Wall Street Journal: GW1516 was once under development by GlaxoSmithKline for a disorder affecting cholesterol and had to be dropped because of adverse side effects.

Whatever the outcome for humans, the take home message is very positive. This series of studies and the Mighty Mouse study, taken together, demonstrate that strength training and aerobic training are tremendously helpful in making and keeping us lean, fit, and healthy.      

For more details and to see the mice running on little treadmills, visit HHMI News: http://www.hhmi.org/news/evans20080731.html 

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