[biomed] [tt] Researchers Identify Drugs that Enhance Exercise Endurance | Science Blog

[Brian Atkins]

http://www.scienceblog.com/cms/researchers-identify-drugs-enhance-exercise-endurance-17039.html

Researchers have identified two drugs that mimic many of the physiological 
effects of exercise. The drugs increase the ability of cells to burn fat and are 
the first compounds that have been shown to enhance exercise endurance.

Both drugs can be given orally and work by genetically reprogramming muscle 
fibers so they use energy better and contract repeatedly without fatigue. In 
laboratory experiments, mice taking the drugs ran faster and longer than normal 
mice on treadmill tests. Animals that were given AICAR, one of the two drugs, 
ran 44 percent longer than untreated animals. The second compound, GW1516, had a 
more dramatic impact on endurance, but only when combined with exercise.

Ronald M. Evans, the Howard Hughes Medical Institute investigator who led the 
study, said drugs that mimic exercise could offer potent protection against 
obesity and related metabolic disorders. They could also help counter the 
effects of devastating muscle-wasting diseases like muscular dystrophy. Evans 
and his colleagues, who are at the Salk Institute for Biological Studies, 
published their findings on July 31, 2008, in an advance online publication in 
the journal Cell.

Concerned about the potential for abuse of the two performance-enhancing drugs, 
Evans has also developed a test to detect the substances in the blood and urine 
of athletes who may be looking for way to gain an edge on the competition.

In 2004, Evans and his colleagues genetically engineered mice that had altered 
muscle composition and enough physical endurance to run twice as far as normal 
mice. These “marathon mice” had an innate resistance to weight gain, even when 
fed a high-fat diet. “We made these mice and they had low blood sugar, they 
resisted weight gain, they had low fats in their blood. They were much healthier 
animals,” Evans said. “And when we put them on a treadmill, the engineered mice 
ran twice as far than normal mice - they transformed into remarkable runners.”

The scientists achieved these effects by modifying a gene called PPAR-delta, a 
master regulator of numerous genes. Evans and his colleagues showed that by 
enhancing PPAR-delta's activity, they had shifted the genetic network in muscle 
cells to favor burning fat over sugar as their energy source. But the effects 
seen in the marathon mice were caused by a genetic manipulation that was present 
in their bodies as their muscles were developing. Evans's group began to wonder 
whether they could duplicate these effects by turning on PPAR-delta in adult mice.

“We had shown that we could pre-program muscle using genetic engineering. If you 
express this gene while the muscle is being formed, you can increase the amount 
of non-fatiguing muscle fibers,” Evans says. “But what about reprogramming in an 
adult? When all the muscles are in place, can you give a drug that washes over 
the muscle for a few hours at a time and reprograms existing muscle fibers? 
That's a very different question.”

PPAR-delta has long been an attractive drug target because of its central role 
in metabolism, so Evans and his colleagues had no shortage of chemical compounds 
available to test. They began by testing a compound called GW1516. They treated 
young adult mice with the drug for five weeks. “We measured gene changes and the 
muscles looked like they were responding, so we knew the drug was working.”

Thus, while fully expecting the drug to dramatically increase endurance - Evans 
says, “There was no change at all in running performance. Nothing — not even a 
percent.”

Surprised by this spectacular failure, Evans and his colleagues decided to try a 
different approach, based on real-life experience. “If you're out of shape - and 
most of us are - and you want to change, you have to do some exercise. The way 
we reprogram muscle in adults is by training.”

So the scientists subjected two groups of mice — one that received the drug and 
one that did not — to interval training. The mice ran for 30 minutes on a slow 
treadmill five days a week for a total of four weeks. At the end of the training 
period, all of the mice - regardless of whether they had received GW1516 - had 
improved their performance. Those that had received GW1516, however, ran 68 
percent longer than those that had only done the exercise training. “The 
dramatic effect of the drug was stunning,” Evans said.

The scientists were intrigued by this synergistic interaction and wanted to know 
how exercise allowed the drug to work. One possibility was an enzyme called AMP 
kinase (AMPK). 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.

Evans's team found that in addition to replenishing the cell's energy stores, 
AMPK also assists PPAR-delta in activating its gene targets. “It hops onto 
PPAR-delta in the nucleus and turbo-charges its transcriptional activity,” Evans 
explained. “We think AMPK activity is the secret to allowing PPAR-delta drugs to 
work.”

The critical question was whether chemical activation of AMPK is sufficient to 
trick the muscle into thinking it has been exercised. The second drug, called 
AICAR, enabled them to answer that question. AICAR mimics AMP, Evans said, “so 
muscle thinks it's burning fat.” The researchers were encouraged when they found 
that when they gave the drug to mice, they activated many of the genes in muscle 
that are turned on by exercise.

After four weeks of treatment with AICAR, Evans and his colleagues once again 
challenged sedentary mice to run on the treadmill. They found that mice that had 
received AICAR were able to run 44 percent longer than untreated mice. “This is 
a drug that is like pharmacological exercise,” Evans says. “After four weeks of 
receiving the drug, the mice were behaving as if they'd been exercised.” In 
fact, he says, those that got the drug actually ran longer and further than 
animals that received exercise training.

The animals receiving AICAR improved their running performance and their ability 
to burn fat. None of these effects, however, were as strong as they were in the 
animals that received both exercise and activation of PPAR-delta via GW1516.

Evans said this indicates that the benefits are likely due to collaboration 
between cells' AMPK and PPAR-delta signaling pathways. The team's genetic 
analyses supported this hypothesis; they found that the drugs alone activated a 
subset of exercise-induced genes, but activating both pathways (by combining 
GW1516 with exercise) activated a larger group of genes. Many of those genes 
regulate metabolism and muscle remodeling. Evans and his colleagues called this 
the “endurance gene signature.”

Like exercise, the two drugs trigger a variety of changes that contribute to 
muscles cells' improved endurance and ability to burn fat. These changes include 
an increase in mitochondria, the structures responsible for producing energy; a 
shift in metabolism that takes advantage of lipids as an energy source; and an 
increase in blood flow, which enables the steady delivery of fat to burn. While 
the scientists only examined the drugs' effects on muscle cells in this study, 
Evans says it is likely that they confer benefits on other systems impacted by 
exercise, such as the heart and lungs.

Based on his group's findings, Evans is optimistic about using small molecules 
that mimic exercise to treat and prevent a variety of common conditions. For 
example, the way in which the drugs transformed the muscle fibers of mice 
suggests they might help reverse the muscle frailty associated with aging or 
diseases like muscular dystrophy. “We have now created the potential for a 
really simple intervention in an area of major health problems for which there 
is no intervention,” he says.

More broadly, the drugs could offer the benefits of exercise to people who do 
not get enough. “Almost no one gets the recommended 40 minutes to an hour per 
day of exercise,” he says. “For this group of people, if there was a way to 
mimic exercise, it would make the quality of exercise that they do much more 
efficient. This might be enough to move people out of the `danger zone' toward a 
lower risk, healthier set point. By intervening early, you may forestall the 
emergence of more serious problems.”

Evans expects these types of drugs will be attractive to a variety of 
individuals. “If you like exercise, you like the idea of getting more bang for 
your buck,” he says of GW1516. “If you don't like exercise, you love the idea of 
getting the benefits from a pill,” as with AICAR. So, while Evans sees 
tremendous opportunities for health benefits from drugs that mimic exercise, he 
also sees serious potential for abuse.

“Drugs that improve health are not only going to be used by people who have 
medical problems. They may also be used by people who are healthy - or by 
athletes who want an edge,” said Evans. He noted that the sports world has long 
been aware of his lab's work demonstrating a link between PPAR-delta and 
endurance. What's more, GW1516 has a relatively simple chemical structure and 
can be synthesized easily. Evans anticipates that athletes will seek their own 
sources of the drug - if they haven't already.

Concerned about the potential for abuse, Evans thought it was important to 
develop a test that could detect whether the drug was being used as a 
performance-enhancing substance. With HHMI support, his group has created a 
highly sensitive test that uses mass spectrometry to detect the two drugs and 
their metabolic by-products in the blood or urine. While the test is very 
reliable in mice, Evans says that further analyses are needed to ensure that it 
is accurate in humans. Evans, HHMI and the World Anti-Doping Agency are now 
working to certify the detection system and make it available in time to 
retroactively test athletes who compete in the 2008 Olympics.

-- 
Brian Atkins
Singularity Institute for Artificial Intelligence
http://www.singinst.org/
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