While steroids can help build the bulky muscles that lend athletes and body builders power and speed, there hadn't been a drug capable of building the endurance needed to run a marathon or to ride a bike through the Alps. Now, there just might be, suggests a new study in mice reported in the journal Cell, a Cell Press publication.
The report shows that a drug developed for the treatment of metabolic disease, when taken in combination with exercise, gives mice the ability to run farther than exercise training alone can.
"When we gave the mice a small amount of daily exercise in the presence or not of the drug, all showed an increased ability to run. But those on the drug gained an additional hour," said Ronald Evans of the Salk Institute.
Moreover, they found, treatment with another compound endowed mice with greater endurance, even without the exercise. "It's tricking the muscle into 'believing' it's been exercised daily," Evans said. "It's basically the couch potato experiment, and it proves you can have a pharmacologic equivalent to exercise."
Both chemicals work by tapping into the molecular pathways that normally reprogram muscle in response to exercise. The findings could be a boon to those with health problems that make exercise difficult, he said. However, they also have a "high potential for abuse" by athletes, despite the fact that the effects seen in the mice may or may not work as well in highly trained individuals who may be "pushing the limits" already.
Skeletal muscle comes in two main types: bulky fast twitch muscles for power and speed and slender slow twitch muscles for endurance. Fast twitch muscles burn sugar that must be stored in the muscle itself while slow twitch muscle burns fat.
Earlier studies by Evans' team showed they could genetically engineer, or "pre-program" mice to produce more of the fat-burning slow twitch muscle fibers, turning them into "marathon mice" with nearly 100 percent greater running endurance as untrained adults. The key was ramping up activity of a gene in muscle called PPARd, known to control other genes important to skeletal muscle metabolism.
But could you re-program rather than pre-program the muscles of adult animals by simply giving a drug that acts on PPARd?
To find out, they gave mice an experimental drug, known only as GW1516, that increases the activity of PPARd. The drug is being tested for the treatment of metabolic disease, but Evans wanted to know what effects it might have on muscle.
"It was a spectacular failure," Evans said. "The drug by itself had no impact on running ability" even though their were changes in muscle gene activity.
Something was missing from the equation, so the researchers took a different tack. They gave the PPARd drug to mice that were undergoing exercise training. The same dose and duration of GW1516 treatment that previously failed to alter performance, when paired with four weeks of exercise training, increased the animals' running time by 68 percent and their running distance by 70 percent over trained mice given a placebo, they report.
The muscles of those mice also showed a unique "endurance gene signature," including patterns of gene activity not seen with either the drug or exercise alone. That pattern did bear a striking resemblance to the one seen years earlier in the genetically engineered marathon mice, they noted.
Since PPARd on its own wasn't enough, the researchers decided to try one more thing: a chemical known as AICAR that was known to act on a gene called AMPK. Evans group suspected AMPK might be the link between exercise and PPARd.
To their surprise, even in sedentary mice, four weeks of AICAR treatment alone induced metabolic genes and enhanced running endurance by 44 percent. "We were blown away that AICAR alone mimicked exercise—not to the same level but a healthy boost," Evans said.
"In this study, we revealed that synthetic PPARd activation and exercise or more importantly AMPK activation alone, provides a robust transcriptional cue that re-programs the skeletal muscle genome and dramatically enhances endurance," the researchers concluded. "We believe that the strategy of re-organizing the preset genetic imprint of muscle (as well as other tissues) using exercise mimetic drugs has therapeutic potential in treating certain muscle diseases such as wasting and frailty as well as obesity where exercise is known to be beneficial."
Given the potential for abuse by athletes set on winning at any cost, Evans said his group has already spoken to the World Anti-Doping Agency and is developing a test aimed at detecting use of the PPARd-boosting drug. That test won't be available in time for this summer's Olympic games, he said. It also wouldn't detect the use of AICAR, a chemical that is available but isn't an FDA-approved drug.
While the potential for important health benefits is substantial, "both [compounds] are very logical targets for athletic abuse, and we need to be aware of that," Evans said.
The researchers include Vihang A. Narkar, Salk Institute, La Jolla, CA; Michael Downes, Salk Institute, La Jolla, CA; Ruth T. Yu, Salk Institute, La Jolla, CA; Emi Embler, Salk Institute, La Jolla, CA; Yong-Xu Wang, University of Massachusetts Medical School, Worcester, MA; Ester Banayo, Howard Hughes Medical Institute, La Jolla, CA; Maria M. Mihaylova, Salk Institute, La Jolla, CA; Michael C. Nelson, Salk Institute, La Jolla, CA; Yuhua Zou, Salk Institute, La Jolla, CA; Henry Juguilon, Salk Institute, La Jolla, CA; Heonjoong Kang, Marine Biotechnology Laboratory, School of Earth and Environmental Sciences, Seoul National University, Seoul, South Korea; Reuben J. Shaw, Salk Institute, La Jolla, CA; and Ronald M. Evans, Salk Institute, La Jolla, CA, Howard Hughes Medical Institute, La Jolla, CA
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