Saturday August 2, 2008 (foodconsumer.org) -- Two drugs may enhance exercise endurance in humans and potentially offer other benefits of exercise as well, according to a new study published on July 31, 2008, in an advance online publication in the journal Cell.

The study led by Howard Hughes Medical Institute (HHMI) researchers at the Salk Institute for Biological Studies showed mice treated with the drugs ran faster and longer than normal mice on treadmill tests.

Ronald M. Evans and colleagues said the drugs generate many of the physiological effects of exercise by genetically reprogramming muscle fibers in a way that the muscle uses energy better and can contract repeatedly without fatigue.

In laboratory experiments, mice orally given one drug called AICAR ran 44 percent longer than the untreated and mice when treated with another drug GW1516 had a more drastic effect on endurance, but only when the animals also received exercise training.

Evans said these drugs could effectively protect against obesity and related metabolic disorders. Somehow, they can turn on genes such that fat is preferably burned over sugar.   They could also fight devastating muscle-wasting diseases like muscular dystrophy.

The finding of the drugs started with some genetic research on mice.   In 2004, Evans and team genetically engineered mice that had altered muscle composition and found the animals had better physical endurance and were able to run twice as far as normal mice.

The genetically altered mice also had an innate resistance to weight gain even if fed a high fat diet. This is because the mice had modified a gene called PPAR-delta, a master regulator of numerous genes.   Enhanced PPAR-delta activity shifted the genetic network in muscle cells to favor burning fat over sugar as their energy source.

The results prompted the researchers to wonder if a drug could be used to turn on PPAR-delta in adult mice to have the same effects observed in the genetically engineered mice.

In the current study, Evans and colleagues treated adult mice with GW1516 for five weeks and the animals increased their endurance, but not running performance.   However, the mice given the drug and receiving exercise training for 30 minutes on a slow treadmill five days a week for a total of four weeks were able to run 68 percent longer than those that received exercise training, but no drug.

The researchers explained during exercise, muscle cells uses energy in the form of ATP and produce AMP, which triggers AMP kinase (AMPK) to produce more ATP for the cells to burn. They found AMPK also assist PPAR-delta to activate its gene targets. Evans explained PPAR-delta drugs affect AMPK activity.

In another experiment, the researchers found mice treated with the second drug AICAR run 44 percent longer than the untreated mice. But their running performance and their ability to burn fat were not as much as those observed in mice receiving both GW1516 and exercise training.

The benefits, according to the authors of the study, are likely due to collaboration between cells' AMPK and PPAR-delta signaling pathways.   Drugs alone activated a small set of exercise-induced genes while GW1516 with exercise activated a larger group of genes. Of these genes, many regulate metabolism and muscle remodeling.

Evans and colleagues said the drugs may offer benefits on other systems induced by exercise such as the heart and lungs.

The drugs can potentially be used to boost athletes’ performance. Evans has developed a test to detect the substances in the blood and urine of athletes and is now working with HHMI and the World Anti-Doping Agency to certify the detection system that is to be used to retroactively test athletes who compete in the 2008 Olympics.