Pill Turns Couch Potatoes into Lean Exercise Machines

A new study describes two signaling pathways that are activated in response to exercise, converging to dramatically increase physical endurance, and oral drugs with the same effect.

Researchers at the Salk Institute for Biological Studies (La Jolla, CA, USA), working with genetically engineered mice, first discovered that permanently activating a genetic switch known as peroxisome proliferator-activated receptor (PPAR) delta turned mice into untiring marathon runners. In addition to their super-endurance, the altered mice were resistant to weight gain, even when fed a high-fat diet that caused obesity in ordinary mice. Insulin response also improved, lowering levels of circulating glucose. However, when an investigational drug (identified as GW1516) was fed to laboratory mice over a period of four weeks, the researchers were surprised to find that although the expected benefits of lowered fatty acids and blood glucose levels were achieved, there was no effect on exercise performance. However, when the mice treated with GW1516 were put on a regular exercise regimen, endurance increase by 77% and the portion of "non-fatiguing” muscle fibers rose by 38%. The dramatic result gave rise to a vexing question: Why is exercise so important?

The researchers knew that exercise depletes Adenosine triphosphate (ATP), the energy currency of the cell. In times of high demand, ATP releases all its energy and forms Adenosine monosphate (AMP); rising AMP levels alert AMPK (a metabolic master regulator), telling the cell it is "running on empty” and increasing the production of ATP. This led the researchers to consider whether AMPK activation was the critical trigger that allowed PPAR delta to work. The researchers therefore fed untrained mice AICAR, a synthetic AMP analog that directly activates AMPK. After only four weeks and without any prior training, the treated mice ran 44% longer on a treadmill than untreated, untrained mice. The study was reported in the August 8, 2008, edition of the journal Cell.

"It essentially puts a turbo charge on PPAR delta, which explains why exercise is so important,” said senior author Ronald Evans, Ph.D., a professor in the gene expression laboratory.

The researchers claim that the results demonstrate that the AMPK-PPAR delta pathway can be targeted by orally active drugs to enhance training adaptation, or even to increase endurance without exercise. Professor Evans has therefore developed a test that can readily detect GW1516 and its metabolites as well as AICAR in blood and urine, and is already working with officials at the World Anti-Doping Association (WADA), in an attempt to have a test ready for athletes in the 2008 Summer Olympics held during August in Beijing (China).

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Salk Institute for Biological Studies