Evans and his team used a genetic trick to flip the PPARdelta switch to a permanently "on" position by affixing it to another gene-prodding protein; then they bred mice that produced this modified PPARdelta in muscle. As the team reported in October 2004 in Public Library of Science (PLoS) Biology, these animals looked like they'd done some serious distance training, even though they weren't on an exercise regime. The mice possessed an abnormally high percentage of slow-twitch fibers; they had more mitochondria and more of a protein that triggers contractions in slow-twitch muscles.

Next, the researchers subjected the animals to a stress test. They put them on a treadmill, gradually cranked up the speed, and timed how long it took the rodents to poop out. Control animals exhausted themselves in about 90 minutes, but the marathon mice with juiced-up PPARdelta scrambled for an extra hour and nearly twice the distance. They showed other signs of exercise benefit as well: they dined on a high-fat diet without gaining nearly as much weight as the control animals did, and they demonstrated increased blood flow. "Exercise causes a whole-body change, increasing metabolism, lowering blood sugar, improving response to insulin, and protecting against weight gain," says Evans. "These animals enjoy all those benefits."

Other findings support the idea that genetic changes can produce high-performance animals. Harvard Medical School's Bruce M. Spiegelman, a member of HHMI's Scientific Review Board who has collaborated with Evans on other projects, generated his own team of endurance athletes as part of his studies of PGC-1alpha and PGC-1beta. These so-called coactivator proteins link up with proteins similar to PPARs and help them turn on genes.

		View Movie By boosting the PPARdelta gene, HHMI investigator Ron Evans creates a mouse that goes the distance. Evans hopes to one day formulate a pill for humans that will mimic this same effect. HHMI BioInteractive

The PGC-1s prod cells to make more mitochondria and turn on oxygen-utilizing metabolism. Muscles forced to produce PGC-1alpha turn into slow-twitch muscles, Spiegelman's team found. They also found that turning on PGC-1beta in muscles alters muscle complement—but in a different way. Animals with PGC-1beta harbored more of an unusual, in-between muscle type: fast-twitch but, like slow-twitch, with lots of mitochondria and active oxidative metabolism.

Because these animals had a greater capacity to burn oxygen in their muscles, Spiegelman wondered if they would perform better on a treadmill. They did: PGC-1beta mice outran normal animals by 25 percent. It's not clear yet which mice to bet on—Spiegelman's rodents didn't run as long as Evans's PPARdelta mice, but Spiegelman's mice ran faster than those in Evans's experiments.

Spiegelman is investigating whether boosting PGC-1 pathways helps fight conditions in which people lose muscle, such as muscular dystrophy and muscle wasting. In addition, PGC-1s might protect against diabetes.

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