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New Ways of Boosting Physical Endurance

Two Studies Make Genetically Engineered 'Marathon Mice'
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WebMD Health News

Aug. 24, 2004 -- While the world's elite athletes go for the gold at the Olympics in Athens, endurance records have been shattered on the other side of the globe. And although these unlikely "competitors" were lab mice, they may shed new light on the mechanics of physical endurance, metabolism, and weight.

In a pair of experiments in Southern California, researchers used genetics to create "marathon mice" that left normal mice in the dust in head-to-head endurance trials.

The tests were done by two separate research teams at the University of California San Diego and the Howard Hughes Medical Institute. The studies took different approaches using genetically altered mice.

University of California San Diego biology professor Randall Johnson, PhD, led one of the research teams. They bred mice without the "HIF-1" gene, which is needed to allow muscles to work when there is little oxygen available or when there is a shift from aerobic to anaerobic metabolism.

Most muscle activities are powered with oxygen or aerobic energy; this allows muscles to work at a consistent level of intensity. During the anaerobic process, muscles can work at a higher level of intensity by using other sources of fuel; this process takes over when there are low oxygen levels such as during a short or intense sprint.

The genetically altered mice showed greater endurance; they swam nearly 45 minutes longer and ran 10 minutes longer uphill on a treadmill than normal mice.

However, the normal mice won out in a downhill treadmill test. Running downhill apparently takes more anaerobic metabolism than the genetically altered mice could muster.

Unfortunately the marathon mice couldn't maintain their pace forever. After four days of exercise tests, their muscles were significantly more damaged and they couldn't keep up with normal mice at running or swimming.

"It's a double-edged sword," says Johnson in a news release.

The study findings could lead to identifying ways to help maximize muscle endurance and may help medical researchers understand genetic disorders such as McArdle's disease, which makes it hard to use anaerobic metabolism. McArdle's patients suffer from severe muscle pain and cramps during normal everyday activities because of abnormal muscle metabolism.

Another set of marathon mice were developed at the Howard Hughes Medical Institute in La Jolla, Calif. Researchers led by Ronald Evans altered a mouse gene to boost the activity of a protein called "PPAR-delta."

Enhancing PPAR-delta activity transformed the mice's muscles, increasing their "slow-twitch" muscle fibers and decreasing their "fast-twitch" muscle fibers. Slow-twitch muscle fibers are muscles that contain a large number of energy-converting machinery; this allows them to be fatigue resistant. These muscles are used during endurance exercise. Fast-twitch muscle fibers tire rapidly; they are used during rapid burst of energy or sprints.

The genetically altered mice ran about twice as long as the normal mice before tiring.

They also resisted weight gain, even when they ate a high-fat, high-calorie diet and were only as active as normal mice.

"The increased number of fat-burning muscle fibers appears by itself to be protective against a high-fat diet," says Evans, in a news release.

If drugs are developed to enhance PPAR-delta in humans, it could let people "increase their metabolism to burn more energy," says Evans.

Of course, even if science makes it possible, athletes would likely be banned from tweaking their genes to improve their physical endurance.

Both studies appear today in the online edition of the journal Public Library of Science Biology.

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