Published online 23 August 2004 | Nature | doi:10.1038/news040823-2


Geneticists engineer marathon mice

Endurance animals point way to athletic enhancement.

Mice engineered to burn more fat rather than sugar could run twice as far as normal.Mice engineered to burn more fat rather than sugar could run twice as far as normal.© PhotoDisc

They can run like Haile Gebrselassie, but these champions are cheats. US scientists have genetically engineered two types of mice with exceptional athletic stamina, raising concerns that athletes might try to use similar strategies.

Marathon runners have far higher physical endurance than an average person does. One reason is that their muscles have a greater capacity to generate energy aerobically, using oxygen. This mechanism allows them to keep producing energy for long periods of time, as opposed to anaerobic activity, which powers short, explosive bursts, such as sprints.

Now two teams of scientists have hit upon molecules that might explain some of this muscular staying power. Ronald Evans of the Salk Institute for Biological Studies in San Diego, California, engineered mice to burn fat not sugar, and Randall Johnson of the University of California, San Diego, created mice that were less able to switch to anaerobic activity.

Aerobic boost

Evans and his team tweaked the genes of mice so that they permanently switched on production of a protein called PPARdelta, which switches muscles from burning sugar to burning fat. Because fat must be metabolized aerobically, this limits a muscle's anaerobic activity.

Like seasoned marathoners, the engineered mice outpaced the competition on a rodent-sized treadmill, Evans found, scampering nearly twice as far before becoming as exhausted as a comparison group. The animals, which the team dubbed 'marathon mice', had far more of the muscle fibres that work aerobically, and fewer of those that burn anaerobically, the team reports in PLoS Biology1.

The finding is "very exciting" as it fits with what is known about endurance athletes, says exercise physiologist Frank Booth at the University of Missouri, Columbia. Around 80% of the muscle fibres of marathon runners are aerobic, while in non-athletes the percentage is typically 30-40%. This is probably partly due to genetics and partly due to training.

Ditching the switch

Johnson and his colleagues created endurance mice by taking a slightly different tack. They engineered mice to lack a gene called HIF-1alpha that is thought to switch muscles from aerobic to anaerobic activity when oxygen is sparse. These mice could run and swim like champions as well, reports the team in PLoS Biology2.

Johnson's team found hints that the mice are churning out less lactic acid, a by-product of anaerobic metabolism commonly thought to cause fatigue, and are clearing it out of their system faster. Again, this has parallels with long-distance runners, who are thought to turn over lactic acid more quickly.

But in this case, the animals' athletic feats came at a high price: after four days of extensive exercise, their performance flagged and their muscles showed signs of damage. This may have been because by-products of aerobic metabolism, such as free radicals, had built up to poisonous levels, Johnson speculates.

Gene doping threat

With the Olympics in full swing, the studies raise the prospect that athletes and coaches might use drugs or 'gene doping' to mimic the effects of the genetic engineering and increase their endurance levels. "Athletes will pick up on this right away," predicts Booth. "I know it's going to happen."

“Athletes will pick up on this right away”

Frank Booth
University of Missouri, Columbia

Evans has already shown that molecules that block another gene, called PPARalpha, increase muscle capacity in mice and stop them gaining weight. He hopes that such chemicals, which are already being put through clinical trials to test whether they lower blood fat levels, might find a use in fighting obesity. But Evans acknowledges that athletes would clamour for them too.

Johnson, however, believes it will take some time to figure out how to manipulate metabolic pathways to get benefits without the risks. "I'm not going out and buying running shoes today," he says. 

University of Missouri, Columbia

  • References

    1. Wang Y-X., et al. PLoS Biology, DOI: 10.1371/journal.pbio.0020294 (2004).
    2. Mason S.D., et al. PLoS Biology, DOI: 10.1371/journal.pbio.0020288 (2004).