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Gene research creates a 'Mighty Mouse'
BY JAMIE TALAN
Staff Writer
August 23, 2004, 2:44 PM EDT
Increasing the activity of a single gene turns a mere rodent into Mighty Mouse, according to a new study.
California scientists have genetically engineered an animal that has more muscle, less fat and more physical endurance than their littermates. The mice go twice as far as expected. They also seem protected against the inevitable weight gain that follows a high fat, high calorie diet.
"We were quite surprised," said Ronald M. Evans, a Howard Hughes Medical Institute investigator at the Salk Institute in La Jolla, Calif. "Most people think that increased endurance comes from training. But we've been able to re-create this entire exercise network by increasing the activity of a single protein."
Evans said that the findings could have implications for human athletes and others who shy away from exercise despite the known benefits for the cardiovascular system, the muscles and bones, and even the brain. "While it could be used for patients who can't exercise, it could also be abused by athletes to enhance performance," said Evans.
Nonetheless, the finding suggests that one gene, called PPAR-delta, is designed to regulate muscle development. In turn, strong muscles have positive effects on other body systems. Scientists modified the PPAR-delta gene to express, or make, more protein.
The PPAR-delta is a master gene that regulates several other genes. Enhancing its activity created animals with attributes associated with extensive physical training.
Evans and his colleagues suspect that enhancing muscle development alters the fat-burning and muscle-making machinery of the body. The study appears Tuesday in the Public Library of Science Biology journal.
In earlier work, the scientists showed that activating PPAR-delta helped animals burn more fat. In the latest studies, they found that the protein also alters the structure and function of muscle fibers, making them more resistant to fatigue. The enhanced protein also allows the animals to keep trim despite a diet rich in fat and calories.
On an exercise wheel, the genetically engineered mice ran twice as long as the normal animals -- an extra hour, Evans said, for the equivalent of a mile.
While researchers altered the gene to make more protein, they also designed a study to test the benefits of an experimental medicine that increases the protein. The animals given the drug experienced the same muscle and metabolic benefits of the genetically-bred mice, including protection against weight gain. The experimental drug, developed by GlaxoSmithKline, is now in clinical studies to test its safety and effectiveness in pre-diabetes conditions.
The new study is the latest to examine how animals' athleticism can be altered. In a study published last year, scientists created the next generation of athletic mice -- animals that ran three times farther and faster than usual.
"They are born to run," said neuroscientist Justin Rhodes. The study appeared in the journal Behavioral Neuroscience. "Give them a wheel and they want to run faster and more intensely than the other animals."
Rhodes, at the Veteran's Administration Medical Center in Portland, Ore., spent years measuring the movement of animals on a running wheel. Then, in collaboration with University of Wisconsin's Stephen Gammie and Ted Garland of the University of California at Riverside, Rhodes mated animals with the longest records. After 32 generations, they had four separate lines of animals that were faster and capable of running farther.
These animals didn't have better hearts, stronger muscles or more robust oxygen consumption than non-runners, Gammie said. But they did have higher levels of the stress-hormone cortisol in their blood. In addition, areas of the brain that regulate motivation were far more active and a brain area known to give birth to new brain cells in adults went into overdrive, producing 30 percent more new neurons in this region.
Gammie said that these findings could prove what scientists have long suspected: That exercise is naturally rewarding.
In that study, half the mice were given unlimited access to the running wheel for six straight days. On the seventh day, only half of these were allowed to use the wheel.
Researchers found a correlation between how much the animals had run and the activity in certain parts of the brain. And brain regions involved with motivation and movement registered more activity in the animals that didn't get to run on the seventh day, suggesting that the motivational circuits were craving the next opportunity, Rhodes said.
Genetic tests in the mice suggest that a gene that regulates the brain chemical dopamine may be involved in this enhanced running ability. Dopamine is a key chemical that regulates motivation and reward, as well as movement. The animals ran into old age but didn't live any longer than their normal littermates.
Gene research creates a 'Mighty Mouse'
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