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Modified Mice Stay Super-Fit -- Without Exercise

Bijal Trivedi
for National Geographic News
August 25, 2004
 
If there were a rodent Olympics, the "marathon mice" in Ronald Evans's lab would be disqualified for gene doping.

Evans and a team of researchers have genetically engineered mice that can run twice as far as their unaltered brethren. The mice also stay in peak condition, even without exercise or a good diet.

"These mice are in inherently good shape," said Evans, a hormone expert at the Salk Institute for Biological Studies in La Jolla, California. "They look like Lance Armstrong without ever getting on a bike."


The super-rodents can run farther and about an hour longer than average mice. The new rodents also appear to resist weight gain in the complete absence of exercise—even when fed a high-fat diet that led normal mice to become obese.

The research is described in yesterday's online edition of the science journal Public Library of Science Biology.

"There were clues out there, so the finding is more cool than surprising," said Mitchell Lazar, an endocrinologist not involved in the study. "These mice are really Schwartzenegger mice. They have increased muscle, low fat, and high endurance," said Lazar, who directs the Penn Diabetes Center at the University of Pennsylvania School of Medicine in Philadelphia.

The high endurance and increase in musculature in the marathon mice arose serendipitously while Evans and his colleagues studied a family of three proteins that influence how the body handles fat and sugar. The researchers found that one protein also affect muscle fibers.

The family of proteins—called peroxisome proliferator activated receptors, or PPARs—come in three types: alpha, gamma, and delta. The alpha class lowers blood fat and cholesterol. The gamma class mediates insulin control of blood sugar. But the role of the delta class in the body was largely unknown.

No Sweat

To learn more, the researchers engineered mice in which a gene produced a form of the delta protein that was permanently "on." Based on previous studies, the team hypothesized that increased activity of PPAR-delta in the muscles of the mice would allow them to burn more fat.

The experiment revealed that the genetic tweaking, indeed, rendered the mice resistant to weight gain. But the more intriguing find, researchers said, was how this change occurred. "The real surprise was that it did so by increasing the amount of slow-twitch muscle," Evans said.

Slow-twitch muscles, like the heart and diaphragm, burn fat and resist fatigue. Such muscles are important for providing energy for sustained, high-endurance activities like long-distance running, let alone regulating blood circulation and breathing.

Most muscles in the human body, however, are fast-twitch muscles. These fibers are essential for providing bursts of energy during short sprints or similar activities. But the muscles also burn sugar and tend to fatigue quickly.

Slow-twitch muscles avoid fatigue, because they contain many more mitochondria—"power plants" in cells that convert fat into energy.

The altered mice with extra slow-twitch muscle fibers were resistant to obesity because those muscle fibers burn fat more rapidly. Fast-twitch muscles, by contrast, have fewer mitochondria and get more of their energy from glucose, a type of sugar obtained from carbohydrates during digestion.

Athletes know that building slow-twitch muscle comes from endurance training and regular exercise. But mice with extra PPAR-delta activity were naturally endowed with a higher proportion of this endurance-enhancing, slow-twitch muscle fiber.

New Wonder Drugs?

Evans said that it was surprising to find that altering the activity of a single gene could trigger such dramatic and wide-ranging physical changes.

Under normal conditions, raising physical endurance is a complex process. Increases in muscle mass must also be accompanied by changes in blood circulation, heart activity, and the nervous system.

"But one change [PPAR-delta] seems to rewire the whole system," Evans said.

The scientist tested the endurance of the "marathon mice" by placing them on a treadmill and making them run. The mice ran about 1.1 miles (1.8 kilometers). Normal mice ran less than half that distance before reaching exhaustion.

Evans's findings on the effects of PPAR-delta proteins and the link to obesity-prevention could lead to new classes of drugs for type II diabetes, heart disease, and other obesity-related illnesses.

"Anything that helps people lose weight is good, because it increases the insulin response and produces better glucose levels, which is good for diabetics," Evans said.

Lazar, the University of Pennsylvania endocrinologist, agreed that the new research holds exciting potential for new drug development.

Medications that target the alpha and gamma classes of PPAR proteins already exist. This may pave the way for the development of new drugs that regulate PPAR-delta.

Lazar noted that if the new research can translate to humans, drugs that mimic PPAR-delta might help people who have lost muscle to cancer, aging, or malnutrition.

"It could also rescue the couch potato. In the U.S. we eat too much and don't exercise enough," Lazar said. Potential new drugs could help people "build muscle and prevent obesity without breaking a sweat," he said.

Evans added that such drugs may interest athletes seeking to boost their performance by adding slow-twitch muscles.

But for now the technology is limited to producing mightier mice.

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