Low-Power Mitochondria May Raise Risk of Cardiovascular Problems

Try as we might, only an elite few will ever win the Tour de France or even the local 10-K foot race. People simply vary widely in their ability to perform aerobic exercise. New work with rats now suggests that individuals with a low tolerance for aerobic exercise may have a lot more to worry about than just their inability to run fast and long. The same underlying defect that reduces aerobic capacity may also predispose a person to a witch's brew of medical problems that could increase the possibility of heart attacks and strokes.

On page 418, a research team including Ulrik Wisloff of the Norwegian University of Science and Technology in Trondheim, Sonia Najjar of the Medical College of Ohio in Toledo, and Steven Britton of the University of Michigan, Ann Arbor, reports that rats that have been selectively bred to have reduced capacity for aerobic exercise show obesity, resistance to the hormone insulin (a sign of type II diabetes), and high blood pressure, all symptoms of the so-called metabolic syndrome that raises the risk of cardiovascular disease. The researchers also provide evidence that impaired function of the mitochondria, small structures that produce most of a cell's energy, underlies the metabolic problems of the rats with low aerobic capacity.

Previous work had implicated poor mito-chondrial function with individual components of metabolic syndrome, but this is the first time researchers have linked it to all of them at once. "This is an incredibly provocative study," says Vamsi Mootha of Massachusetts General Hospital in Boston,

Running for their lives. These rats, bred to have high aerobic capacity, appear to have fewer cardiovascular risk factors than their couch-potato cousins.

whose own work has linked mitochondrial malfunction to type II diabetes. "They linked metabolic syndrome to mitochondria in a way that hasn't been done before."

The rat-breeding experiments began in 1996, motivated mainly, Britton recalls, by dissatisfaction with existing animal models for diabetes and cardiovascular disease. Most of those models were created by very nonphysiological means, such as tying off the arteries of the heart or administering a drug that destroys the insulin-producing cells of the pancreas, far removed from the way the conditions develop naturally.

To produce animals whose diseases more closely mimic those in humans, the researchers selectively bred rats to have either high or low capacity for aerobic exercise. They identified rats with a high capacity to run on a treadmill and mated them with one another, and they did the same for animals with a low running capacity. "Since oxygen metabolism is such a large part of biology, defects in it should underlie our pathology," explains Britton.

The animals described in the current report, the products of 11 generations of selective breeding, have a 350% difference in their running abilities. And by every measure tested, the couch-potato rats rank high on the cardiovascular risk factor scale: Compared to high-capacity runners, they are more obese, have higher blood pressures and higher levels of blood fats, and have increased insulin resistance.

Although obesity itself can decrease aerobic running capacity, a statistical analysis showed that it accounts for no more than 20% of the decreased aerobic capacity. Indeed, studies of very young rats who were poor exercisers showed that metabolic changes, such as increased blood concentrations of fat and the sugar glucose, occurred before any weight differences became apparent.

Because mitochondria provide the energy for exercise, Britton and his colleagues examined whether these organelles exhibited signs of reduced function in the low-aerobic-capacity rats. The researchers found that muscle from those rats had much lower concentrations of a number of key mitochondrial proteins than did muscle from the high-capacity animals. This indicates that they had either fewer mitochondria or less effective ones.

The work provides "a strong link ►

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