Jan. 25, 2005 ANN ARBOR, MI - If your New Year’s resolution to exercise is now just a distant memory, there are some rats at the University of Michigan Medical School that may convince you to climb back on the treadmill.
A new research study, to be published in the Jan. 21 issue of Science, found that rats selected and bred for low aerobic exercise capacity had more cardiovascular disease risk factors than rats bred for high exercise capacity. The study was conducted by scientists from the Norwegian University of Science and Technology, the Medical College of Ohio, Williams College and the U-M Medical School.
The rats in the study are the product of 11 generations of artificial selection for exercise capacity conducted by U-M scientists Steven Britton, Ph.D., and Lauren Gerard Koch, Ph.D. Although they are all descended from the same founder population of genetically mixed lab rats, the experimental rats now differ substantially in their ability to use oxygen efficiently and generate the energy it takes to run for long periods of time.
For example, the high-capacity runners in generation 11 can exercise continuously on a treadmill for 42 minutes on average before exhaustion forces them to stop, while the low-capacity runners average only 14 minutes. The overall difference in running capacity between the two groups of rats in the Science study was 347 percent.
The most clinically useful finding reported in the paper was the close association in the experimental rats between low aerobic exercise capacity and high scores for risk factors linked to metabolic syndrome – physical changes often seen in people who later develop cardiovascular disease and diabetes.
“We found that rats with low aerobic capacity scored higher on risk factors linked to cardiovascular disease – including high blood pressure and vascular dysfunction,” says Ulrik Wisloff, Ph.D., a professor of cellular and molecular exercise physiology at the Norwegian University of Science and Technology in Trondheim, Norway, who was co-first author of the Science paper.
“Rats with low aerobic capacity also had higher levels of blood fat disorders, insulin-resistance and more abdominal fat than high-capacity rats – all consistent with metabolic syndrome,” says Sonia M. Najjar, Ph.D., an associate professor of pharmacology at the Medical College of Ohio in Toledo, and co-first author of the paper. “In addition, we found evidence of mitochondrial dysfunction in the low-capacity rats. Compared to high-capacity rats, the low-capacity rats had lower levels of oxidative enzymes and proteins used by mitochondria to generate energy in skeletal muscle.”
“Our goal in selecting and breeding these rats over many generations was to concentrate genetic differences related to exercise capacity,” says Britton, a U-M professor of physical medicine and rehabilitation. Britton and Koch started developing their rat model eight years ago while they were at the Medical College of Ohio. “Essentially, we are breeding for genes that code for low levels of proteins involved in mitochondrial function. Our hypothesis is that impaired mitochondrial function may be what links low aerobic capacity and disease.”
Mitochondria are tiny factories within cells that generate the energy cells need to function. Inside the mitochondria, enzymes break down glucose and fatty acids from food and combine them with oxygen to produce an energy-storing molecule called ATP. Every cell in the body uses energy from ATP. Without it, blood vessels can’t maintain normal pressure, the heart can’t pump blood efficiently and cells can’t take up enough oxygen – all of which are required for healthy cardiovascular function and the capacity for exercise.
“After 11 generations of selective breeding, our low-capacity rats have abnormally low levels of proteins required to maintain adequate production of ATP,” Britton says.
The high-capacity rats, on the other hand, have accumulated genes that code for increased production of mitochondrial proteins and ATP. Sleek and trim, with an inborn ability to generate energy and metabolize oxygen efficiently, the high-capacity rats were literally born to run.
“We don’t train the rats to build up their exercise capacity,” says Koch, an assistant professor of physical medicine and rehabilitation in the Medical School. “At about 11 weeks of age, we introduce the rats to the treadmill and run them five times. Then we identify the 13 males and females with the highest inherent aerobic capacity and 13 males and females with the lowest aerobic capacity. Each group serves as the mating population for the next generation of high-capacity and low-capacity runners.”
The original founder population of 168 rats could run for an average of 23 minutes, according to Koch. Since then, the average treadmill running capacity has been increasing 41.8 meters per generation in the high-capacity rats and dropping 16.1 meters per generation in the low-capacity rats. The overall number of rats raised and tested so far stands at 2,912.
Britton and Koch hope their rats will help scientists evaluate new therapeutic drugs for cardiovascular disease and diabetes, or develop diagnostic tests to identify people most likely to develop these diseases as they get older. The rats are available for study by other researchers through a standard university materials transfer agreement.
In the meantime, what about the human equivalent of low-capacity rats – those of us who get tired just thinking about a treadmill?
Epidemiological and clinical studies with thousands of people have found low aerobic exercise capacity to be the strongest predictor of mortality among all risk factors for cardiovascular disease, Britton says. So increasing the capacity for exercise is important to anyone who wants to lower their risk of dying from a heart attack or stroke.
“The reality of having a genetic determinant of our existence is that there are some people who are born with less ability to take up oxygen and transfer energy than others,” Britton says. “These people may have to work harder and will never reach the level of a professional athlete, but almost everyone can improve their aerobic capacity and health status with regular exercise.”
Research conducted by Wisloff and his associates in Norway confirms Britton’s statement. After taking baseline measurements of 12 variables associated with exercise capacity and heart function in a small group of Britton’s rats, Wisloff put the animals through a six-week training regimen on the treadmill. He found that even the low-capacity rats improved significantly in 11 of the 12 measures of exercise capacity, although not as much as the high-capacity rats.
“It’s important to remember that, as a result of artificial selection over 11 generations, our low-capacity rats have an abnormally low concentration of proteins required for energy production that may underlie the development of common diseases in humans,” Britton adds. “And, while our results are intriguing, future research will be needed to prove a direct cause-and-effect relationship between mitochondrial function and disease.”
The study was funded by the National Institutes of Health, the American Diabetes Association, the National Science Foundation and the Norwegian Council on Cardiovascular Research.
Collaborators from the Norwegian University of Science and Technology included Oyvind Ellingsen and Per Magnus Haram. Collaborators from the Medical College of Ohio were Qusai Al-Share, Mats Fernstrom, Khadija Rezaei, and Sang Jun Lee. Steven Swoap from Williams College also was a collaborator in the study.
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