Running rats link exercise levels and disease
If your New Year's resolution to exercise now is just a distant memory, there are some rats at the Medical School that may convince you to climb back on the treadmill.
A new research study 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 rats in the study are the product of 11 generations of artificial selection for exercise capacity conducted by U-M scientists Steven Britton and Lauren Gerard Koch. Although all are 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 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 syndromephysical 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 diseaseincluding high blood pressure and vascular dysfunction," says Ulrik Wisloff, 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 ratsall consistent with metabolic syndrome," says Sonia M. Najjar, 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."
Britton and Koch started developing their rat model eight years ago while they were at the Medical College of Ohio.
"Our goal in selecting and breeding these rats over many generations was to concentrate genetic differences related to exercise capacity," says Britton, a professor of physical medicine and rehabilitation. "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 needed 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.
"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 study was funded by the National Institutes of Health, the American Diabetes Association, the National Science Foundation and the Norwegian Council on Cardiovascular Research.