UF studies find cause of muscle damage in those with poor circulation

November 6, 2003

GAINESVILLE, Fla. — University of Florida researchers have discovered the cause of severe muscle damage that occurs when people with poor circulation work up a good sweat: free radicals. Now they hope to use the information to unlock the secrets of how to shut down those pesky body wastes.

The discovery eventually may help sufferers of a type of poor circulation called peripheral vascular disease get the exercise that’s so beneficial to them without the pain that often accompanies it. Peripheral vascular disease affects one in 20 people over 50, or about 8 million Americans, and leads to about 100,000 amputations every year, according to the Society of Cardiovascular Interventional Radiology.

“Exercise is prescribed to patients with this condition because we know that it has a number of positive effects, but it may also damage the muscles,” said Andrew Judge, a visiting assistant professor in the UF College of Health and Human Performance and the lead researcher on the study. “Ultimately, our goal is for these patients to be able to exercise without causing this damage.”

Prior studies revealed this damage occurred, but the UF research is the first to pinpoint its source as free radicals – highly reactive molecules resulting from all the chemical reactions occurring in the body, which have previously been linked to cardiac problems, aging-related disorders, stroke and even cancer.

The researchers also looked at important pathways for production of the free radicals in rats and will use the information to develop treatments to help reduce the muscle damage they cause in people with peripheral vascular disease. Results from the pair of studies are scheduled to be published in the January issues of Atherosclerosis and the American Journal of Physiology.

“Before now, no one had ever shown that exercise with blood flow restriction from blocked arteries would cause this damage in skeletal muscle,” Judge said. “We then looked at some of the major pathways for the free radicals to see if we could lessen it in some way.”

Because of its excellent cardiovascular benefits, exercise is often prescribed as one of the best ways to increase blood flow in people suffering from peripheral vascular disease, which causes the blood vessels to become narrowed or blocked by fatty deposits.

The condition restricts the flow of oxygen to muscles causing severe pain and cramping during exercise, and although this pain subsides during rest as the oxygen demands of the muscle decline, the studies showed this process causes significant free radical damage to muscle cells, Judge said.

For the study, Judge and co-researcher Stephen Dodd mimicked the human form of the disease in rats by blocking the major artery delivering blood to the muscles and then made them exercise. After the increased oxygen demands of exercise, examination of the muscles showed significant damage due to oxidative stress, a condition that may result from the presence of free radicals that react with and modify cellular proteins and lipids. Following exercise with restricted blood flow in rats, they found an approximate 50 percent increase of oxidative stress to both proteins and lipids, Judge said.

Further investigation revealed that inhibiting the activity of an enzyme called xanthine oxidase and a type of inflammatory white blood cells called neutrophils – both known to produce free radicals – prevented this damage to the rats’ limb muscles. Neutrophils were found to cause the majority of harm, resulting in significant damage to the muscles, Judge said. While depleting neutrophils is possible in rodents, doing so is not feasible in people because the cells play a vital role in immune response.

“Realistically, we can’t give these inhibitors (to humans), we just used them to find out the important pathways,” Judge said. “Now we are using this information to come up with a feasible treatment that will reduce this free radical damage based on what we now know about the pathways of production. If we can prevent the free radical-mediated damage in animals, we would like to move on to looking at (doing it in) humans.”

Kerry Stewart, an associate professor of medicine and director of Johns Hopkins Heart Health at Johns Hopkins University Bayview Medical Center, said the UF studies demonstrate several physiological pathways by which limited blood flow leads to muscle damage with exercise.

“Although the studies were done in rats, they provide insight into what causes muscle damage in the legs of humans with peripheral arterial disease, a condition that also limits blood flow because of blocked arteries,” Stewart said. “These studies are important in that they increase our understanding of why muscle damage occurs.”

While the studies provide important evidence about the mechanisms of this muscle damage, they should not be interpreted as a reason for people with reduced blood flow not to exercise on a regular basis-the most consistently effective treatment for the condition, Stewart said.

“Regular exercise, which is done several times per week, has been shown to produce beneficial adaptations that would gradually reduce oxidative stress and muscle damage over a period of several months,” Stewart said.

Judge said he hopes further research will lead them to find an effective supplement to block the initial oxidative muscle damage so patients with poor limb circulation can continue their exercise regimens with less discomfort in order to receive the greatest benefits.

By understanding the mechanisms that produce the damage, it will be possible to develop the best countermeasure to reduce it, Judge said.