Modulation of Antioxidant Defense by Exercise in Old Age

LifeSource Vitamins

L.L. Ji

Department of Kinesiology and Nutritional Science University of Wisconsin-Madison Madison, Wisconsin USA

Keeping an active lifestyle and maintaining mobility is essential for the quality of life at old age. Unfortunately, the skeletal muscle loses mass and function during aging. This process is thought to be related to increased free radical generation and oxidative stress.

The benefits of endurance exercise on health and disease have been well-established. Recent evidence suggests that resistance exercise can also increase muscle mass. However, heavy exercise increases free radical generation and the risk of oxidative stress. In the elderly, this problem is compounded by the fact that aging also increases free radical production in the skeletal muscle. Aged muscle is also more susceptible to exercise-induced damage, which can cause inflammation and lead to further oxidative stress and abnormal function. Aging also decreases the ability of the muscle to repair itself.

Although the antioxidant defense system can be boosted by many methods, none of them seem to prevent age-related loss of muscle mass and function. We developed a working hypothesis based on the concept that a sublethal dose of toxin increases the body's ability to tolerate higher doses of toxin ("whatever is not killing you will make you stronger"). We hypothesized that exercise would change the antioxidant capacity of the cells as it increased free radical generation, thus improving the ability of the cells to withstand age-related oxidative stress.

In our first study testing this hypothesis, we found that an acute bout of exercise activated the antioxidant enzyme superoxide dismutase (SOD) in rat skeletal muscle. Skeletal muscle cells contain manganese SOD and copper-zinc SOD. Each of these different types of SOD has characteristic properties. To determine which SOD was involved in the response to exercise, we evaluated SOD activity in rats after they had exercised strenuously for one hour. The results confirmed that manganese SOD messenger RNA was increased after a single bout of exercise. (Messenger RNA is a molecule that transmits the genetic instructions for protein synthesis from DNA to the site of production in the cell.) The higher enzyme protein levels were not detectable until 48 hours after exercise. No changes in copper-zinc SOD were observed.

We next evaluated the effect of endurance training on SOD activation in muscle. Rats (fed a diet with standard antioxidant level) were exercised for two hours per day for ten weeks. Significant increases in manganese SOD were observed in all types of skeletal muscle, but no changes in copper-zinc SOD occurred.

Mitochondria are tiny cell parts that use a process called respiration to produce energy for the cell. They are frequently a target for oxidative damage. To determine the biological significance of the increase in manganese SOD, we isolated mitochondria from muscles of the trained and untrained rats and exposed them to superoxide free radicals in the laboratory. Mitochondrial respiration was less inhibited in the trained rats than in the untrained ones. This indicated that the increase in manganese SOD induced by training probably protected the mitochondria from oxidative stress.

As for the effect of training in aging muscle, researchers in 1991 found that aging did not seem to abolish the training effect of rigorous exercise in rats. In a later study, however, training at moderate intensity was shown to cause significant activation of SOD in young rats, but not in older ones. This indicated that the muscle sensitivity to training was diminished with aging, possibly due to a decreased exercise capacity or a decreased responsiveness to cell signaling.

The heart muscle requires oxygen for proper functioning. The oxygen reaches the heart in the blood supplied by the coronary arteries. If a blockage occurs in a coronary artery, blood flow to part of the heart may stop. This process, which is called ischemia, can cause chemical and functional damage to the heart. When the blockage is relieved, blood flow resumes in a process called reperfusion. Paradoxically, reperfusion often worsens the damage by generating free radicals and oxidative stress.

Glutathione is an antioxidant that is synthesized in the liver and transported in the blood to other tissues. Oxidative stress seems to increase tissue uptake and turnover of glutathione in both skeletal muscle and heart. With this in mind, we set out to determine whether exercise training in conjunction with glutathione supplementation would increase the heart's resistance to injury caused by ischemia-reperfusion.

Our study used rats that were fed diets with or without glutathione supplementation. The rats were either sedentary (untrained) or subjected to exercise training for ten weeks. At the end of the training/supplementation part of the study, the rats were anesthetized and surgery performed to implant the devices that we used to reversibly occlude a coronary artery and measure the resulting effects. Some rats received 45 minutes of coronary artery occlusion (ischemia), followed by 30 minutes of reperfusion. The remaining rats served as controls and received neither occlusion nor reperfusion.

We measured blood pressure within the left ventricle of the heart as an index of heart function. Coronary artery occlusion caused left ventricular pressure to decrease. Reperfusion initially restored pressure, but over the next 30 minutes pressure decreased again. This indicated that the heart muscle had been permanently damaged. The hearts of the trained glutathione-supplemented rats had significantly higher glutathione content with or without ischemia-reperfusion. This indicated that glutathione had been taken up by the heart. We also found that the ratio of glutathione to glutathione disulfide, its oxidation product, was highest in the trained glutathione-supplemented rats during ischemia-reperfusion.

Glutathione supplementation and training protected the heart from ischemia-reperfusion damage. The trained glutathione-supplemented rats showed the greatest recovery of heart function after reperfusion. Release of lactic dehydrogenase, an enzyme that is an indicator of cell damage, was also less in this group. Lipid peroxidation, an indicator of oxidative stress, was not elevated in the trained glutathione-supplemented rats but was significantly elevated in the other groups.

Why do these adaptations occur? Training, either with or without glutathione supplementation increased the activity of important antioxidant enzymes. It also increased the activity of the enzyme that stimulates glutathione uptake into the heart muscle cells. Training also increased the activity of the liver enzyme that triggers the production of glutathione. As a result, liver glutathione levels were significantly increased. This, in turn, increased the plasma level of glutathione. So during ischemia-reperfusion, the liver increased glutathione production and movement of glutathione into the heart muscle cells was facilitated.

In conclusion, glutathione supplementation in conjunction with endurance training increased the resistance to ischemia-reperfusion in rat heart. This effect is thought to be due to an increase in the activity of antioxidant enzymes in the heart and an increase in heart glutathione content. Others factors involved in this response include an increase in the activity of enzymes triggering glutathione production by the liver and an increase in glutathione uptake by the heart during ischemia-reperfusion.

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