The Immune System Mediates Some of the Benefits of Exercise
It is uncontroversial to point out that exercise is good for long-term health. It slows aging, reduces risk of age-related disease, reduces mortality. A mountain of evidence supports these assertions, both animal studies demonstrating causation, and any number of large human studies showing correlation. Exercise, like the practice of calorie restriction, produces sweeping changes in the operation of metabolism. Near everything is different, both in the short term following exercise, and over the long term when looking at differences between the biochemistry of a fit individual versus that a sedentary individual. This can make it hard to determine which of the countless specific changes are important, or where they sit in the network of cause and effect.
Cellular biochemistry remains incompletely understood and explored. There is plenty of room to take even a very well studied subject, such as the beneficial effects of exercise, and find something novel to say about it. In today's research materials, scientists discuss a recent discovery related to the role of the immune system in mediating some of the benefits to health that result from exercise, such as reductions in inflammatory signaling. Given the age-related decline of the immune system, and the chronic inflammation of aging, it is interesting to consider how this part of the response to exercise likely breaks down with age.
Some benefits of exercise stem from the immune system
Most previous research on exercise physiology has focused on the role of various hormones released during exercise and their effects on different organs such as the heart and the lungs. A new study unravels the immunological cascade that unfolds inside the actual site of exertion - the muscle. Exercise is known to cause temporary damage to the muscles, unleashing a cascade of inflammatory responses. It boosts the expression of genes that regulate muscle structure, metabolism, and the activity of mitochondria, the tiny powerhouses that fuel cell function. Mitochondria play a key role in exercise adaptation by helping cells meet the greater energy demand of exercise. In the new study, the team analyzed what happens in cells taken from the hind-leg muscles of mice that ran on a treadmill once and animals that ran regularly. Then, the researchers compared them with muscle cells obtained from sedentary mice.
The muscle cells of the mice that ran on treadmills, whether once or regularly, showed classic signs of inflammation - greater activity in genes that regulate various metabolic processes and higher levels of chemicals that promote inflammation, including interferon. Both groups had elevated levels of regulatory T cells (Treg cells) in their muscles. Further analyses showed that in both groups, Tregs lowered exercise-induced inflammation. None of those changes were seen in the muscle cells of sedentary mice. However, the metabolic and performance benefits of exercise were apparent only in the regular exercisers - the mice that had repeated bouts of running. In that group, Tregs not only subdued exertion-induced inflammation and muscle damage, but also altered muscle metabolism and muscle performance, the experiments showed. This finding aligns with well-established observations in humans that a single bout of exercise does not lead to significant improvements in performance and that regular activity over time is needed to yield benefits.
Further analyses confirmed that Tregs were, indeed, responsible for the broader benefits seen in regular exercisers. Animals that lacked Tregs had unrestrained muscle inflammation, marked by the rapid accumulation of inflammation-promoting cells in their hindleg muscles. Their muscle cells also had strikingly swollen mitochondria, a sign of metabolic abnormality. More importantly, animals lacking Tregs did not adapt to increasing demands of exercise over time the way mice with intact Tregs did. They did not derive the same whole-body benefits from exercise and had diminished aerobic fitness. These animals' muscles also had excessive amounts of interferon, a known driver of inflammation. Further analyses revealed that interferon acts directly on muscle fibers to alter mitochondrial function and limit energy production. Blocking interferon prevented metabolic abnormalities and improved aerobic fitness in mice lacking Tregs. "The villain here is interferon. In the absence of guardian Tregs to counter it, interferon went on to cause uncontrolled damage. We've only looked in the muscle, but it's possible that exercise is boosting Treg activity elsewhere in the body as well."
Exercise enhances physical performance and reduces the risk of many disorders such as cardiovascular disease, type 2 diabetes, dementia, and cancer. Exercise characteristically incites an inflammatory response, notably in skeletal muscles. Although some effector mechanisms have been identified, regulatory elements activated in response to exercise remain obscure. Here, we have addressed the roles of Foxp3+CD4+ regulatory T cells (Tregs) in the healthful activities of exercise via immunologic, transcriptomic, histologic, metabolic, and biochemical analyses of acute and chronic exercise models in mice. Exercise rapidly induced expansion of the muscle Treg compartment, thereby guarding against overexuberant production of interferon-γ and consequent metabolic disruptions, particularly mitochondrial aberrancies. The performance-enhancing effects of exercise training were dampened in the absence of Tregs. Thus, exercise is a natural Treg booster with therapeutic potential in disease and aging contexts.