In an early 20th century study, it was found that the link between exercise and inflammation in the blood of Boston Marathon runners proliferated after a race has captured the imagination of researchers.
Now, a new study from Harvard Medical School, published in Science Immunology, may provide a molecular explanation for this century-old observation.
This study in mice suggests that the beneficial effects of exercise may be at least partly driven by the immune system. It shows that muscle inflammation caused by exertion mobilizes anti-inflammatory T cells, or regulatory T cells, to enhance the muscles' ability to use energy as fuel, improving overall exercise endurance.
Regulatory T cells, long known for their role in fighting abnormal inflammation associated with autoimmune diseases, are now also key players in the body's immune response during exercise, according to the research team.
"The immune system, especially T cells, has a broad impact on tissue health, and it's not just about protecting pathogens and controlling cancer. Diane Mathis, Professor of Immunology and Senior Research Fellow at the HMS Blavatnik Institute, said: "Our research shows that the immune system produces a powerful effect within the muscles during exercise. ”
The researchers warn that mice are not humans, and that these findings are still to be replicated by further studies. However, this study is an important step in detailing the cellular and molecular changes that occur during exercise and conferring health benefits.
Prevent cardiovascular disease, reduce the risk of diabetes, and prevent dementia. The beneficial effects of exercise are well known. But how exactly does exercise keep us healthy? This question has long fascinated researchers.
The new discovery comes as an intensified effort to understand the molecular basis of the practice. Unraveling the immune system's involvement in this process is only one aspect of these research efforts.
Kent Langston, a postdoctoral researcher in Mathis's lab, said we have long known that physical exertion can lead to inflammation, but we don't fully understand the immune processes involved. Our study shows at very high resolution what T cells do in the parts of the muscles that work.
Most previous studies on exercise physiology have focused on the role of the various hormones released during exercise and their effects on different organs such as the heart and lungs. The new study reveals immune-level connections that unfold inside the muscles at the site of actual exertion.
Exercise is known to cause temporary damage to muscles, triggering a range of inflammatory responses. It promotes gene expression that regulates muscle structure, metabolism, and mitochondrial activity, a miniature powerhouse for fuel cell function. Mitochondria play a key role in motor adaptation by helping cells meet the greater energy demands of exercise.
In the new study, the team analyzed what happened to cells taken from the hind leg muscles of mice that used to run on treadmills and animals that ran regularly. The researchers then compared them to muscle cells obtained from sedentary mice.
The muscle cells of mice running on treadmills, both once and on a regular basis, showed typical signs of inflammation – greater activity of genes that regulate various metabolic processes, and higher levels of chemicals that promote inflammation, including interferon.
Tregue cell levels were elevated in both groups of muscles. Further analysis showed that in both groups, regulatory T cells reduced exercise-induced inflammation. These changes were not seen in the muscle cells of sedentary mice.
However, the metabolic and performance benefits of exercise were only evident in regular exercisers – those mice that ran repeatedly. Experiments showed that in that group, regulatory T cells not only inhibited exertion-induced inflammation and muscle damage, but also altered muscle metabolism and muscle performance.
This finding is consistent with the human-accepted observation that a single round of exercise does not lead to significant improvements in performance, and that regular activity over time is required to generate benefits.
Further analysis confirmed that Tregs were indeed responsible for the broader benefits seen by regular exercisers. Animals lacking Tregs have unconstrained muscle inflammation, which is characterized by the rapid accumulation of inflammation-promoting cells in the hind leg muscles. Their muscle cells also have noticeably swollen mitochondria, which is a sign of metabolic abnormalities.
What's more, over time, Tregs-deficient animals did not adapt to the growing demand for exercise in the same way as mice with intact Tregs. They didn't get the same whole-body benefits from exercise and had reduced aerobic capacity.
The muscles of these animals also had excess interferon, which is a known driver of inflammation. Further analysis revealed that interferon acts directly on muscle fibers, altering mitochondrial function and limiting energy production. Blocking interferon prevents metabolic abnormalities and improves aerobic fitness in Tregs-deficient mice.
The villain here is interferon, Langston says. In the absence of guardian regulatory T cells to cope, interferon continues to cause uncontrolled damage.
Interferon is known to promote chronic inflammation, a process that underlies many chronic and age-related diseases and has become an attractive target for therapies aimed at reducing inflammation. Regulatory T cells have also attracted the attention of scientists and industry as a treatment for a range of immune diseases marked by abnormal inflammation.
The researchers say the findings provide a glimpse into the inner workings of cells behind the anti-inflammatory effects of exercise and underscore its importance in harnessing the body's own immune defenses.
Efforts are underway to design interventions that target regulatory T cells in the context of specific immune-mediated diseases. While immune conditions driven by abnormal inflammation require well-calibrated therapies, exercise is another way to fight inflammation, the researchers say.
"Our research shows that by exercising, we have a natural way to boost the body's immune response to reduce inflammation," Mathis said. We only looked at muscle, but exercise may also be boosting regulatory T-cell activity elsewhere in the body.
Bibliography:
Paul Langston et al, Regulatory T cells shield muscle mitochondria from interferon-γ-mediated damage to promote the beneficial effects of exercise, Science Immunology (2023).