The connection between exercise and inflammation has captured the imagination of researchers since an early 20th century study showed a spike in white blood cells in the blood of Boston Marathon runners following a race.
Now, a new Harvard Medical School study published Nov. 3 inches Science Immunology A molecular explanation may be behind this centuries-old observation.
This study in mice suggests that the beneficial effects of exercise may be driven, at least in part, by the immune system. It shows that exercise-induced muscle inflammation mobilizes anti-inflammatory T cells, or Tregs, which increase the muscle’s ability to use energy as fuel and improve overall exercise endurance.
Long known for their role in combating the aberrant inflammation associated with autoimmune diseases, Tregs have now emerged as key players in the body’s immune response during exercise, the research team said.
The immune system, and particularly the T cell arm, has a broad impact on tissue health that goes beyond protection against pathogens and cancer control. Our research shows that the immune system has a powerful effect inside the muscles during exercise.”
Diane Mathis, study senior investigator, Morton Grove-Rasmussen Professor of Immunology at the Blavatnik Institute at HMS
Mice are not humans, and the study’s findings will need to be replicated in further studies, the researchers cautioned. However, the study provides an important step toward elucidating the cellular and molecular changes that occur during exercise and the health benefits.
Understanding the molecular basis of exercise
Protecting against cardiovascular diseases, reducing the risk of diabetes, protecting against dementia. The novel effects of exercise are well established. But exactly how does exercise make us healthy? The question has long intrigued researchers.
The new findings come amid intense efforts to understand the molecular basis of exercise. One aspect of this research effort is to unravel the involvement of the immune system in this process.
“We’ve known for a long time that exercise causes inflammation, but we don’t fully understand the immune mechanisms involved,” said study first author Kent Langston, a postdoctoral researcher in the Mathis lab. “Our study shows, at very high resolution, what T cells do in muscle where exercise occurs.”
Much of the previous research on exercise physiology has focused on the role of various hormones released during exercise and their effects on various organs such as the heart and lungs. New research uncovers the immunological cascade that unfolds inside the actual site of labor -; muscle
T cells are heroes and inflammation-fueling villains
Exercise triggers a cascade of inflammatory responses, known to cause temporary muscle damage. It boosts the expression of genes that control muscle formation, 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 demands of exercise.
In the new study, the team analyzed cells taken from the hind leg muscles of mice that ran once on a treadmill and animals that ran regularly. Then, the researchers compared them with muscle cells obtained from sedentary mice.
Muscle cells in mice that ran on treadmills, once or regularly, showed classic signs of inflammation -; Greater activity of genes that regulate various metabolic processes and higher levels of chemicals that promote inflammation, including interferon.
Both groups had high levels of Treg cells in their muscles. Further analysis showed that in both groups, Tregs reduced exercise-induced inflammation. None of these changes were observed in muscle cells of sedentary mice.
However, the metabolic and performance benefits of exercise were only evident in regular exercise -; The rats that tried to run repeatedly. In that group, Tregs not only suppressed exercise-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 single bouts of exercise do not lead to significant improvements in performance and that regular activity over time is required to reap the benefits.
Further analysis confirmed that Tregs are, in fact, responsible for the broad range of benefits seen in regular exercisers. Animals that lacked Tregs had uncontrolled muscle inflammation, characterized by rapid accumulation of inflammatory-promoting cells in their back muscles. Their muscle cells also had abnormally swollen mitochondria, a sign of metabolic abnormalities.
More importantly, animals lacking Tregs did not adapt to the increasing demands of exercise over time as well as mice with intact Tregs did. They did not gain the same whole-body benefits from exercise and had reduced aerobic fitness.
The muscles of these animals also had excessive amounts of interferon, a known driver of inflammation. Further analysis showed that interferon acts directly on muscle fibers to alter mitochondrial function and limit energy production. Blocking interferon prevents metabolic abnormalities and improves aerobic fitness in Tregs-deficient mice.
“The villain here is interferon,” Langston said. “In the absence of parental Tregs to counter it, interferon causes uncontrolled damage.”
Interferon is known to promote chronic inflammation, a process that underlies many chronic diseases and age-related conditions and has become an exciting target for therapies aimed at reducing inflammation. Tregs have attracted the attention of scientists and industry as a treatment for a range of immunologic conditions characterized by abnormal inflammation.
The study findings provide a glimpse into the cellular inner workings behind exercise’s anti-inflammatory effects and underscore its importance in harnessing the body’s own immune defenses, the researchers said.
There are efforts to design interventions targeting Tregs in the context of specific immune-mediated diseases. And while immunologic conditions driven by chronic inflammation require carefully calibrated therapy, exercise is another way to combat inflammation, the researchers said.
“Our research suggests that with exercise, we have a natural way to boost the body’s immune system to reduce inflammation,” Mathis said. “We only looked at muscle, but it’s possible that exercise is increasing Treg activity elsewhere in the body.”
Authorship, Funding, Disclosure
Co-investigators included Izzy Sun, Birgitta Ryback, Bruce Spiegelman, Amber Muller, and Christophe Benoist.
The work was funded by National Institutes of Health grants R01 AR070334, F32 AG072874, and F32 AG069363; and by the JPB Foundation.
Kent Langston, P., etc (2023) Regulatory T cells protect muscle mitochondria from interferon--mediated damage to promote the beneficial effects of exercise.. Science Immunology. doi.org/10.1126/sciimmunol.adi5377.