A new study published in Science Immunology has hinted at the possible molecular mechanisms linking exercise to inflammation control.

We’ve known for many years that exercise conveys health benefits: cardiovascular disease protection, diabetes risk reduction and even a reduced chance of developing dementia. But the mechanisms that link workouts to better health have remained unclear. 

The research, conducted on mice, indicates that muscle inflammation triggered by exercise prompts the activation of T regulatory cells (Tregs), which not only counteract inflammation but also enhance the muscle's ability to utilize energy, thereby improving endurance. Tregs, which have previously caught the limelight for their role in autoimmune disease management, may now also be placed at the center of the inflammation–exercise axis.   

The “powerful effects” of exercise

Diane Mathis, the study's senior investigator and the Morton Grove-Rasmussen Professor of Immunology in the Blavatnik Institute at Harvard Medical School, said in a press release that the study shows that immune cells’ functions go far beyond protection against pathogens. "Our study demonstrates that the immune system exerts powerful effects inside the muscle during exercise," Mathis stated.

The researchers warned that the results have yet to be replicated in humans, but they believe that the study is a significant stride toward understanding the cellular and molecular dynamics of exercise that lead to health benefits.

Kent Langston, a postdoctoral researcher in the Mathis lab and first author of the study, said, "We’ve known for a long time that physical exertion causes inflammation, but we don't fully understand the immune processes involved." He explained that the research provides a high-resolution view of T cells' activity at the point of exercise — the muscle. This aspect of exercise has been overlooked in previous studies that focused more on hormonal release during exercise.

Exercise causes short-lasting damage to our muscles, which kicks off an inflammatory cascade. This is part of a process that includes enhanced gene expression for muscle structure, metabolism and mitochondrial function, all of which help adapt the body to the increased energy demands of exercise.

Regular running secures big benefits

The researchers divided their mice into three groups: those who ran on a treadmill regularly, those who ran just once and sedentary mice. Both groups who had recently used the treadmill showed increased metabolic and inflammatory markers of exercise. These markers included higher levels of Tregs, which dampened the inflammation. No such markers were noted in the sedentary mice.

Sadly, that doesn’t mean a single running session will secure you the benefits of a regular running program. In the mice that ran regularly, Tregs acted on muscle metabolism and performance in addition to their immune-suppressing function. These changes are key to long-term performance benefits, say the researchers.

Further analysis showed that animals who had no Tregs showed out-of-control inflammation in response to exercise and metabolic problems. These animals also didn’t derive the same benefits of exercise as mice with Tregs.

Tackling interferon

Moreover, the study pointed out the detrimental role of the inflammatory molecule interferon in the absence of Tregs. It was shown to cause unchecked damage by directly affecting muscle fibers, thus disrupting mitochondrial function and energy production. Blocking interferon improved metabolic health and aerobic fitness in mice without Tregs. “In the absence of guardian Tregs to counter it, interferon went on to cause uncontrolled damage,” explained Langston.

Interferon has also been linked to long-term inflammation that underlies autoimmune conditions. Tregs have likewise been seen as a target that could be boosted to tackle these illnesses. Many of these conditions will require carefully balanced therapeutic interventions to manage, but the new study highlights the beneficial effects of exercise.

“Our research suggests that with exercise, we have a natural way to boost the body’s immune responses to reduce inflammation,” concluded Mathis.

Reference: Langston PK, Sun Y, Ryback BA, et al. Regulatory T cells shield muscle mitochondria from interferon-γ–mediated damage to promote the beneficial effects of exercise. Sci Immunol. 2023;8(89):eadi5377. doi:10.1126/sciimmunol.adi5377

This article is a rework of a press release issued by Harvard Medical School. Material has been edited for length and content.

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