Some Benefits of Exercise Stem from the Immune System

The connection between exercise and inflammation has captivated the imagination of researchers ever since an early 20th-century study showed a spike of white cells in the blood of Boston marathon runners following the race.

Now, a new Harvard Medical School study published Nov. 3 in Science Immunology may offer a molecular explanation behind this century-old observation.

The study, done in mice, suggests that the beneficial effects of exercise may be driven, at least partly, by the immune system. It shows that muscle inflammation caused by exertion mobilizes inflammation-countering T cells, or Tregs, which enhance the muscles’ ability to use energy as fuel and improve overall exercise endurance.

Protecting from cardiovascular disease, reducing the risk of diabetes, shielding against dementia. The salutary effects of exercise are well established. But exactly how does exercise make us healthy? The question has intrigued researchers for a long time.

The new findings come amid intensifying efforts to understand the molecular underpinnings of exercises. Untangling the immune system’s involvement in this process is but one aspect of these research efforts.

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 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.

Interferon is known to promote chronic inflammation, a process that underlies many chronic diseases and age-related conditions and has become a tantalizing target for therapies aimed at reducing inflammation. Tregs have also captured the attention of scientists and industry as treatments for a range of immunologic conditions marked by abnormal inflammation.

There are efforts afoot to design interventions targeting Tregs in the context of specific immune-mediated diseases. And while immunologic conditions driven by aberrant inflammation require carefully calibrated therapies, exercise is yet another way to counter inflammation, the researchers said.


P. Kent Langston, Yizhi Sun, Birgitta A. Ryback, Amber L. Mueller, Bruce M. Spiegelman, Christophe Benoist, Diane Mathis. Regulatory T cells shield muscle mitochondria from interferon-γ–mediated damage to promote the beneficial effects of exercise. Science Immunology, 2023; 8 (89) DOI: 10.1126/sciimmunol.adi5377

Harvard Medical School. (2023, November 3). Some benefits of exercise stem from the immune system. ScienceDaily. Retrieved November 8, 2023 from

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