ABOVE: Regulatory T cells play a key role in muscle repair after endurance exercise. ©istock, Pavel1964

Whether it’s a jog through the park or a weight lifting session in a sweaty gym, exercise fosters good health. Compared to remaining sedentary, regular movement associates with a 20-30 percent lower risk of dying from all causes.1

However, exercise causes mechanical stress in skeletal muscles; this, along with microinjuries, can spark mild inflammation. A short bout of inflammation is helpful to clear damaged material, but muscles must quickly move on to a state of repair, or else they could endure chronic, harmful inflammation. Understanding the transition from inflammation to repair could help researchers better grasp how exercise fends off inflammatory diseases like cardiovascular disease, type 2 diabetes, and cancer.

Immunologists Kent Langston, Diane Mathis, and their team at Harvard Medical School recently discovered that after exercise, regulatory T cells (Treg) quench inflammation, preventing the inflammatory cytokine interferon-gamma (IFN-gamma) from damaging muscle mitochondria in mice.Furthermore, these protective Treg were necessary for mice to adapt to endurance exercise.

“They showed that regulatory T cells are important for the general muscle responsiveness to exercise, and that’s really important and really new,” said molecular biologist Mark Febbraio at Monash University, who was not involved in this work.

T cells are white blood cells that are major players in the adaptive immune response, and Treg are a class of T cell that regulates other immune cells. Mathis’s group had previously discovered that Treg help injured muscles transition from an inflammatory to a repair state, in part by making mediators that promote muscle regeneration.3 If Treg are absent, muscle repair slows.

Langston, a postdoctoral fellow in Mathis’s research group, wanted to determine whether a similar phenomenon occurred during exercise, so he and the team put mice on treadmills and had them run at moderate intensity for 90 minutes. This acute exercise rapidly triggered an increase in both pro-inflammatory macrophages and anti-inflammatory Treg in muscles. Researchers then performed whole tissue transcriptional profiling of the muscles. Several genes were transcribed differently in weight-bearing versus non-weight-bearing muscles, including some involved in building muscle structure and wound healing.

The team then ran the same tests with endurance exercise training, giving mice wheels and letting them run as much as they wanted for four weeks. In this instance, said Mathis, levels of inflammation and Treg were highest two weeks into training. 

Next, the team eliminated Treg cells in one group of mice. After exercise, there were more pro-inflammatory macrophages and increased IFN-gamma in mice without Treg cells compared to those with Treg, as well as increased transcription of inflammatory genes. Furthermore, mice without Treg didn’t experience the performance enhancing effect of exercise training, such as longer running times and more mechanical work performed.

The team also wanted to examine and compare the mitochondria from the two types of mice, since mitochondria power the muscles. They extracted quadricep muscles from exercise-trained mice and looked at them with a transmission electron microscope. Treg-deficient muscles had more “swollen” mitochondria, which were larger, had lost some of their intricate inner folds, and had a dilution of matrix contents. They also performed high-resolution respirometry on muscle fibers from exercise-trained mice. Exercise increased respiration in mice with Treg but not in mice without Treg. In other words, the mitochondria in exercised muscles without Treg were less healthy and produced less energy than those in exercised muscles with Treg.

          Two black and white images show normal skeletal muscle mitochondria on the left and enlarged, disturbed, white-dotted Treg-deficient skeletal muscle mitochondria on the right.
In Treg-deficient skeletal muscle cells (right), mitochondria are swollen compared to those in muscles from mice with Treg.
Diane Mathis and Kent Langston


Finally, the team wanted to know how exactly Treg protected the muscles. Since their earlier experiments hinted that IFN-gamma played a role, they reduced IFN-gamma in Treg-deficient mice. These mice could run longer and perform more work than their littermates with IFN-gamma. “With the interferon, you didn’t have the performance-enhancing effect that exercise training allowed,” said Mathis.

In addition, these IFN-gamma-deficient mice also had fewer swollen mitochondria in some of their muscles and more electron transport chain complexes in the mitochondria. “That benefit of exercise training is dependent on Treg, because they’re controlling interferon-gamma production,” said Mathis. Ablation of Treg causes increased production of IFN-gamma by natural killer cells and other cells.4

Treating muscle fibers with recombinant IFN-gamma significantly reduced mitochondrial respiration. The team also generated a mouse strain with a conditional deletion of IFN-gamma receptor on muscle cells. The exercise capacity of these mice improved much more after training than that of control mice, and this associated with an increase in most complexes of the electron transport chain in mitochondria.

“It’s difficult to tease out whether the immunological response is truly a bonafide response to exercise per se, or is there a muscle damaging component to the exercise that results in this regulatory T cell response?" Febbraio noted. “I want to make clear that it’s not a criticism of the paper; it’s just an element of the study design that is difficult to get around.” Perhaps, in the future, he said, the researchers could also study different modalities of exercise.

Mathis said that understanding this pathway could someday help counter some of the effects of aging. “As people age, they lose the ability to repair their muscle very well, and that’s probably partially because there’s more inflammation and less Treg,” said Mathis, who cofounded companies that study Treg in multiple sclerosis and type 1 diabetes. In the future, she said, researchers could explore whether interventions to increase Treg or reduce interferon activity in older individuals could help manage inflammation and improve health.

References

  1. Arem H, et al. Leisure time physical activity and mortality: a detailed pooled analysis of the dose-response relationship. JAMA Intern Med. 2015;175(6):959-967.
  2. Langston PK, et al. Regulatory T cells shield muscle mitochondria from interferon-gamma-mediated damage to promote the beneficial effects of exercise. Sci Immunol. 2023;8(89):adi5377.
  3. Burzyn D, et al. A special population of regulatory T cells potentiates muscle repair. Cell. 2013;155(6):1282-1295.
  4. Panduro M, et al. Treg cells limit IFN-gamma production to control macrophage accrual and phenotype during skeletal muscle regeneration. Proc Natl Acad Sci. 2018; 115(11):E2585-E2593.