Exercise does undisputable good for musculoskeletal and endocrine health, but it also causes minor, temporary inflammation and muscle damage. Until now, scientists have known relatively little about how the immune system controls for just the right amount of post-exercise inflammation — the level that builds endurance without severely harming muscles.
Now, a new Science Immunology study in mice finds that a cell group called regulatory T (Treg) cells prevents excessive muscle inflammation during and after physical activity by suppressing production of a pro-inflammatory messenger protein, or cytokine, called IFNγ. Doing so essentially "shields" muscle cells' energy-making compartments — or mitochondria — from IFNγ's potent effects.
The analysis also reveals that mice without T reg cells create more IFNγ during exercise, and that these higher cytokine levels reduce the animals' ability to gain physical endurance.
"What is valuable about uncovering the Treg-IFNγ-mitochondria pathway is that it highlights how some factors stimulated by exercise are actually bad for muscle function, as is the case for IFNγ, and these factors require a balancing force that is stimulated in parallel, i.e., Tregs," said P. Kent Langston, first author of the study and specialist in immunometabolism at Harvard Medical School.
Working It Out
It's clear that physical activity over the course of a lifetime can support healthy aging and even lessen holistic inflammation. However, on a cellular level, the immediate act of exercising generates molecules that trigger inflammation and damage muscle fibers. What keeps this inflammation and damage under control and enables long-term benefits to emerge has been a mystery.
"Very little is known about what is happening in the muscle tissue itself," said Diane Mathis, corresponding author of the paper and immunobiologist with a focus on T cell-based autoimmunity at Harvard Medical School.
Muscle tissue contains not only muscle cells but also immune cells. While many immune cell groups produce inflammation-causing cytokines as a disease-fighting response, some subsets actually decrease such activity. Treg cells fall into this latter camp. By curbing inflammation in muscle fiber, they can help create a calmer environment more conducive to healing.
"We discovered several years ago that a distinct population of Tregs rapidly accumulates in skeletal muscle shortly after injury and that these cells are important for effective muscle regeneration," said Mathis. "So, naturally we wondered about how skeletal muscle Tregs might respond to exercise."
The team suspected that the T reg cells might be fine-tuning inflammatory responses during and after physical activity, controlling the degree of muscle damage and supporting physical endurance.
Lab Rats to Gym Rats
To determine whether T reg cells were operating behind the scenes, Mathis and her colleagues designed a way to assess how immune cells in mice respond during short- and long-term exercise. In the short-term exercise experiment, they had standard laboratory mice run for 90 minutes on a treadmill at roughly 55% of their maximum speed and measured the mice's muscle-located immune cells on day one, day three, and day seven of the training program. For the long-term endurance setup, they gave mice unlimited access to running wheels and measured the animals' immune cells after two, three or four weeks.
"We found that exercise induces a mild local inflammatory response and, at the same time, accumulation of Tregs to control the inflammation," said Mathis.
The results indicated that immune cells — most notably, T reg cells — do not merely react but also mediate the responses of other muscle cells to physical activity. This T reg cell-based effect was particularly obvious in the long-term exercising mice.
Next, the researchers wanted to understand what cellular-level mechanisms were happening after T reg cell accumulation. They turned to mice without Treg cells and saw that the animals had elevated levels of IFNγ when placed in the long-term exercise regime.
"We actually expended a considerable amount of effort trying to figure out whether the impaired exercise performance in our Treg-deficient mice was due to excessive muscle damage," said Langston. "It wasn't until we looked at the muscles under an electron microscope that we noticed mitochondrial aberrancies in the high IFNγ condition."
In the end, their examination shows that, when unimpeded by T reg cells, IFNγ harm energy-generating protein structures in muscle cells' mitochondria. Without these electron transport chain complexes working efficiently, muscle cells become metabolically compromised and cannot meet exercise-related energy demands or develop endurance as well.
"Our findings demonstrate that the muscle inflammation induced by exercise, in particular IFNγ production, must be kept in check by a special population of regulatory T cells for the beneficial effects of exercise to be achieved," said Langston.
Next (Non-Treadmill) Steps
Overall, T reg cells and the immune system at large modulate responses to IFNγ and other cytokines present during physical activity. This observation is particularly noteworthy in the context of muscle disorders and aging. Other studies have established that IFNγ increases in many tissues as people age.
"Whether this means that IFNγ causes age-related decline in the functions of every tissue remains to be seen," said Langston. "However, if the effects of IFNγ on muscle metabolism can be generalized, one might predict that IFNγ does more than merely indicate age-related decline."
If IFNγ is eventually proven to be actively contributing to age-related tissue damage, then therapies that target it — possibly through manipulation of T reg cells — might help geriatric patients improve their health without inflammatory repercussions. "We are actively testing some age-protective interventions that target aspects of the exciting biology uncovered by our Treg project," said Langston.
This line of thought requires additional testing and much more evidence. In the meantime, Langston, Mathis and their co-authors have several new projects. They plan to investigate what triggers IFNγ and other pro-inflammatory cytokine production in the first place during exercise. They also want to explore whether T reg cells in other tissues besides muscle fibers influence reactions to exercise.