Regulatory T cells shield muscle mitochondria from interferon-γ–mediated damage to promote the beneficial effects of exercise, 2023, Mathis et al

Regulatory T cells shield muscle mitochondria from interferon-γ–mediated damage to promote the beneficial effects of exercise

Editor’s summary
Regulatory T cells (Tregs) support repair of injured muscle, but whether they participate in the response of healthy muscle to exercise training remains unclear. Using acute and chronic models of exercise in mice, Langston et al. found that Tregs suppress exercise-induced skeletal muscle inflammation that is counterproductive for performance enhancement. Tregs were required for gains in exercise capacity and promoted muscle metabolic reprogramming by protecting mitochondria from interferon-γ–driven damage. These results identify Tregs as a key regulatory element that is activated in response to exercise and needed to support performance-enhancing muscle adaptations. —Claire Olingy

Abstract
Exercise enhances physical performance and reduces the risk of many disorders such as cardiovascular disease, type 2 diabetes, dementia, and cancer. Exercise characteristically incites an inflammatory response, notably in skeletal muscles. Although some effector mechanisms have been identified, regulatory elements activated in response to exercise remain obscure.

Here, we have addressed the roles of Foxp3+CD4+ regulatory T cells (Tregs) in the healthful activities of exercise via immunologic, transcriptomic, histologic, metabolic, and biochemical analyses of acute and chronic exercise models in mice. Exercise rapidly induced expansion of the muscle Treg compartment, thereby guarding against overexuberant production of interferon-γ and consequent metabolic disruptions, particularly mitochondrial aberrancies. The performance-enhancing effects of exercise training were dampened in the absence of Tregs.

Thus, exercise is a natural Treg booster with therapeutic potential in disease and aging contexts.


https://www.science.org/doi/10.1126/sciimmunol.adi5377

 

Useful information. A full understanding of how exercise causes various responses might be useful for figuring out PEM.

How long will it take for the fitness and bodybuilding industries to promote T-reg boosters and other such products promising huge gains from this preliminary study?

 

Nor me.

Spoiler: some of their listed references that are available (most open access, one via SciHub)

Regulation of muscle growth and regeneration by the immune system (2017, Nature Reviews Immunology)

A Special Population of Regulatory T Cells Potentiates Muscle Repair (2013, Cell)

T-regulatory cells exhibit a biphasic response to prolonged endurance exercise in humans (2017, European Journal of Applied Physiology)

Transcriptomic profiling of skeletal muscle adaptations to exercise and inactivity (2020, Nature Communications)

Treg cells limit IFN-γ production to control macrophage accrual and phenotype during skeletal muscle regeneration (2018, Proceedings of the National Academy of Sciences)

The potential for Treg-enhancing therapies in tissue, in particular skeletal muscle, regeneration (2023, Clinical and Experimental Immunology)

Parsing the Interferon Transcriptional Network and Its Disease Associations (2016, Cell)

 

That caught my eye and, while I realise it's not the same protein, I recall there was a preprint LC GWAS study that highlighted FOXP4 — Genome-wide Association Study of Long COVID (2023, Preprint: MedRxiv) which had this comment in our thread —

I found the following papers —

Foxp4 Is Dispensable for T Cell Development, but Required for Robust Recall Responses (2012, PLOS ONE)

Identification of a forkhead box protein transcriptional network induced in human neutrophils in response to inflammatory stimuli (2023, Frontiers in Immunology)

 

The summary page on Tregs from the British Society for Immunology says —

I presume they also have FoxP4 but I haven't read through the above papers yet. The abstract from the 2012 paper implies this with —

 

A simpler explanation would be that muscle cell damage, whether by exercise or massage, triggers immune activation, which in turn leads to glial activation which leads to PEM symptoms due to abnormalities in the response to glial activation. That also explains cognitive-induced PEM, which skips the muscle cells and body immune cells, and goes straight to glial activation, without the consistent delay from the muscle-immune pathway.

 

Yes, most definitely! And increasingly severe PEM with increasing disease severity to the extent that simply patting on my arm now that I am severe can create PEM. Not being able to tolerate massage seems to be a common experience in my network of PWME on social media.

Related is Alain Moreau's use of a gently pulsing arm device similar to a blood pressure monitor to induce PEM in his research.

 

And yet people who work hard physical labor jobs usually live shorter lives, have more health problems, so this is clearly not the whole thing.

They seem to mean recreational exercise again, which only some people have the luxury to commit to.

 

For that, I wonder whether the PEM is being induced by cognitive exertion from processing that data, rather than a physical effect. Is the delay lengthy and consistent, such as 24 hrs, or shorter and inconsistent?

 

Interesting thought. The incident I'm thinking of was definitely a delayed PEM response happening the next day. It was actually patting my back, not my arm. I do have an immediate aversion to any patting or movement on my skin, just seems like it is exhausting me so maybe that is cognitive exertion from processing the data? But, on the other hand the effect of a full body massage was definitely full on delayed PEM. So possibly two different routes?

 

There seem to be two definite routes to PEM, so it's difficult to determine which one did the triggering. I think it's also possible that the two (or even more?) different triggers can be additive: talking for 1 minute might not be enough, and washing one dish might not be enough, but if you do both of those within x hours, it might trigger PEM. Maybe a viral infection that is stopped before symptoms occur can add to triggering PEM, or lower the threshold for triggering. Likewise, our guts are constantly fighting microbes, so if eating a certain food results in some nasty bacteria replicating more, there might be more cytokines or LPS reaching the bloodstream, adding to the chance of triggering PEM.

Has anyone bothered to enter detailed food/activity/symptoms data into a computer so that they could look for this sort of correlation? That might be a good student project: enter the data for one or more ME--or long-Covid--patients to have a lot of detailed data to search for correlations.

 

Muscles normally fill up with T cells after at least unaccustomed exercise. If you were short on T regs there would probably be more pain and oedema of the muscle. But in ME as far as I know there is nothing unusual about T regs and muscle does not show more inflammation. Basically we would expect creatine kinase levels to go up more with exercise (they normally do a bit) and I am pretty sure there is no evidence for that in ME. People who have done CPET must have looked at that.

 

It seems tortuous. The entry of T cells into muscle after exercise is almost certainly just a non-specific upgrade in traffic as for monocytes due to some adhesion molecule up regulation. If T regs are there, they will go in too. None of these T cells has much to do in this situation since there is no foreign agent to recognise. They just come in to check, like ticket inspectors. So it all seems a bit hard work as a theory.

 

My view is that my body's immune cells are probably working normally, and cytokine production, such as IFN-g rises normally after exertion. The problem is an abnormal response to those cytokines. Maybe that abnormal response is in glial cells, or maybe they are functioning normally too, but the response of some other cells or other structures to the glial's normal response is abnormal.

 

I'm not sure we can declare that with certainty.