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

[EndME]

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

 

[Creekside]

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?

 

[Hutan]

I can't access this paper. What do people reckon about the idea of Tregs not doing their job of controlling an inflammatory response to exercise properly in people with ME/CFS? What would prove that idea wrong?

I have been interested in the idea of rhabdomyolysis as part of ME/CFS pathology. Early on in my disease, I bought 10 massage sessions, thinking massage might help make things better somehow. But I found that I would end up with PEM for two or three days after each massage, in much the same way as I would with a session of pilates. That seemed completely ridiculous, I didn't believe that a massage could possibly be causing that (even a fairly full-on, sometimes quite painful one, as these were), but by massage 5 it was clear to me that they were doing a lot more harm than good and I stopped having them. (Has anyone else had PEM brought on by a massage?)

Could there be a vicious cycle of muscle damage, an exuberant, poorly controlled inflammatory response, and then damage to mitochondria and reduction in ATP production that causes all sorts of problems including potentially more muscle damage? Could the crushing pain in limbs that comes as part of PEM be due to an uncontrolled inflammatory response to muscle damage?

From Rhabdomyolysis: Pathogenesis, Diagnosis, and Treatment, Torres et al, 2015

Rhabdomyolysis has been described in all types of infections, ranging from localized muscle infections with erythema (bacterial pyomyositis) to patients with sepsis and no direct muscle infection.1,46 Proposed mechanisms for the development of rhabdomyolysis include tissue hypoxia secondary to sepsis or dehydration, toxin release, associated fever, direct bacterial invasion of muscle, or rigors/tremors.1Classically, Legionella bacteria have been associated with bacterial rhabdomyolysis.47 Viral infections have also been implicated in rhabdomyolysis development, most commonly influenza A and B viruses.48,49Rhabdomyolysis because of other viruses such as HIV,50 coxsackie virus,51 Epstein-Barr virus,52Cytomegalovirus,53 herpes simplex virus,54 varicella zoster virus,55 and West Nile virus56 has also been described.

But, if this was happening, wouldn't there be more evidence of muscle damage?

Presenting symptoms tend to reflect the primary disease process, as well as superimposed symptoms of renal failure or muscle injury. The classic triad of symptoms of rhabdomyolysis consists of myalgia, weakness, and tea-colored urine. The muscle mass of the patient, the concentration of urine, and glomerular function can affect the color of the urine. Gabow et al, in a study of 87 cases (CK >500 IU/L), found that 26% of patients tested negative with the urine orthotolidine-toluidine dipstick test for myoglobin.57 Mannix et al showed that common presenting symptoms of pediatric rhabdomyolysis, regardless of kidney injury, were muscle pain, fever, and viral prodromes.19 Dark or tea-colored urine was reported in only 3.6% of cases.19 Patients may also have tense and swollen muscles on examination. The classic triad is observed in <10% of patients only, and >50% of patients do not complain of muscle pain or weakness. Systemic manifestations may include tachycardia, general malaise, fever, and nausea and vomiting and as such are nonspecific. The clinical manifestations of ARF, disseminated intravascular coagulation, and multiorgan failure may subsequently appear.2

And more evidence of the metabolites resulting from muscle damage?

The gold standard for laboratory diagnosis is the determination of plasma CK. Although a cutoff threshold has not been established, a concentration 5 times the upper limit of the normal reference range (ie, 1,000 IU/L) is commonly used.2 CK level is generally considered predictive of the likelihood of developing ARF, and a concentration >5,000 IU/L is closely related to the development of kidney damage. CK has a half-life of 1.5 days. As a consequence, CK blood levels remain increased longer than the concentration of myoglobin that has a half-life of 2-4 hours. Myoglobin concentrations tend to normalize within 6-8 hours following the muscle injury.2 Plasma myoglobin is not as sensitive as CK for diagnosis because of its short half-life, resulting in false-negative tests.16 Urine myoglobin will show erythrocyte positivity on urine dipstick because the orthotoluidine portion of the dipstick turns blue in the presence of myoglobin.

Higher levels of creatine kinase have been found, but that might just be the product of periods of immobility. I do get changes in the colour of my urine (browner) in PEM. Have we seen abnormal increases in CK specifically after exertion in ME/CFS? Rhabdomyolysis does cause hypovolemia.

I'm aware that I'm rambling here, maybe grasping at straws. And quite possibly taking things off-topic, away from the idea of an inadequate t-cell response.

If someone who can access the paper could post any interesting bits, that would be great.

 

[SNT Gatchaman]

I can't access this paper. [...] If someone who can access the paper could post any interesting bits, that would be great.

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)

 

[SNT Gatchaman]

Here, we have addressed the roles of Foxp3+CD4+ regulatory T cells (Tregs) in the healthful activities of exercise

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 —

A very interesting finding.
It is sufficiently close to known immune regulators (such as FOXP3) to seem maybe relevant but also suitably obscure - maybe responsible for some control mechanism we don't yet know. much about.

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)

 

[Hutan]

I assumed that a cell had to have the Foxp3 and the CD4 to be a Treg. If it had Foxp4, would it be some other sort of cell?

Have we had studies looking at the variation in cell markers in Tregs in ME/CFS?

 

[SNT Gatchaman]

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

Natural Treg are characterised as expressing both the CD4 T cell co-receptor and CD25, which is a component of the IL-2 receptor. Treg are thus CD4+ CD25+. Expression of the nuclear transcription factor Forkhead box P3 (FoxP3) is the defining property which determines natural Treg development and function.

FoxP3 is crucial for maintaining suppression of the immune system. Naturally occurring mutations in the FOXP3 gene can result in self-reactive lymphocytes that cause a rare but severe disease IPEX (Immune Dysregulation, Polyendocrinopathy, Enteropathy, X-Linked) in humans and scurfy in mice.

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 —

We report the initial characterization of Foxp4 in T lymphocytes. Foxp4 is expressed in both thymocytes and peripheral CD4+ and CD8+ T cells. We used a CD4Cre mediated approach to evaluate the cell autonomous role for Foxp4 in murine T lymphocytes

 

[Creekside]

Could there be a vicious cycle of muscle damage, an exuberant, poorly controlled inflammatory response, and then damage to mitochondria and reduction in ATP production that causes all sorts of problems including potentially more muscle damage?

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.

 

[Helene]

Early on in my disease, I bought 10 massage sessions, thinking massage might help make things better somehow. But I found that I would end up with PEM for two or three days after each massage, in much the same way as I would with a session of pilates. That seemed completely ridiculous, I didn't believe that a massage could possibly be causing that (even a fairly full-on, sometimes quite painful one, as these were), but by massage 5 it was clear to me that they were doing a lot more harm than good and I stopped having them. (Has anyone else had PEM brought on by a massage?)

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.

 

[rvallee]

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.

 

[Creekside]

simply patting on my arm now that I am severe can create PEM.

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?

 

[Helene]

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?

 

[Creekside]

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.

 

[Jonathan Edwards]

I can't access this paper. What do people reckon about the idea of Tregs not doing their job of controlling an inflammatory response to exercise properly in people with ME/CFS? What would prove that idea wrong?

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.

 

[Hutan]

Personally, my tregs numbers have actually been measured as bit higher than the normal and I don't think we've seen any evidence of differences in numbers in either direction in ME/CFS on average. So, if it's an issue with tregs, it's a problem of function not numbers.

I'm wondering if the muscle damage and the inflammation could be disconnected. So, similar amounts of muscle damage after exercise, but more activation of immune cells to the site (is that inflammation?), some abnormal response to the damage. If that happened, if the muscle damage wasn't very different, maybe creatine kinase levels would not necessarily be different? Is that possible?

 

[Jonathan Edwards]

I'm wondering if the muscle damage and the inflammation could be disconnected. So, similar amounts of muscle damage after exercise, but more activation of immune cells to the site (is that inflammation?), some abnormal response to the damage. If that happened, if the muscle damage wasn't very different, maybe creatine kinase levels would not necessarily be different? Is that possible?

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.

 

[Creekside]

But in ME as far as I know there is nothing unusual about T regs and muscle does not show more inflammation.

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.

 

[duncan]

None of these T cells has much to do in this situation since there is no foreign agent to recognise.

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

 

[SNT Gatchaman]

Now available at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10860652/