The great question for chronic fatigue syndrome and long COVID is: what causes post-exertional malaise (PEM)? The latest study to come out of Nancy Klimas’s Institute for Neuroimmune Medicine – led by Lubov Nathanson (senior author) and directed by Derek J. Van Booven (lead author) – defines PEM as “as a worsening of symptoms following even minor physical or mental exertion”.
The study’s title, “Stress-Induced Transcriptomic Changes in Females with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Reveal Disrupted Immune Signatures“, says it all. They applied a stressor – an exercise session on a bicycle – to women with ME/CFS (given the gender differences showing up, they’re understandably concentrating on women) and then measured how the expression of the genes found in immune cells (T, B, NK, monocytes, dendritic cells) in the blood changed.
We tend to think of the metabolism, blood flows, and the mitochondria when we think of exercise-induced PEM. It’s clear, of course, that ME/CFS is many things – it’s a metabolic disease, an autonomic nervous system disease, a neuroendocrine disease, and an immune disease. We’ll see in this study that the immune system plays a major role in our body’s response to exercise as well – and in ME/CFS, it’s not responding very well.
The study was small and not so small. It was small in numbers (20 ME/CFS / 20 healthy controls), but it dug deep. It used RNA sequencing (RNA-seq) to explore gene expressions at three different time points: baseline before exercise challenge (T0), maximal exertion (T1), and 4 h after maximal exertion (T2).
The results were startling – and not so startling. The genes in the immune cells of the healthy controls responded dramatically to the exercise bout. From prior to the exercise study to the point of maximal exertion, 102 genes significantly changed their level of expression. The healthy controls’ (HC) immune cells were “on”; virtually all of the genes (98) became more expressed.
Not so in the ME/CFS patients. As 102 genes in the HC” immune cells exploded into action, the genes in the immune cells of the ME/CFS patients lay low. They basically sat the exercise bout out – no significant changes in gene expression were found.
That was a pretty startling finding, but it aligns with other recent findings from the Hanson group. A small urine metabolomics study that found an explosion in altered metabolites (n=400) in healthy controls but no significant change in ME/CFS patients’ metabolites 24 hours after exercise later prompted the authors to write:
“Our most unanticipated discovery is the lack of changes in the urine metabolome of ME/CFS patients during recovery while significant changes are induced in controls after CPET, potentially demonstrating the lack of adaptation to severe stress in ME/CFS patients.”
So it was with protein levels as well (!). Germain’s study found exercise triggered a much bigger change in the proteins found in the sedentary, but healthy, controls than in the ME/CFS patients. The healthy controls responded to the rigors of the second exercise test by scrambling their protein mix more. Lacking the same ability to do so, the ME/CFS patients did not.
Immune genes, metabolites, proteins – that’s a pretty heady mix. The problem appears to be less that ME/CFS patients’ systems are responding in strange ways to exercise than that they’re not responding at all. Whatever switch gets turned on in the body to allow humans to tolerate and benefit from exercise – it’s not happening on multiple levels in ME/CFS.
It got even more interesting. The genes in the immune cells that got turned on in the healthy controls turned out to cluster in none other than our old “friend” – natural killer (NK) cells. NK cells are the one messed-up immune cell that’s been identified with ME/CFS from the very beginning. Plus, the number of NK cells in the blood increased during the exercise in the HCs but remained flat in the ME/CFS patients.
We tend to associate the poor cytotoxic or killing abilities of the NK cells in ME/CFS with problems responding to pathogen invasion, but they, to my knowledge, have never been linked with exercise before.
Studies indicate, though, that NK cells are the most responsive immune cell to exercise – and what an interesting coincidence that is! As soon as we start to exercise, our NK cells wake up, become activated and move into the bloodstream on the alert for possible problems. Their levels in the blood increase 2-5xs normal during exercise, and then rapidly fall as soon as the exercise stops. (Because exercise-activated NK cells exhibit an anti-tumor profile, exercise is now being assessed as an adjunct to cancer treatment. )
Interestingly, it’s precisely the feature of the NK cells that’s gotten whacked in ME/CFS – cytotoxicity – that gets amplified during exercise – another interesting coincidence.
The fun continued in the after-exercise recovery period. This time, perhaps struggling to clean up the damage, it was the ME/CFS patients’ immune cells whose gene expression exploded as about 50 percent more of their genes became activated.
- It appears that problems with blood flows, oxygen utilization, and energy production combine together to make exercise pretty miserable in ME/CFS. The latest study from Nancy Klimas’s Institute for Neuroimmune Medicine makes it clear, though, we can’t keep the immune system out of the mix. This is, after all, an all-purpose disease.
- This study assessed how the genes of immune cells (T, B, NK, dendritic, monocytes) in people with ME/CFS and healthy controls expressed themselves in response to exercise.
- The genes of the healthy controls expressed themselves well. Over a hundred genes leapt into action during the exercise period. The immune cells of the ME/CFS patients, on the other hand, laid low and were basically MIA during the exercise period. In fact, not one gene met the criteria for activation.
- This strange non-response or very limited response to a pretty darn big stressor like intense exercise has shown up in metabolic and protein studies in ME/CFS. For whatever reason (cellular exhaustion?), major systems in ME/CFS are simply not responding to exercise.
- In the case of the immune cells this study was examining the major “downer” in the study was the inability of our old “friend” natural killer cells (NK cells) to show up. Problems with NK cells showed up early in ME/CFS and they’ve been consistently found.
- In a rather remarkable coincidence (coincidence?), NK cells turn out to be the most exercise-responsive immune cell. During exercise NK cells become activated, and jump into the bloodstream where their levels increased 2-5xs. Unless you have ME/CFS that is. They didn’t “jump” nor did they appear to be become activated.
- These cells apparently troll the bloodstream because exercise inevitably produces some damage as the free radicals leak out of the mitochondria. Studies suggest that in ME/CFS, exercise produces a lot of damage as it produces more free radicals than usual and the antioxidants that keep the free radicals in check are low.
- Because exercise appears to produce leaky gut in ME/CFS as well, NK cells would be needed to combat the bacteria that are showing up in the bloodstream.
- In the after-exercise recovery period, perhaps struggling to clean up the damage, it was the ME/CFS patients’ immune cells whose gene expression exploded as about 50 percent more of their genes became activated. indeed, genes associated with the cellular response to stress and regulation of cellular response to stress that were amongst the most upregulated.
- Plus 4 hours after exercise it appeared that the ME/CFS patient’s immune cells – in contrast to the healthy controls immune cells – were still trying to tamp down inflammation.
- The authors concluded that “after significant exertion, ME/CFS patients are unable to mount the proper defenses to combat cellular stress, leaving their immune cells vulnerable to apoptosis (cell death)”.
- Finally, because herpesviruses can infect natural killer cells, it’s possible that herpesvirus reactivation may play a role in all this.
In contrast, the immune cells in the healthy controls were more prone to turn on genes involved in immune-response signaling and leukocyte activation.
What kind of stress were the ME/CFS patients’ cells facing? Recent studies suggest that high rates of oxidative stress – perhaps produced by malfunctioning mitochondria – could be hammering away at the lipid coatings of cells, releasing free radicals that feed a free radical storm. The authors suggested something similar, writing that:
“after significant exertion, ME/CFS patients are unable to mount the proper defenses to combat cellular stress, leaving their immune cells vulnerable to apoptosis (cell death)”.
The finding of an increased expression of genes involved in “positive regulation of cytokine production” 4 hours after exercise suggested ME/CFS patients’ immune systems were, long after the inflammatory pathways of the healthy controls systems had settled down, still trying to tamp down cytokine production; i.e. low-grade inflammation.
The authors concluded: “These gene expression changes may indicate that dysregulated immune responses are contributing to the PEM that characterizes this disease.”
A Gut-NK Cell-PEM Connection in ME/CFS?
We don’t know what’s happening with NK cells in the gut, but they apparently play a major role in batting down intestinal infections and immune regulation. We do know that exercise in ME/CFS increases leaky gut, which results in the transference of gut bacteria into the bloodstream. Having gut bacteria in the bloodstream is a big no-no and the immune system, including NK cells, jumps to kill and remove the bacteria, that is – if the NK cells are there and functioning.
In ME/CFS, though, it appears they’re not. NK cell numbers neither increased nor became activated during exercise, potentially setting up an intriguing NK-cell-gut-exercise-PEM-ME/CFS connection. People with ME/CFS exercise, their guts leak bacteria into the bloodstream, which NK cells, in particular, fail to clean up quickly, leading to inflammation and PEM.
A Herpesvirus-NK Cell Connection?
Herpesviruses have made waves in both ME/CFS and long COVID recently, and it’s possible that a herpesvirus-NK cell connection could be present. The Epstein-Barr virus can infect NK cells, and one review noted that “increasing evidence indicates that most, if not all, members of the herpesvirus family suppress NK cell activity to some extent”. One study found that a latent CMV infection compromised NK cells’ ability to conduct immune surveillance after exercise.
The authors of the present study noted that reactivated herpes viruses in ME/CFS appear to result in mitochondrial dysfunction (remodeling) that pushes cells toward a hypometabolic (Dauer) state, and suggested that exercise in ME/CFS may be resulting in herpes virus reactivation.
They may be exhausted in fibromyalgia as well. A study suggesting that NK cells are attacking nerve fibers in fibromyalgia also found that they displayed markers of exhaustion.
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As a used to be athlete who loved nothing more than to press his body to its limits nothing has struck me more than the huge payback that occurs after even mild exertion. Exercise inevitably brings out the worst in us – both in the lab and in our lives. If the answer is going to pop out its going to pop out in exercise studies more quickly than anyplace else. That’s why I latch onto exercise studies like a bee onto honey. If that makes sense to you support HR in a way that works for you 🙂
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