Stress-Induced Transcriptomic Changes in Females with ME/CFS Reveal Disrupted Immune Signatures, 2023, van Booven et al.

Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic, complex multi-organ illness characterized by unexplained debilitating fatigue and post-exertional malaise (PEM), which is defined as a worsening of symptoms following even minor physical or mental exertion. Our study aimed to evaluate transcriptomic changes in ME/CFS female patients undergoing an exercise challenge intended to precipitate PEM. Our time points (baseline before exercise challenge, the point of maximal exertion, and after an exercise challenge) allowed for the exploration of the transcriptomic response to exercise and recovery in female patients with ME/CFS, as compared to healthy controls (HCs).

Under maximal exertion, ME/CFS patients did not show significant changes in gene expression, while HCs demonstrated altered functional gene networks related to signaling and integral functions of their immune cells. During the recovery period (commonly during onset of PEM), female ME/CFS patients showed dysregulated immune signaling pathways and dysfunctional cellular responses to stress. The unique functional pathways identified provide a foundation for future research efforts into the disease, as well as for potential targeted treatment options.

https://www.mdpi.com/1422-0067/24/3/2698

 

20 female ME/CFS v 20 female healthy controls, so smallish study, but looks sound:

Conclusions

"Overall, our results indicate that female ME/CFS patients respond differently to an exercise challenge that stimulates PEM, as compared to female HCs. Under maximum stress, ME/CFS patients are unable to facilitate transcriptomic changes in the cells of their immune system that would allow them to permit recovery. Meanwhile, in response to stress, HCs make several transcriptomic changes related to the integrity and function of their immune cells. During recovery, ME/CFS immune cells have dysfunctional cytokine signaling networks and are vulnerable to cell death due to poor defense systems and dysregulated epigenetic regulation of apoptotic pathways, whereas HCs regulate their lymphocytes and inactivate the inflammatory response. The findings presented in our study will help to advance our understanding of the pathways and genes that are relevant to PEM and fatigue tied to ME/CFS, with the goal of identifying targets to improve diagnosis and identify more targeted therapeutic options for female ME/CFS patients"

 

This is the second study that has found a lack of response to exercise at some timepoint, compared to controls who have some kind of response.

 

The conflict goes back to early stress research: "Stress was originally defined as the non-specific response of the body to any noxious stimulus."

Inevitably there's an enduring psych versus physio turf war: Stress revisited: A critical evaluation of the stress concept

Abstract
"With the steadily increasing number of publications in the field of stress research it has become evident that the conventional usage of the stress concept bears considerable problems. The use of the term ‘stress’ to conditions ranging from even the mildest challenging stimulation to severely aversive conditions, is in our view inappropriate. Review of the literature reveals that the physiological ‘stress’ response to appetitive, rewarding stimuli that are often not considered to be stressors can be as large as the response to negative stimuli. Analysis of the physiological response during exercise supports the view that the magnitude of the neuroendocrine response reflects the metabolic and physiological demands required for behavioural activity. We propose that the term ‘stress’ should be restricted to conditions where an environmental demand exceeds the natural regulatory capacity of an organism, in particular situations that include unpredictability and uncontrollability. Physiologically, stress seems to be characterized by either the absence of an anticipatory response (unpredictable) or a reduced recovery (uncontrollable) of the neuroendocrine reaction. The consequences of this restricted definition for stress research and the interpretation of results in terms of the adaptive and/or maladaptive nature of the response are discussed."

 

This is medical literature language so I'm ok with it. I've read numerous papers that mention exercise-induced stress behaviour.

 

Could you reference the other/previous study? Was there a thread on it here?

 

Given @Jonathan Edwards expertise it would be interesting to get his views.

Wonder if this could relate to lack of sedentary controls?

 

Figure 11 published in Plasma metabolomics reveals disrupted response and recovery following maximal exercise in myalgic encephalomyelitis/chronic fatigue syndrome

The figure shows a metabolite in patients that changes much less between several timepoints compared to the controls. On some level there appears to be a lack of response to exercise. Sadly we don't know what that metabolite is.

 

I accepted the word "stress" as meaning stress on the muscles, rather than the psychological meaning of the word. That's the engineer in me, not thinking along soft-science lines.

I do think the paper is important. I believe that PEM is triggered by the immune system's response to muscle damage, rather than the mitochondrial demands. Elevated mitochondrial demands are the obvious correlation with physical exertion, but the immune response is also a strong correlation. I could do considerable exertion (hours of hiking/biking/digging) without triggering PEM, yet less than a minute of unaccustomed exertion (washing a window, or climbing a ladder) would trigger PEM, so I've always assumed it was due to the muscle cells being damaged by unaccustomed strain, resulting in an immune response. The 24 hr delay in my PEM fits the well-known rise in IFN-g after exertion. Since I couldn't tell the difference between my PEM and the symptoms from viral infections (also involving elevated IFN-g), that's more evidence for that theory.

I think if they'd taken samples 24 hrs after exertion, they'd have found even more differences between PWME and the controls. I hope someone repeats the study, with more people (males too), later samples (24 hrs), physically-limited controls (not healthy, fully active ones), and samples from within the brain, rather than the spine.

 

All I can see in the abstract and conclusions are vague suppositions about regulation of some unspecified immune response. A decent paper gives you some data, without too much interpretation.

If there are interesting results here, why not tell us?

 

im divided in this in actually wanting us to get ownership of the correct definition of the word back.

BPS are getting away with warping any term and sometimes corrections are due.

I can see they’ve used stress because of the maximal exercise and recovery - whilst for ME we might one day find that’s any exercise when I used to train you’d have ‘jog back recoveries’ and warm ups etc weren’t ‘stress’ but loosening in someone fit and healthy where the pint of all out sprints was indeed ‘stress’

so I think it’s a term that is needed and we need to be able to slot into - that is if exercise literature hadn’t got warped too.

I know stress is still used in engineering/physics etc as a term so I just think it’s naughty and more telling of medicines issues that they don’t differentiate or even understand that psychological, cognitive, physical stress are all different things which can be present at once - but selling it as ‘like anxiety’ is just inaccurate misinformation really. Like branding ‘virus’ as now meaning ‘colds’ (EDIT: or even worse because anxiety isn't necessarily stress of the types inferred nor vice-versa). As it’s a term that is needed it needs to be reclaimed

 

All ME participants met both Fukuda and CCC. Good. There's no info about how sedentary the controls were. Not so good.

A rare - and welcome - attempt at trying to account for menstrual cycle effects.

Is this a good way to try and control for digestion effects? The intention is sensible but if some of the participants normally eat low carb or keto - and this may not be evenly distributed between the two groups - what effect would the sudden introduction of high sugar foods have?

I disagree in this case. Whether you choose single or repeat exercise protocol depends on what a study is looking for.

This particular study wasn't a CPET study to look at ability to repeat performance or similar. Instead its aim was to look at what happens with the blood chemistry during and soon after exercise that might point to a potential PEM mechanism. A single exercise provocation is enough to achieve this. I mean, we all know that a single occasion of overexertion is plenty enough to send us into PEM.

Sure, it would have been interesting to squeeze more into this study, as is the case for most studies. But there are trade-offs to be made with respect to available funding and, most importantly, patient safety. You shouldn't subject patients to the risk of two exercise sessions if a single one is likely to give you enough data for your purpose. If anything I would have liked to see them sample at more time points after the exercise but a second exercise session really wasn't necessary here.

I accept they use the term stress in the technical sense here and that this is strictly speaking a correct use of the term but it would have been better if they'd chosen something else, given the extremely strong association with psychological stress in most people's minds and the way this has been/is being weaponised against pwME.

Interesting indeed.

Discussion thread here https://www.s4me.info/threads/plasm...ud-germain-maureen-r-hanson-et-al-2022.25196/

 

Apologies could you post the relevant extract - thanks

 

Health Rising article about this study:

Exercise Triggers Major Immune System Letdown in ME/CFS - Health Rising

It really is a very interesting study, and another puzzle piece in the emerging picture on what exactly happens in an ME/CFS patient's body upon exertion or even exercise.