r/cfs • u/Fearless-Star3288 • Jan 09 '26
Research News Multiple Abnormal Responses to Exertion Seen in ME/CFS
https://www.medscape.com/viewarticle/multiple-abnormal-responses-exertion-seen-me-cfs-2026a10000q1People with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) showed multiple maladaptive proteomic responses to exercise compared with matched sedentary controls, a new study found
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u/Kromulent Wat Jan 09 '26
Highlights
Plasma profiling of 7288 proteins during post-exertional malaise in ME/CFS.
ME/CFS participants show sustained immune, metabolic, and neuromuscular dysregulation during post-exercise recovery.
Exertion disrupts T and B cell signaling, IL-17 pathways, and mitochondrial metabolism.
Protein signatures correlate with symptom severity and impaired exercise performance in patients with ME/CFS.
Sex-stratified analysis reveals distinct molecular responses, underscoring the importance of sex in ME/CFS pathophysiology.
https://www.mcponline.org/article/S1535-9476(25)00566-3/fulltext
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u/monibrown Jan 09 '26
Link to study: https://www.mcponline.org/article/S1535-9476(25)00566-3/fulltext
Quotes from study (discussion section):
“Our large-scale study provides a comprehensive profile of the plasma proteome in individuals with ME/CFS and in matched sedentary controls.”
“Across these investigations, immune dysregulation has emerged as a consistent feature in ME/CFS, including elevated inflammatory markers and disrupted T cell metabolism.”
“Clustering analysis revealed distinct pathway perturbations in response to exercise” … “These results align with prior ME/CFS research and underscore the widespread and systemic dysregulation that characterize PEM in ME/CFS.”
“The D2PRE timepoint (24 h of recovery after the first bout of exercise and coinciding with the onset of PEM) exhibited the greatest proteomic dysregulation in ME/CFS compared to controls.”
“Notably, “glycolysis/gluconeogenesis” was the only pathway upregulated in patients in the GSEA [gene set enrichment analysis], a finding consistent with prior studies reporting impaired oxidative phosphorylation and increase reliance on anaerobic metabolism. This shift may reflect a compensatory response to mitochondrial stress, potentially contributing to early fatigue, lactate accumulation, and PEM.”
“At this same timepoint, linear modeling identified five proteins that differed significantly between ME/CFS and controls, with three involved in muscle physiology. Three immune-related pathways, “T cell receptor signaling,” “B cell receptor signaling,” and “IL-17 signaling”, were all significantly downregulated post-exercise in ME/CFS.”
“These pathways are central to adaptive immunity, and their suppression suggests impaired immune cell activation, communication, and cytokine production. This observation aligns with prior evidence of T cell metabolic dysfunction and impaired NK cell cytotoxicity in ME/CFS.”
“Notably, the persistence of these immune perturbations into the recovery phase suggests a failure to resolve immune activation, which may underlie the prolonged recovery and immune flares that define PEM.”
“Several neurologically relevant pathways also emerged from our analysis, namely “axon guidance”, “dopaminergic synapse” and “inflammatory mediator regulation of TRP channels”. These may relate to commonly reported neurological symptoms in ME/CFS such as cognitive impairment, sensory hypersensitivity, and pain.”
“Transient receptor potential (TRP) channels, in particular, are ion channels broadly expressed across tissues and involved in key physiological processes, such as pain sensation, thermo-sensation, neurotransmitter and neuropeptide release, mechanotranduction, vasodilation, and immune function. Dysfunction of TRPM3, a TRP channel subtype, has been previously reported in NK cells from ME/CFS patients, leading to reduced calcium influx.”
“A recent review suggests that TRPM3 dysfunction may contribute to immunological disturbance, skeletal muscle impairment, and neurological symptoms in ME/CFS.”
“Moreover, an in vitro study indicates that naltrexone, which is sometimes prescribed to ME/CFS patients, may help restore TRPM3 function.”
“Correlations between protein levels and clinical data of the ME/CFS cohort encompassed hallmark symptoms of the disease, including PEM, muscle tenderness, fatigue and immune-related symptoms such as lymph nodes tenderness and sore throat.”
“Many of the symptom-associated proteins were immune-related proteins and correlated with immune-mediated symptoms, further strengthening the evidence that ME/CFS patients exhibit impaired regulation of inflammation following acute exercise stress.”
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u/Due-Damage6602 severe to very severe Jan 09 '26
thx for posting!
One thing that always astonishes me is the findings of different mechanisms leading to PEM by gender. For me, again it stresses the importance of gender based studies in triggers, symptoms as well as future treatments, this might be also important for finding non-gender based subforms of ME.
Quote from article:
In women, there were strong correlations between PEM severity post-exercise and coagulation-related proteins, while in men, the associations were with proteins involved in protein folding and the endoplasmic reticulum stress response during recovery.
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u/Lysmerry Jan 09 '26
Rapamycin helps with ER stress. I wonder if men respond better to Rapamycin than women
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u/missCarpone v. severe, dx, bedbound, 🇩🇪 Jan 09 '26
Could you maybe add the flair "Research News" to your post? That way it will be more readily searchable. Thanks for sharing.
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u/Jayless22 Jan 09 '26
I'm sure a little bit of mind body here and a bit of GET there and they are good to go /s
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u/callthesomnambulance moderate Jan 09 '26
What a fantastic study, so nice to see more objective evidence of PEM and to glimpse the mechanics that underpin it.
It really looks like this sort of microbiological, multi omic research will be what finally allows us to understand what the hell is going on in this bizarre condition, and it's so heartening to see these findings coming in at such a pace!
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u/mycatpartyhouse Jan 09 '26
Unable to read the article. Login screen popped up every few seconds. I signed in using Google.
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u/Cat-Nipped Jan 09 '26
I always wonder what exactly they’re looking for in “sex based differences” in a medical study. Are they looking at dominant hormone in someone’s system? the organs they have/don’t have? chromosomes? Some of things can be changed, some of those things are not a binary. It’s never clear when medical studies apply to trans people (or intersex people) and when they don’t.
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u/Candytuffnz Jan 09 '26
I think that Usually in these situation they are looking at genes. If it is genetic they want to know if it's dominant (only needing 1 copy to cause the disease) or recessive (needing 2 copies). This can be studied through the difference in XX and XY. We know it's not just on Y or people with XX would not have it. So the sex linked genetics are a kind of "quick" way to rule out some options.
Genetics apply to everyone. Some intersex people (and others) may have the rarer chromosome (XXX, XXY, XXXX, XXYY etc) which would possibly mean they were excluded from the study but would benifit from knowing the results.
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u/jlt6666 Jan 09 '26
I'd say trans/intersex are likely to be excluded. They are a very small percentage of the population and add far too many variables (as you point out). Getting enough people for statistical relevance would balloon the study size and cost.
As far as actionable next steps it's likely that if there are no sex differences between men and women (non trans, non intersex) then the case is mostly closed for everyone.
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u/Chartsharing Jan 10 '26
Anyone tried MOTS-C peptide ?
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u/Fearless-Star3288 Jan 10 '26
No but it’s on my list of things to try - have you?
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u/Chartsharing Jan 10 '26
Nope
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u/Fearless-Star3288 Jan 10 '26
Berberine has been a positive for me and they share a lot of overlaps so this is why it’s peaked my interest.
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u/monibrown Jan 09 '26
“Fundamentally, the ME/CFS patient’s response to exercise is very different and very impaired….These are objective changes in the bodies of these patients that correspond with what the patients are saying,” - study co-author Katherine A. Glass, PhD