Activin B is a novel biomarker for chronic CFS/ME diagnosis

ash0787

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So was this one of the multiple changes picked up on the various metabolomics ? didn't they only do a certain number like 800 ? from everything we have heard about recently I have been feeling like there is probably some sort of aberrant signaling coming from the immune system either cytyokine or hormone or something, not entirely sure how it all works, not necessarily even the same exact thing as what ron is looking for. I guess we need to know is like how do all the cells in the body communicate with each other to produce various altered states.
 

alex3619

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Metabolism has its own regulating system, though it does interlock with immune, neurological and hormonal factors, and of course it all ties into both inherited and epigenetics. This could be very interesting in the short term rather than the long, as Ron Davis and colleagues might do some of their own testing and he is pushing to operate in time frames of days rather than years.
 

ljimbo423

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So a major question is (assuming this study's results are confirmed in a larger cohort), what commonality could be causing both the increased production of activin B and the under-activation of mTORC1 (and hence the decreased follistatin) in ME/CFS?
It seems like oxidative stress is one possible reason for activin B to be increased and mTOR1 to be under-activated.

Activin A has long been known to be a critical regulator of inflammation and immunity, and similar roles are now emerging for activin B, with which it shares 65% sequence homology. These molecules and their binding protein, follistatin, are widely expressed, and their production is increased in many acute and chronic inflammatory conditions. Synthesis and release of the activins are stimulated by inflammatory cytokines, Toll-like receptor ligands, and oxidative stress.
https://www.ncbi.nlm.nih.gov/pubmed/21353885

As a central cell growth controller, mTORC1 is potently inhibited by stress conditions such as hypoxia, oxidative stress, and hyperosmotic stress. Under physiological condition, ∼1%–3% of the oxygen consumed by cells is metabolized to reactive oxygen species (ROS), which generates oxidative stress in the cell. Oxidative stress potently and rapidly inhibits mTORC1, possibly through activating AMPK kinase
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4691891/
 
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nandixon

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This work was preliminarily presented in part in 2014 as an oral presentation:

Serum Activin A, B and follistatin levels provide novel markers of Chronic Fatigue Syndrome (CFS) patients.

Patients with symptoms of Chronic Fatigue Syndrome (CFS) create a diagnostic dilemma as no definitive tests have established its pathophysiological basis. While progress in defining and measuring the degree of the fatigue are available, biochemical tests have been unhelpful determining their cause. In some patients, the onset of their symptoms may be linked to an earlier inflammatory illness, but supportive biochemical data are unavailable. Activin A and B, TGFβ family members, have been identified as proinflammatory cytokines and are regulated by Follistatin (Fst), a high affinity binding protein and all can be measured by specific assays. In mice, serum activin A, B and Fst increase following a lipopolysaccharide injection and are elevated in many patients in intensive care 1,2,3 . In contrast, in the CFS cohort diagnosed by accepted clinical measures (n=47), serum activin A was not increased (97.5 ±10.1pg/ml) but serum activin B was increased (117 ±13.4 pg/ml, p<0.05) and lower Fst levels (7.92 ± 0.85 ng/ml p<0.05) were found compared to normal subjects (serum activin A 107.9 ± 6.8pg/ml; activin B 70.4 ± 4.6 pg/ml & FST 10.1± 0.5 ng/ml). The higher activin B:Fst and the activin A:Fst ratios indicate an increase in activin bioactivity. While the actions of activin B require further definition, the increased activin A bioactivity can cause apoptosis of hepatocytes and B lymphocytes as well as cachexia and muscle wasting 4,5 . Longitudinal studies of CFS patients are required to confirm the pathophysiological consequences of these changes. Elevated Activin B and decreased Fst may be a biological signature for the diagnosis of CFS. Further studies are required to define the actions of the elevated serum activin B levels. (95%CI=mean+/-2SE)
(my bold)

They more correctly state there how a definitive marker test for ME/CFS would need to work, because there are actually at least a few disease states that have an elevated activin B level. But none (that I can find) that have both an elevated activin B and a low follistatin.

This makes sense because the number of diseases that involve an under-activated mTORC1 can be counted on one hand, of which ME/CFS appears to be one, versus probably dozens for an over-activated mTORC1 (multiple sclerosis, cancer, etc). And mTORC1 regulates follistatin.

So the definitive marker (if this study is confirmed) would presumably need to be the ratio of activin B to follistatin, rather than just the level of activin B. And as shown in Figure 3d of the current study, the difference in that ratio between the ME/CFS patients versus the reference population seems very impressive:

12967_2017_1161_Fig3_HTML.gif
 
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A.B.

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And presumably catabolic states that can accompany major illness or stressor such as chemotherapy or infection.
 

CFS_for_19_years

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I haven't got the brain power to contrast this with what is happening in ME/CFS, but it warrants a good look.

This was a presentation discussing the role of activins and follistatin in Chronic Hepatitis C from 2014:
https://www.omicsonline.org/speaker...mm_AlQura_Saudi_Arabia_Immunology_Summit2014/

The correlations of activins and follistatin with viral load, liver damage, Interleukin-6 and tumour necrosis factor-α in treatment naïve patients with chronic hepatitis C genotype 1 and 4: A case-control study

Background: Activins and follistatin are involved in the regulation of immune system and their importance in liver diseases has recently emerged

Objectives:To measure the effect(s) of chronic hepatitis C (CHC) genotype 1 and 4 on the serum concentrations of activin-A, activin-B and follistatin, and to determine their correlations with viral load, liver damage, interleukin-6 (IL-6) and tumour necrosis factor (TNF)-α.

Methods: Serum samples were collected from 20 male and 20 female treatment naïve CHC genotype 1 and 4 Saudi patients (10 males and 10 females for each genotype), to measure activin-A, activin-B and follistatin by ELISA and the results were compared with 40 gender and age matched healthy participants. Additionally, the serum levels of the candidate proteins were correlated with IL-6, TNF-α, viral load and AST platelet ratio index (APRI).

Results: SerumIL-6, TNF-α,activin-A and activin-B were significantly increased, whereas serum follistatin was significantly decreased, in both genders of CHC patients compared to control subjects. In both viral genotypes, activin-A was strongly and positively correlated with the viral load, APRI, IL-6 and TNF-α, and negatively with albumin (P < 0.01). Activin-B showed similar correlations to activin-A but only in CHC genotype 1 patients and it was weaker than activin-A. No correlation was detected for follistatin.

Conclusion: CHC genotype 1 and 4 significantly altered serum activins and follistatin, and the dysregulation of activins/follistatin axis could be associated with host immune response, viral replication and liver injury. More studies are required to elucidate the role(s) and clinical value of activins and follistatin in CHC.
The slides from the presentation are here and they are well done. If anyone can figure out how to post some of them, please have a go at it:
https://www.omicsonline.org/confere...hi-university-of-umm-al-qura-saudi-arabia.pdf
 
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Marco

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Given that elevated activin B appears to be catabolic it may tie in somehow with Fluge/Mella's findings that male PWME (unlike females) seem to use muscle catabolism as an alternative energy source :

http://forums.phoenixrising.me/inde...c-encephalopathy-cfs.48446/page-2#post-796746

I also wondered if extreme activin B values for the small number of male subjects in the current study (5 out of 45) might have skewed the whole ME/CFS cohort but the standard error looks much to small for it to me a male only thing.
 

Marco

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One curiousity that stood out was that the ME/CFS were significantly shorter.

OK they were small samples but they did control as best they could for age and gender and, a priori, unless you're studying a condition likely to directly affect growth you wouldn't expect to see a signifcant height difference between the disease cohort and healthy controls.

Probably just an artefact but not something I've come across before.
 

CFS_for_19_years

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One curiousity that stood out was that the ME/CFS were significantly shorter.

OK they were small samples but they did control as best they could for age and gender and, a priori, unless you're studying a condition likely to directly affect growth you wouldn't expect to see a signifcant height difference between the disease cohort and healthy controls.

Probably just an artefact but not something I've come across before.
The median height difference between cohorts was only 4%, i.e. 165 cm vs 171.5 cm. It's possible there were one or more subjects in the ME/CFS cohort who brought the median down because the respective ranges were 122-188cm and 153-187cm. The ME/CFS cohort weighed less, but their BMIs were nearly equal. From this I would surmise there were several smaller individuals in the ME/CFS cohort.

The ME/CFS cohort had 40 females and 5 males; the controls were 13 females and 4 males, so the ratio of females:males wasn't kept constant, i.e. 8:1 vs. 3.25:1. The higher ratio of females in the ME/CFS cohort could explain some of the height difference.

More important though, I wonder if they made a mistake in recording the height of one of the participants in the ME/CFS cohort. 122cm = 48 inches = 4 feet. The youngest age in the ME/CFS cohort was 19 years. I don't know that many adults who are 4 feet tall, but this would definitely skew the median.

 
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The median height difference between cohorts was only 4%, i.e. 165 cm vs 171.5 cm. It's possible there were one or more subjects in the ME/CFS cohort who brought the median down because the respective ranges were 122-188cm and 153-187cm. The ME/CFS cohort weighed less, but their BMIs were nearly equal. From this I would surmise there were several smaller individuals in the ME/CFS cohort.

The ME/CFS cohort had 40 females and 5 males; the controls were 13 females and 4 males, so the ratio of females:males wasn't kept constant, i.e. 8:1 vs. 3.25:1. The higher ratio of females in the ME/CFS cohort could explain some of the height difference.

More important though, I wonder if they made a mistake in recording the height of one of the participants in the ME/CFS cohort. 122cm = 48 inches = 4 feet. The youngest age in the ME/CFS cohort was 19 years. I don't know that many adults who are 4 feet tall, but this would definitely skew the median.
good catch! data transcription errors are more common than dwarfism so I'm going to say that's the occam's razor answer.
 

dreampop

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Has anyone tried Follistatin supplements?
From a quick look around the internet, there doesn't seem to be many. Its something bodybuilders have been looking for because it inhibits Myostatin which caps muscle growth. That is mentioned in the study. The product linked first in the thread, Myo-X and Epicatechin look the most promising. Myo-X does have 2250 iu's of Vitamin A, though, so I don't know if that's a problem.