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

Kati

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Activin B is a novel biomarker for chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) diagnosis: a cross sectional study

Brett A. Lidbury, Badina Kita, Donald P. Lewis, Susan Hayward, Helen Ludlow, Mark P. Hedger and David M. de Kretser

Journal of Translational Medicine201715:60

Received: 11 January 2017
Accepted: 10 March 2017
Published: 16 March 2017

Abstract

Background

Investigations of activin family proteins as serum biomarkers for chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME). CFS/ME is a disease with complex, wide-ranging symptoms, featuring persistent fatigue of 6 months or longer, particularly post exertion. No definitive biomarkers are available.

Methods

A cross-sectional, observational study of CFS/ME patients fulfilling the 2003 Canadian Consensus Criteria, in parallel with healthy non-fatigued controls, was conducted. Comparisons with a previously defined activin reference population were also performed. For the total study cohort the age range was 18–65 years with a female: male participant ratio of greater than 3:1. All participants were assessed via a primary care community clinic. Blood samples were collected for pathology testing after physical examination and orthostatic intolerance assessment. Cytokines, activin A, activin B and follistatin were also measured in sera from these samples. All data were compared between the CFS/ME and control cohorts, with the activins and follistatin also compared with previously defined reference intervals.

Results

Serum activin B levels for CFS/ME participants were significantly elevated when compared to the study controls, as well as the established reference interval. Serum activin A and follistatin were within their normal ranges. All routine and special pathology markers were within the normal laboratory reference intervals for the total study cohort, with no significant differences detected between CFS/ME and control groups. Also, no significant differences were detected for IL-2, IL-4, IL-6, IL-10, IL-17A, TNF or IFN-gamma
.

Conclusion
Elevated activin B levels together with normal activin A levels identified patients with the diagnostic symptoms of CFS/ME, thus providing a novel serum based test. The activins have multiple physiological roles and capture the diverse array of symptoms experienced by CFS/ME patients.

Keywords
Myalgic encephalomyelitis (ME) Chronic fatigue syndrome (CFS) Biomarker Activins Diagnosis
 

Alvin2

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There have been many biomarkers shown in studies to be unique in ME/CFS, what will it take for one of them (hopefully the best one) to go mainstream and be available at doctor's offices?
 

CFS_for_19_years

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From the article:
Participants in this study included 45 patients (40 females and 5 males: age 19–66 years) diagnosed with chronic fatigue syndrome at the CFS Discovery Clinic, a primary care community clinic that works exclusively with CFS/ME patients, located in Donvale (Victoria, Australia). Patients were diagnosed with CFS/ME if they fulfilled the Canadian Diagnostic Criteria, [3] as conducted by a medical practitioner and registered nurse both with 15–20 years’ experience with CFS/ME patients. For the CFS/ME cohort, length of illness ranged from 2 to 40 years. During the early phase of the study, the 2011 International Criteria for CFS/ME diagnosis were published, [4] but since the study had commenced participant recruitment and assessment under the 2003 criteria, the application of the 2003 criteria persisted for the duration of this study.

The study also recruited 17 healthy control participants, comprising 13 females and 4 males (age 24–60 years).
[...]
Activin B levels do not change with respect to age, sex, BMI, ethnicity, smoking, allergies or type of medication [8] and to date, activin B levels have not been reported to be elevated or reduced in other diseases. Together with an established reference interval [8, 14], activin B has the potential to be a biomarker of clinical utility for CFS/ME, once validated on additional cohorts and other clinical criteria [2].

Activin A is a known modulator of the inflammatory cascade with its role as a pro-inflammatory cytokine discovered following its rapid elevation after lipopolysaccharide (LPS) was administered to mice [31], and there is evidence that activin B exerts actions similar to activin A, for example in muscle wasting and renal injury [32, 33]. However, others have shown that activin B exerts distinct functions to activin A, such as regulating hepcidin expression during the pathogenesis of inflammation-induced anaemia via Smad 1/5/8 signalling, while activin A exerts its actions through Smad 2/3 signalling [10]. Our data shows that levels of activin A and inflammatory cytokines were not elevated in CFS/ME patients, indicating an absence of underlying inflammation in these patients. The observed elevation of activin B levels, as well as elevated activin to follistatin ratios, indicates an increased systemic bioavailability of activins; however, the mechanisms by which activin B is causally linked requires further investigation.

The finding of an elevated serum activin B level also raises the possibility that treatment with follistatin may be of value in the management of patients with CFS/ME, since follistatin, in addition to blocking the actions of activin A, also can block the actions of activin B. Further, treatment with follistatin has the potential advantage that in addition to attenuating the actions of the activins, it can also block the actions of myostatin, thus enhancing muscle mass [34]
 
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CFS_for_19_years

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https://en.wikipedia.org/wiki/Follistatin
Follistatin also known as activin-binding protein is a protein that in humans is encoded by the FST gene.[3][4] Follistatin is an autocrine glycoprotein that is expressed in nearly all tissues of higher animals.[4]

Its primary function is the binding and bioneutralization of members of the TGF-β superfamily, with a particular focus on activin, a paracrine hormone.

An earlier name for the same protein was FSH-suppressing protein (FSP). At the time of its initial isolation from follicular fluid, it was found to inhibit the anterior pituitary's secretion of follicle-stimulating hormone (FSH).
https://content.tigerfitness.com/follistatin-344-build-muscle/
Human-grade follistatin is extremely expensive; costing more than $4,500 for just 1 milligram.
Umm, ok.:(

https://racehorsemeds.com/product/follistatin-injection/
Follistatin Injection 1mg Single Dose Vial – 4 Pack
$599.95
[....]
Day 1: Split one vial injection bilaterally into hind quarters.
Day 3: Split one vial injection bilaterally into hind quarters.
Day 5: Split one vial injection bilaterally into hind quarters.
Day 7: Split one vial injection bilaterally into hind quarters.

The muscle building effects can last for up to 3 months afterwards, slowly diminishing. It is recommended to give the horse a week off while receiving the series of injections.

Storage: Store below 3 degrees C (REFRIGERATE), do not freeze and protect from light. Use within 7 days of mixing.

For: Horses and Camels.
 
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Kati

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"Competing interests:
DdK is a founder of Paranta Biosciences, a company developing follistatin for clinical use, and a shareholder in the company, with a patent 2014366827 licensed to Paranta Biosciences Ltd"

(Just saying) it may or may not be relevant. The study needs to be replicated with larger samples.
 

Alvin2

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CFS_for_19_years

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Supplement of the Month: MHP MYO-X
http://www.muscleandfitness.com/supplements/build-muscle/supplement-month-mhp-myo-x
The main ingredient in MYO-X is a follistatin-rich extract of egg yolk known as MYO-T12. Follistatin is a protein that has been shown to inhibit myostatin, the protein that inhibits muscle from growing “too big.” You’ve probably seen photos of mice, cattle, and even a human baby with a natural myostatin defect that caused them to develop enormous mass. While the precise action of MYO-T12 is not known, it is thought to inhibit myostatin at the gene level.
"Click to buy" link on the above page above leads to a 404 error page.

https://proteinfactory.com/follistatin/
Benefits of Follastatin:

    • reduces myostatin
    • aids in reduce muscle loss
    • sports nutrition application
    • fertile egg yolk
    • rich in protein subfraction
Myos Rens is a publicly traded corporation that owns the patent for the production of fertile egg yolk powder. All other follistatin supplements are scams. This is the only product in the world that is clinically validated to reduce myostatin in the body. Dr. Carlon Colker is the inventor of fertile egg yolk powder.

MYOS RENS’ all natural nutracuetical research proven to increase muscle mass, lean muscle tissue and strength. Myo-T12 is a bioactive pro-peptidesteo-fatty complex composed of about 200 proteins, 40 fat, several of the peptides and various bioactive peptides targeted at an exact stage of process from fertilized egg yolks using a patented process that leaves intact the biological properties and activity of the blended powder.

Today MYOS RENS‘ patented nutritional supplement Myo-T12 is the only safe and natural myostatin reducing dietary supplement available with clinically validated positive result on both muscle thickness and lean body mass.
At the bottom of the page when you click on the picture of the box of MHP MYO-X, it takes you to an Amazon page with the following description:
MHP MYO-X Myostatin Inhibitor, Vanilla, 300 Gram $49.99
 
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alex3619

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There have been many biomarkers shown in studies to be unique in ME/CFS, what will it take for one of them (hopefully the best one) to go mainstream and be available at doctor's offices?
There are steps required, such as calculation of specificity and sensitivity, including a study to find those, plus extra validating studies.

Companies can market tests but in the US they will be blocked by the FDA unless they meet specific data requirements such as the above. I suspect many can move overseas, market the test, and get data to establish a history, but nobody has done this yet, with the exception of the approval of Ampligen in Argentina.

All other biomarkers have not proven reliable enough to date.

Once one biomarker is validated then we have a reference standard to compare other biomarkers to. It will also give a clue as to pathophysiology and causation.
 

Alvin2

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There are steps required, such as calculation of specificity and sensitivity, including a study to find those, plus extra validating studies.

Companies can market tests but in the US they will be blocked by the FDA unless they meet specific data requirements such as the above. I suspect many can move overseas, market the test, and get data to establish a history, but nobody has done this yet, with the exception of the approval of Ampligen in Argentina.

All other biomarkers have not proven reliable enough to date.

Once one biomarker is validated then we have a reference standard to compare other biomarkers to. It will also give a clue as to pathophysiology and causation.
fair enough, but with antipathy towards ME/CFS and lack of research money how are any test going to get through this process
 

alex3619

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fair enough, but with antipathy towards ME/CFS and lack of research money how are any test going to get through this process
This appears to be pharma related. Sometimes that means deep pockets or at least the ability to raise funds. However I think many promising leads have failed to be followed through because of lack of funds. The existence of an expensive potential drug therapy also boosts chances of pharma funding.

This is best viewed as a pilot study. Often this means they have more data to back their grant applications.
 

Alvin2

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This appears to be pharma related. Sometimes that means deep pockets or at least the ability to raise funds. However I think many promising leads have failed to be followed through because of lack of funds. The existence of an expensive potential drug therapy also boosts chances of pharma funding.

This is best viewed as a pilot study. Often this means they have more data to back their grant applications.
i don't think the antipathy is pharma related. That said if a mechanism\ is discovered by OMF and a pharma company thinks its profitable to develop a drug then they will spend money to do so. However that has little to do with my original query.
 

Hutan

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http://joe.endocrinology-journals.org/content/202/1/1.full.pdf
The biology of activin: recent advances in structure, regulation and function
Yin Xia and Alan L Schneyer1

It appears that activin B acts by reducing glucose-stimulated calcium influx (Bertolino et al. 2008). Moreover, activin B KO mice have hyperinsulinemia consistent with activin B negatively regulating insulin production and secretion in b-cells (Bertolino et al. 2008).
(note the b cells being talked about here are pancreatic beta cells; activin BKO mice are Activin B knock out mice, they don't have activin B)

@JaimeS - you had some interest in insulin lately?

Activin expression has been detected in many immune cells including monocytes (Eramaa et al. 1992, Abe et al. 2002), macrophages (Ebert et al. 2007), dendritic cells (Robson et al. 2008), T and B lymphocytes (Ogawa et al. 2006, 2008), and mast cells (Cho et al. 2003, Funaba et al. 2003), and its expression increases when these cells are activated by immune stimuli and toll-like receptor agonists.
...
In addition to upregulation of activin expression in activated immune cells, activin expression is also stimulated by inflammatory mediators including LPS in endothelial cells
...
These results demonstrate that activin plays a crucial role in the inflammatory response and that blocking its actions may have therapeutic potential in treatment modalities for acute inflammatory disorders
 

nandixon

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This looks promising. When they compared the ME/CFS patients to their larger “normal reference population,” i.e., 141 healthy volunteers, they found that not only was activin B higher in ME/CFS, but additionally:

Comparisons to the reference data also showed that follistatin levels were significantly lower in the CFS/ME group (p < 0.0001) (Fig. 3c), and therefore, both activin A:follistatin (ActA:FST, p < 0.015) and activin B:follistatin (ActB:FST, p < 0.0001) ratios were significantly higher in CFS/ME patients (Fig. 3d, e), with a greater difference seen for the activin B/follistatin ratio. Concordantly, activin B levels relative to activin A levels (ActB: ActA ratio) were significantly elevated in CFS/ME patients (p < 0.0001) compared to the reference data (Fig. 3f). These data show that activin B levels, as well as activin A or B to follistatin ratios, were elevated above the normal range in patients with CFS/ME.
(my bold)

The recent Fluge & Mella study strongly suggested that mTOR (mTORC1) is under-activated in ME/CFS, and Ron Davis confirmed that he believes mTOR is playing an important role.

Critically, mTORC1 is a master controller of follistatin production:

Mammalian target of rapamycin regulates miRNA-1 and follistatin in skeletal myogenesis

Our current study has revealed follistatin as this long-sought fusion factor regulated by mTORC1 through an miR-1–mediated pathway.
...
The capacity of exogenous follistatin to fully rescue from rapamycin inhibition myotube maturation in vitro (Fig. 9) and muscle regeneration in vivo (Fig. 10, B and C), together with the inhibitory effect of rapamycin on follistatin expression both in vitro and in vivo (Fig. 8 B and Fig. 10 A), makes follistatin the major, if not the only, fusion factor regulated by mTORC1.
(my bold)

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?
 
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Another Aussie study! yay!

However, is a bit under powered on the control side. They aimed to recruit 45 controls and only got 17. (How hard is it to get a few more people to give blood?!)

Anyway I'm pleased they have population reference data to compare the CFS cohort to and reveal real differences. Our activin b levels seem to be really high, and the difference is big.
Screen Shot 2017-03-17 at 6.08.41 PM.png


The really exciting news is this:

"to date, activin B levels have not been reported to be elevated or reduced in other diseases."

might this be the great white whale? the unique biomarker? Only replication will tell.
 
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Hutan

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"to date, activin B levels have not been reported to be elevated or reduced in other diseases."
I think they probably have - this for example:
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0111276

Activin B belongs to the TGFβ family of growth factors and is upregulated in clear cell renal cell carcinoma cells by hypoxia inducible factors.

Hypoxia-inducible factors
(HIFs) are transcription factors that respond to decreases in available oxygen in the cellular environment

HIF-1, when stabilized by hypoxic conditions, upregulates several genes to promote survival in low-oxygen conditions. These include glycolysis enzymes, which allow ATP synthesis in an oxygen-independent manner, and vascular endothelial growth factor (VEGF), which promotes angiogenesis.

Could the raised levels of activin B in people with ME be a result of the some of the symptoms we may experience - POTS, hypoperfusion of our brains, gut ischaemia after eating, circulatory issues causing numbness and pins and needles?

And perhaps it's a good thing.

http://onlinelibrary.wiley.com/stor...3m&s=97cf88c7469eb808ea00b4804da69affd2325374
The neuroprotective effect of Activin A and B: implication for neurodegenerative diseases

This study examined the neuroprotective effect of both Activin A and B in serum withdrawal and oxidative stress apoptotic cellular models and investigated the expression of pro- and anti-apoptotic proteins, which may account for the mechanism of Activin-induced neuroprotection.

Here, we report that recombinant Activin A and B are neuroprotective against serum deprivation- and toxin- ... induced neuronal death in human SH-SY5Y neuro-blastoma cells. Furthermore, we demonstrate for the first time that transient transfection with Activin bA or bB significantly protect SH-SY5Y and rat pheochromocytoma PC12 cells against serum withdrawal-induced apoptosis. ...These results indicate that both Activin-A and -B share the potential to induce neuroprotective activity and thus may have positive impact on aging and neurodegenerative diseases to retard the accelerated rate of neuronal degeneration.
It would be interesting to see some more measurement of activin A and B and follistatin in people with ME, with MS, brain injury and POTS, amongst others.
 

A.B.

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mTOR reacts to environmental cues such as nutrients and oxygen supply, and adjusts cellular metabolism accordingly.

Endothelial dysfunction has been reported in ME/CFS. If I understand it right, this could be an upstream source of poor oxygen supply, which then causes the various changes in metabolism and the difficulties meeting high energy demands that would result in PEM.

However that seems at odds with there being something in the serum that is sufficient to cause problems. Maybe my mental model is just shoddy.
 
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