Heat Shock Proteins - Impaired Response to Oxidative Stress

Have we been missing a trick lately?

While there are numerous (often conflicting) studies on various immune parameters, cytokines, chemokines etc, one consistent finding is that ME/CFS is characterised by high levels of oxidative stress.

One aspect of oxidative stress and the body's response to it that hasn't had much attention is the influence of heat shocks proteins (HSPs). Perhaps they are a little too old school, but they are also a fundamental part of the body's response to 'stressors' of all types (heat, cold, exercise, infection, chemical, psychological stress etc). In fact, heat shock proteins should protect against any physiological stressor associated with day to day living and any dysfunction in the expression of HSPs would leave the body very exposed to ongoing oxidative stress leading to cell death and senescence (a reduction in HSP expression is associated with ageing).

I'm not going to wax lyrical here. Just provide a few comments and links for anyone interested.

On Heat shock Proteins generally

http://en.wikipedia.org/wiki/Heat_shock_protein

What should happen is that HSP expression remains at base levels until a potentially damaging stressor causes the rapid, massive and sustained release in order to prevent cellular damage from oxidative stress.

HSPs in ME/CFS

Three studies have found certain abnormalities in HSP production in ME/CFS patients compared to controls. HSP27 is chronically significantly raised in ME/CFS but, in response to exercise, production of HSPs (HSP27, 60 and 70) declines rapidly rather than remain elevated exposing cells to oxidative stress.

Thambirajah et al, 2008 (full paper) :

http://www.name-us.org/ResearchPage...idativeArticles/2008ChowHeatShockProteins.pdf

Jammes et al, 2009 (full paper) :

http://www.co-cure.org/Jammes.pdf

Jammes et al, 2011 (abstract only)

http://www.ncbi.nlm.nih.gov/pubmed/22112145

Interestingly, in this paper, they find this dysfunction most strongly associated with those reporting a prior viral illness of high intensity exercise.

Here's the description of the function of the relevant HSPs from Thambirajah et al :

In a nice piece of symmetry, normally HSP production peaks at 48 hours after exercise, at the time that markers of PEM appear to be most pronounced.

http://jap.physiology.org/content/101/1/176.full.pdf


The consequences of ongoing inadequate protection against oxidative stress are easy to imagine and this lack of protection negates the need to look for pathogens that cross the blood brain barrier. The absence of the protective effects of HSPs against oxidative stress can explain neurodegeneration.

Far from being a 'complex' or 'mysterious' disease, a deficient HSP response to stressors suggests a very fundamental systemic pathology with many downstream effects.

I'm sure we've been missing a number.

Awww... Go on.

Thanks for posting. I read the Jammes paper some time ago but had missed the 2011 study. HSPs are interesting little fellas for sure.

I hadn't realised that (or remembered). Very significant.

You might be interested in this which is available in full, if you haven't got to it already.

Modelling the role of the Hsp70/Hsp90 system in the maintenance of protein homeostasis.

http://www.ncbi.nlm.nih.gov/pubmed/21779370

It's from Centre for Integrated Systems Biology of Ageing and Nutrition at Julia Newton's Institute of Aging at
Newcastle University, which is an interesting co-incidence.

So we need a large scale study. Where do we go from here?

I should have realised that the full 2011 Jammes paper is in the library. Its interesting for a number of reasons :

• The results clearly show that abnormalities only show up when patients are exposed to a 'stressor';
  
• The abnormal HSP response is most strongly associated with particular subsets;
  
• The response does not appear to be associated with any aberrant innate immune response at rest or under 'stress';
  
• Nor do the results suggest any deficit in physiological exercise performance or evidence of deconditioning;
  
• The abnormal HSP response ties in with previous findings of a switch in muscle fibre type;
  
• This abnormal HSP may be a unique objective biomarker.

Thanks for that. I'd like to see some more discussion in these papers of the implications of the now routine findings of elevated levels of oxidative stress since this is associated with just about every physiological and neurological disease process known to man.

When it comes to ME/CFS it seems that they assume it just makes us tired and that's the end of the story.

I'd also like to know whether the authors believe that maximal exercise should be contraindicated in some patients and/or if sub-maximal exercise also contributes to increased oxidative stress. What are the implications for GET?

Additionally, is there anything can be done to restore an appropriate HSP response or is the only approach to try to reduce oxidative stress?

Good question. You would think that when objective and relevant physiological abnormalities can be shown and replicated (which may actually be a biomarker) that this would be built on.

For one thing we really need researchers to be networking and sharing and extending these findings. The newly established centres should help in this regard but it sometimes appears that apparently significant findings don't really get picked up on.

Do researchers tend to visit this forum?

Cort has posted a number of interviews with prominent researchers but I wonder if people like Jammes could be invited to write a 'guest article' explaining their research in more detail. On the other hand they may prefer not to discuss their work outside of the confines of scientific journals.

Hi Marco, too ill today to read your posts in full, just to let you know that i am listening. Its interesting to me how anything interesting, research wise, about mitochondrial dysfucntion and oxidative stress in M.E doesnt get much of a response on these forums - not sexy enough?

I keep reading your posts because i had the mito profile tests done through Acumen labs and i did a lot of research to understand them. I see and feel the dysfunctions in my body all the time. My cell free DNA was considered highly significant at 26, and thats when i thought i was doing ok!!?

Keep plugging on and i'll keep responding.
Justy.

Lots of thoughts there Marco. I'll have a think and rummage and scan some old papers. I might be gone for some time...
Could you tell me how I access the library on PR? Do I have to be a senior member?

Thanks for listening Justy.

I'll certainly keep digging.

Astrocyte PM sent.

HI Marco & Justy.
"
I have great interest in mitochondrial issues and oxidative stress,like Justy i have had the tests by Acumen,and have poor results.I put them on here,in the hope of some answers,but like Justy was dissappointed at the response.I am mostly unable to reply/respond due to very limited ability,i do greatly appreciate others efforts. Justy, I have great resonance ith your posts,you very articulately describe many of the weird things/symptoms i have suffered over the last 20 years.Thank you all for your posts.I really ish I could heal my mitochondria"unstick them" ! and clear away the high oxadatiive stress levels.I feel certain i would improve. Kind Regards

Hi Unity, ive just been over to the othr thread and read your results. They are very similar to mine. with a similar activity level given - mine was 30. I also seem to have a SODase gene blockage - which no one else seems to have. My carnitine is very low - i dont think it should be related to diet, although i have been a vegetarian for over 20 years.

Did you have the tests via Dr Myhill? are you following her supplements protocol? For me the best thing i am doing right now is B12 injections daily which helps to counteract the oxidative stress by acting as an antioxidant 'cover' This is especially important for me as i have the gene blockage and very high cell free DNA .
All the best, Justy.

Alcohol

To quote again the conclusions of Jammes et al, 2009 (my bolds) :

Heat shock proteins provide protection against oxidative stress in response to a wide range of stressors including chemical toxins.

A common chemical toxin, including neurotoxin, is ethanol, aka alcohol. Folks with ME/CFS don't appear to mix very well with alcohol.


Here's a nice little study (abstract only I'm afraid) which looked at the protective effects of Hsp27 using transgenic mice which over-express Hsp27.

My bolding and paragraph splits :

Neuroprotective effect of small heat shock protein, HSP27, after acute and chronic alcohol administration

Toth et al, 2010

http://www.jstor.org/discover/10.2307/20799976?uid=3738016&uid=2&uid=4&sid=47698727700197


The little transgenic critters didn't even end up drunk!

Could it be that the underexpression of heat shock proteins, including Hsp27, found by Jammes in response to exercise induced oxidative stress is also responsible for our inability to counter oxidative stress induced by alcohol, i.e. we lack the usual neuroprotection provided by Hsp27?

Hi Justy' Yes i had the tests thru Dr.Myhill in March2010,i Have not had a consultation with her [ expense+ too far to travel]. But she sent out a very long letter to my GP plus sheet of supplements etc to take + b12 jags recommendation...{my GP would not agree to these !! and is generally unhelpful re M.E..sadly only GP s in my small town.}.so i used shot of b12 sub lingual. I thought i felt worse after a year of B12..so stopped it about a year ago,have coninued with other recommendations....no real benefit....but think i may try b12 again. Have also thought to try the methylation protocol....but think its difficult without any support or real knowledge,i have huge difficulty with the science of it all, but think i may be a genetically poor detoxifier? Best Regards

You might want to look at the interaction between probiotics and heat shock proteins.

First of all, bacteria ferments fibre to creates short-chain fatty acids. These in turn have an effect on heat shock proteins.

Short-chain fatty acids induce intestinal epithelial heat shock protein 25 expression in rats and IEC 18 cells.
http://www.ncbi.nlm.nih.gov/pubmed/11522747

Short-chain fatty acids induce acute phosphorylation of the p38 mitogen-activated protein kinase/heat shock protein 27 pathway via GPR43 in the MCF-7 human breast cancer cell line.
http://www.ncbi.nlm.nih.gov/pubmed/16887331

Soluble factors from Lactobacillus GG activate MAPKs and induce cytoprotective heat shock proteins in intestinal epithelial cells.
http://www.ncbi.nlm.nih.gov/pubmed/16306130

Probiotics inhibit nuclear factor-KB and induce heat shock proteins in colonic epithelial cells through proteasome inhibition
http://www.gastrojournal.org/article/S0016-5085(04)01569-0/abstract

Effect of Lactobacillus plantarum 299v on cardiovascular disease risk factors in smokers
We showed previously in patients with moderately elevated cholesterol concentrations that supplementation of the diet with ProViva (Probi AB, Lund, Sweden), a functional food product containing fruit juice, fermented oat, and Lactobacillus plantarum 299 v, significantly lowers concentrations of LDL cholesterol and fibrinogen (14). These bacteria settle in the large intestine, where they are responsible for the fermentation of dietary fiber. The end products of this process are short-chain fatty acids, chiefly acetic, propionic, and butyric acids. Only acetic and propionic acids are absorbed into the blood, pass into the liver, and enter the metabolic pathways (15). It has been postulated that short-chain fatty acids, mainly propionic acid, improve glucose tolerance and inhibit cholesterol synthesis in the liver, presumably by inhibiting the rise in the serum concentration of free fatty acids and by improving insulin sensitivity (1618). We also recently showed that ibuprofen, a nonsteroidal antiinflammatory drug derived from propionic acid, significantly reduces IL-6 and fibrinogen and increases HDL-cholesterol concentrations in smokers (19).
http://www.ajcn.org/content/76/6/1249.full

The Alcohol thing is interesting, My translocator protein studies showed that i have a type of alcohol (ethanol?) stuck on my mito membranes, seeing as i dont ingest any (sadyl) for a few years my doc presumes my body is creating its own - so im kind of like and alcoholic (no wonder i feel so woozy all the time!)

Marco - im trying to underatnd what HSP are, but its hard for my brain to do science - this forum has been a real challenge for me. Are the studies suggecting we dont have enough HSP or is it a gene thing or what? (sorry so thick)

Unity - i have sent you a pm so we dont derail this thread.

Not sure if this is related, but when it lacks oxygen, pyruvate undergoes fermentation instead of entering the Citric Acid Cycle. It produces a little energy this way, but far less than the citric acid cycle would.

Hi Justy

I'll try bearing in mind I'm no scientist myself so this is a very simplistic overview.

Heat shock proteins are chemical messengers which play a fundamental role in protecting our bodies from the damaging effects of 'stress' that we encounter every day.

By 'stress' I'm using the original meaning of the word as used by Selye to describe any external or external event (stressor) that places a physiological burden on an organism which might include bacterial or viral infection, exercise or other activities, cognitive or psychological stressors, heat, cold, hunger etc. Just the everyday process of living involves cellular damage that must be repaired.

Various heat shock proteins are increased in response to various stressors and can play both an inflammatory or anti-inflammatory role but generally interact with other processes, including the immune response, to protect cells from damage due to oxidative stress and assist in their repair. Normally hsps stay at a basal level until induced by some stressor, reach peak levels and then return to base levels again.

Jammes el al found that hsps in ME/CFS patients are underexpressed in response to exercise. That is they don't reach the same peak as with healthy controls and decline much more quickly meaning we are less protected against the damage caused by oxidative stress caused by any of the stressors mentioned above.

The expression of heat shock proteins does have a genetic basis. Its well known that, for example, some athletes, or military recruits are more susceptible to overtraining syndrome or heatstroke which may well be due to the particular genetic variant they inherit.

Epigenetics, that is the interaction between your genetic inheritance and any environmental stressors you encounter, also appear to play a role. Environmental stressors can cause a 'switch' in gene expression that can last over extended periods or may be lifelong.

The 2009 Jammes paper mentions research that reports that some elite cyclists develop CFS many years after stopping competitive sport. The 2011 Jammes paper also shows that the hsp underexpression they found is most marked in those reporting either a history of viral illness, high intensity exercise or both combined.

So they can link abnormal hsp expression to these two external stressors. What they can't tell is whether or not these people had a prior genetic predisposition that was triggered or worsened by the stressor.

This works for me for two reasons. Firstly the pattern of onset (sudden or gradual) and range of triggers proposed for ME/CFS (viral, bacterial, exercise, heavy metal toxicity, organophosphates, psychological stress etc). Secondly the fact that we react so badly to everyday stressors that would normally be easily coped with, for example trivial levels of physical or mental activity, everyday foods and chemicals, heat, cold, common viruses etc.

This suggests to me that the specific 'stressor' is less important in the etiology and maintenance of the illness than the stress response. The underexpression of hsps constitutes an impaired stress response that leaves us open to ongoing high levels of oxidative stress and all that follows.
Unfortunately we can't 'supplement' with heat shock proteins although there may be ways to increase their expression (curcumin and alpha lipoic acid are proposed to increase expression or, as April posted, probiotics).

Whether this is desirable or not though is debatable as chronic long term overexpression of hsps may be inflammatory as well as anti-inflammatory. What we really need is to restore the appropriate expression of hsps in response to stressors.

I hope this makes more sense (probably not).

Perfect sense! Marco you're a star, thank you. This all makes sense to me and i can tie it in with my own experiences very well.

So how to restore the appropriate expression of hsps?

Good explanation Marco!

Aprilk, you do come up with some interesting papers. I wonder how expression of hsps in the gut impact on expression elsewhere in the body.

Justy, I'm interested in your translocator protein thing. Is there another thread on this? Are you saying that ethanol (or something) has bound to your translocator protein or what, and how did you find this out?

April

Thank you for the links. I want to get back to you on this once I can locate the appropriate paper. One which links heat intolerance to a dual mechanism involving overheating (where the hsps should come in) but also gut derived endotoxins.

Justy and Astrocyte.

Thanks for the vote of confidence which just shows that I can be much less obtuse if I put my mind to it!

How do we restore the appropriate expression of hsps?

That's the biggie. But if it is due to an epigentic switch then (as per the epigentics thread elsewhere - which is interesting because of quite an overlap between some of the features of ME/CFS and type II diabetes/metabolic syndrome) it may be possible to switch it back either temporarily or permanently. If we do have a genetic polymorphism though that predisposes us to this switch then we would need to try to avoid the same triggers that put us there in the first place.

I also sometimes consider the possibility that the CBT and GET crowd may have got some of the solutions right for all the wrong reasons. Cort's 'recovery' article might also unearth some evidence that prolonged absolute rest might aid recovery at the early stages? For the rest of us 'proper' CBT or related techniques such as mindfulness may help by avoiding psychological stress that only adds to the oxidative stress burden (CBT which is based on 'false illness beliefs' is likely to have the opposite effect for anyone who has reasonably concluded, on the basis of the available evidence, that their illness is organic).

GET may in theory be able to reset the switch for hsps (as long as it doesn't make things worse) although its not clear to me if this would also work for those with a viral:bacterial onset or with ongoing infections.

It may be that the switch (if such a thing happened) can't be reset and all we can do in the circumstances is reduce oxidative stress and boost our antioxidant capacity. Who knows until someone experiments?

I believe though that, while we are all impatient for treatment, that its rather putting the cart before the horse.

I'd rather see hsp expression becoming a standard measurement included in all studies involving physiological/immune response and that all such studies need to include a suitable 'stressor'.

If others can confirm/replicate the hsp underexpression then we have a clear phsyiological deficit, possible biomarker and can start looking in earnest at causes and potential cures.

Thanks Marco, that was a great post. In my journey around the internet today - looking to understand HSP's and what they do i cam across this very good article about proteins in general,
https://sitn.hms.harvard.edu/sitnflash_wp/2010/02/issue65/

which then goes on to talk about HSP's - they are in fact a chaperone protein, helping other (cellular) proteins to fold correctly. In some diseases that we know about proetiens dont fold correctly and cause 'globs' of unfloded proteins - this happens in some neuro diseases such as Alzheimers and Parkinsons. Other diseases, siuch as some mito diseases also have poor folding.

This got me thinking, because it reminded me that Dr Myhill mentions a folding problem in my translocator protein fuction tests. I looked them up and she refers to a lack of cardiolipin causing this problem for me, so i got back on google and came across this fascinating blog entry
http://jana-sovereignstate.blogspot.com/2011/07/cardiolipin-energy-and-order.html
I have no idea who this person is or what their credentials are, but what they are talking about (the type of illness described) exactly matches with ALL my test results so far, and makes sense with the other things we have been discussing.
All very interesting.
Justy.

Astrocyte - here is the link to my thread about my Translocator Protein Test results - i didnt get much feedback as you can see. I had the test done at Acumen labs through Dr Myhill. At the moment i think it may have been a waste of money - although it has now helped me to understand the cellular processes somewhat better it hasnt helped much with treatment = i take lots of antioxidants and cant afford a FAR sauna at the moment to test wether sweating/detox regime really will help. I suspect it may move the toxins, but something is causing me to be a person who has this happen in the first place and the test doesnt really help with this.
http://forums.phoenixrising.me/showthread.php?14908-translocator-protein-studies-Help-please