Looking at Muscle Cells in Chronic Fatigue Syndrome

MJulia -  I'm actually a geriatrician by training.  My clinical work focuses on patients with blackouts and falls, generally in older people.

Chris -  So, what's the association between going from working with people who were falling over and feeling very faint to chronic fatigue syndrome?

Julia -  Well, the common thing is blood pressure regulation and I'm particularly interested in the autonomic nervous system, so that's the subconscious nervous system that controls things like your respiration, your heart pumping, your bowels, and your bladder working.  The particular area of that that interests me is blood pressure.  So the head of steam that keeps the blood pumping around your body and if that doesn't happen effectively enough and your blood pressure drops, at the extreme end of things, you'll black out and at the more subtle end of things, then not enough blood gets to - not only your brain - but your heart, your muscles, and the other organs, and that's what I believe leads to the symptom of fatigue.

Chris -  So, how did you make that association in the first place?- that you've got this cohort of old people who very frequently do get problems with their blood pressure going up and down in ways it shouldn't.  How did you link that to the group of people who have this entity, chronic fatigue syndrome?

Julia -  It's really talking to your patients actually and it became clear having seen patients with blackouts and falls for a number of years that, actually, they were experiencing symptoms that were very familiar to me from seeing patients with fatigue associated diseases.  So we set about quantifying how much fatigue patients with blackouts were experiencing and lo and behold, they actually had a lot more fatigue than you would've imagined.  And then if we treated their blackouts and made the blood pressure drop less, their fatigue appeared to be less.  So, it looked like there was a spectrum of disease at the extreme end with patients with blackouts and at the more subtle end, patients who were just experiencing the symptom of fatigue.  We then went to patients with chronic fatigue syndrome and other fatigue associated diseases, and began to think about whether or not they might be experiencing more blackouts than we would've anticipated.  And when we actually asked patients, lo and behold, yes, the blackouts were much more common than we would've expected in patients with fatigue associated diseases.

Chris -  But lots of old people have blackouts.  They don't all have the other manifestations of chronic fatigue, so are we dealing with two different things or is there an area which is an overlap between the two different conditions?  They both have a sort of common origin in terms of the blood pressure problem.

Julia -  I think that that's absolutely right.  I think what we're seeing is an underlying pathophysiological phenomena that is common to the two diseases.

Chris -  And if you do some tests, can you see very characteristic similarities between the changes that happen in the blood pressure control of the people with chronic fatigue and elderly people who have these problems from time to time?

Julia -  We tend to find that blood pressure drops quite precipitously when people stand up.  So, what I think is it's the physiological stress of standing that is a problem in patients with both falls and blackouts and fatigue associated problems.  When we stand up, 700 mls of blood drops into our legs, so to try and compensate for that, there's a microsecond response, trying to push your blood pressure up to where it needs to be which is your head.  To do that, we make our heart go a little bit faster and our peripheral blood vessels constrict and if that doesn't happen fast enough, that means that we're not getting enough blood to where it needs to be.

Chris -  So if you ask groups of patients with chronic fatigue if they have these symptoms, what fraction of them will say, "Yes, I do suffer faints and blackouts" and that kind of thing?

Julia -  If we actually ask them about symptoms when they stand up, we've shown that almost 90% of patients with chronic fatigue syndrome will have symptoms when they stand up of light-headedness and dizziness, and when we actually ask people about blackouts then 56% of patients with chronic fatigue syndrome/ME will describe a history of loss of consciousness.

Chris -  What's actually going on in the muscles of people who are suffering with these changes in blood flow? Because if you've got a change in blood pressure, you're continuously escalating and reducing blood flow and perfusion to muscles which presumably makes their metabolism hard for the muscle cells to control?

Julia -  Absolutely and that's one of the things that we've been studying here in Newcastle.  We've done some MRI-based studies now where we've had patients with chronic fatigue syndrome ME and fatigue associated other diseases, and we've had them exercising in the MRI scanner.  Using that technology, we've been able to show that patients with fatigue accumulate lots of acid within their muscles when they exercise and have difficulty getting rid of that acid from their muscles when they finish exercising.  The next step with those studies are some laboratory based studies.  So, we've begun to take cells from muscle biopsies in patients with CFS/ME and grow those muscle cells in the laboratory.  So, these cells aren't being influenced by anything else within the human.  They're then exercised to a known amount of exercise to see how they respond, and we've developed something called a nanosensor technology that will put small nanosensors across the cell wall of the muscle cells without destroying the cell, and then these nanosensors will fluoresce at various different pHs within the cells as the cells exercise.

Chris -  And that's going to enable you to see these fluxes in acid, the accumulation or loss of acid, according to how the blood flow's changing.  How do you know though that the muscle changes you're seeing are downstream of a nerve problem and not just two independent things which are both just characteristic of people with chronic fatigue?

Julia -  That's a really good question, one that I get asked all the time.  Is this just because patients with fatigue aren't exercising and they become what's called deconditioned?  And that's why these laboratory experiments are so important, because these cells can't be influenced by deconditioning and the MRI studies have allowed us to show that the severity of the acid accumulation is directly related to the degree of abnormality with the autonomic nervous system.  What that actually means we still need to explore in more detail, and whether it's just a problem of vascular run off, i.e. the blood vessels are not working well enough to get rid of the acid as the muscles exercise, or whether or not it's a problem of the transporters on the cell walls of muscle cells that are actively engaged in getting rid of acid from the cells, and we know that a number of those are under the control of the autonomic nervous system.  So, we do need to do more experiments to see where the abnormality lies and therefore, where we could target treatments that would be of benefit to the symptoms experienced by patients.

Chris -  And based on these experiments in the muscle cells, can you manipulate the outcome?  Can you reverse it?

Julia -  Well, we've got very exciting pilot data now that suggests that yes, we can.  When we've used a number of medications in the laboratory, so taking the cells in the test tube and seeing whether we can reverse the acid that accumulates within the cells then yes, we can.  So, I would say at the moment, we're in a very optimistic place.  That if we begin to tease out these pathways of metabolism that we can begin to look at identifying specific abnormalities that we could direct drugs at, and that's part of what we're aiming to do with the Action for ME fellowship that we've been awarded.