Preprint Mitochondrial function in patients affected with fibromyalgia syndrome is impaired and correlates with disease severity, 2024, Macchi

https://www.researchsquare.com/article/rs-4654793/v1

Mitochondrial function in patients affected with fibromyalgia syndrome is impaired and correlates with disease severity

Chiara Macchi1

Andrea Giachi1

Isabella Fichtner1

Silvia Pedretti1

Piercarlo Sarzi Puttini2

Nico Mitro1

Alberto Corsini1

Massimiliano Ruscica1

Email

Roberta Gualtierotti1

1 Università degli Studi di Milano,

2 IRCCS Galeazzi-S.Ambrogio Hospital


Fibromyalgia is a musculoskeletal syndrome characterized by chronic widespread pain that is often associated with systemic manifestations.

Since mitochondria are the main source of cellular energy, we hypothesized that fibromyalgia syndrome could be linked to mitochondrial impairment.

Aim was to study mitochondrial dysfunction in peripheral blood mononuclear cells isolated from 50 patients with primary fibromyalgia syndrome and 10 apparently healthy controls.

Although no differences in mitochondrial basal respiration were observed between patients with primary fibromyalgia syndrome and healthy controls, a lower median bioenergetic health index (BHI; -22.4%, p = 0.03), a proxy of mitochondrial function, was found in patients.

According to fibromyalgia severity score (FSS), a composite of widespread pain index and symptom severity scale, a lower median BHI (-18.7%) was found in patients with a FS ≥ 20 compared to those with a FSS < 20.

Negative moderate correlations were found only between BHI and FSS (r= -0.36) and widespread pain index (r= -0.38).

We demonstrated that patients with fibromyalgia syndrome had an impaired mitochondrial function.

Additionally, we found a mild correlation between the widespread pain index and the BHI, possibly indicating that the altered mitochondrial function, in these patients, narrows musculoskeletal rather than central nervous system involvement.

 

Fairly simple technique used. Pull out some PBMCs and run them through the Seahorse machine. Then create this BHI index based on the numbers it spits out.

The findings appear significant between groups and also to distinguish severity levels. I wonder if it would be even more sensitive with further differentiation of cell types.

 

@Murph

Given that "Chronic Fatigue Syndrome" (How I hate that term!) seems to be triggered after any physiologic demand on one's body, (although not in direct proportion to caloric output), aren't mitochondria the most likely common pathway? Put another way, almost anything that causes my body to need to rise above vegetating such heat response, standing, simply being upright without laying flat for too long, etc sets off a payback period. It seems like this requires that something's broken at the lowest level of energy production, which is mitochondria.

Nobody else seems to think this is the obvious common nexus of our problems, and I know 0 biology. What am I missing?

 

I think this is the obvious common nexus of our problems, and I know 0 biology too.

I posted this just a few weeks ago :

https://www.s4me.info/threads/a-question-about-mitochondria.38774/

 

The problem is that for systems with complex regulation it is never that simple.
Take my lawn mower. After being used for ten minutes it starts slowing down and speeding up and then conks out. The 'mitochondrion' there is the cylinder head where the petrol is burnt. But the problem is a fault in the filter in the air cooling system. After ten minutes the engine gets too hot and the combustion timing goes wrong.

In other words, the lowest level event isn't particularly likely to be what is wrong.

Moreover, in a more sophisticated system like a human or a modern car, the problem is very likely due to some complex control signalling feedback failure. Most things not working these days are due to some clever device that is supposed to regulate but instead stops things working. Like the new regulation trip switches on ring mains.

The results in this paper cannot possibly explain anything in FM because they simply show a statistical shift. If they were the cause of the problem the FM group would all be out of normal range.

 

Well,

1. there's a lot of the body outside the mitochondria. most diseases find their cause other parts of the body. e.g. for us maybe the mitochondria are in themselves fine but they aren't getting enough substrate or oxygen or they keep gettign sent signals to fragment, or the cell itself hasn't undergone autophagy recently enough. Even if the problem can be traced to one subcellular organelle, it might be the peroxisomes or the endoplasmic reticulum or the lysosomes or something. Everything gets asked to do more when we exercise. (one of my hobby horses is that humans turn on the unfolded protein response when we exercise, and if you google mecfs+"unfolded protein response" on pubmed there's zero hits)
2. fatigue is a few different things, including control systems the body uses to control and reallocate energy. A problem in our fatigue systems doesn't have to mean our energy-producing systems are broken, it could be our energy allocation systems. The whole immune system is an energy allocation system (and to be fair the mitochondria are involved in this!)

But,

I think a lot of people do suspect the mitochondria. A great recent paper is Hwang on WASF3. He thinks this protein is being prodced in the endoplasmic reticulum and getting pumped into the mitochondria, where it is damagign one of the energy-producing systems, called mitochondrial supercomplex.(My profile pic at left <- is a chart from his paper, showing how if you engineer mice to have more wasf3 they can't run nearly as far as normal mice)

After the recent Hwang paper on WASF3, I started reading more about the electron transport chain and the way in which mitochondrial complexes work, spitting electrons back and forth across the mitochondrial wall and combining themselves into supercomplexes to do so more efficiently. There's a lot of complexity inside mitochondria and they're tiny fiddly little guys, in many ways it'd be easier if the problem was at a more macro scale.

 

Interesting! Can you explain how it shows a statistical shift but no material significance? I have no background, so I can't read the study and sort it into a 'keep' or 'toss' file.

 

People in science working n problems where we are not making much progress scrabble around for evidence that patients are different from controls at least on average a little bit. That is fair enough if they are simply hoping to find some indirect clue to what really matters. But it is only a way to help decide where to look for an actual cause.

If you are dealing with a single crucial causal factor for a set of symptoms then everyone with the symptoms has a value outside the normal range. It isn't quite as simple as that - in gout the evil may be just at the top of the normal range because there are other critical factors that complicate things, but it is generally so.

All diabetics have sugar levels above normal when they are having diabetic symptoms, or have had them above normal for a long period in the past. All active rheumatoid arthritis patients have a C reactive protein level above normal. The CRP isn't actually the cause of symptoms but it is close to it. Everyone with active TB has a positive culture for mycobacteria. All healthy people don't. In simple terms, all people who bang their head on a door frame 6ft 1 inch high are taller than 6ft 1. That is the cause of banging their head.

When I worked on RA we have thousands of papers showing statistical differences in this or that that turned out not to tell us much or just something indirectly relevant but not very helpful. When we began to understand we found that everyone had certain things wrong. It then made sense to propose that this was telling us the cause.

If we had results that were reliably replicated for things like mitochondrial function that showed just a statistical shift we could reasonably say that there was evidence that something was not right somewhere. But if we want to believe we have found an explanation or a cause then we need to find something that separates people with symptoms clearly from those who don't.

 

When you're supposedly a grown up, but still give your sister a dead arm.

 

Yes, but when that happens you usually get some indication of bimodality.
The reality, at least from my experience of research, is that when you hit on something that is causal it hits you back in the face as being slam dunk. That happens maybe once in twenty years, maybe once in a lifetime. The rest is trying to get indirect clues.