OMF: Muscle Biopsy and Plasma Study into Post-Exertional Malaise, David Systrom, 2022

Dr Systrom wants to understand PEM - Analysing blood biomarkers and muscle biopsies may shed some light on the pathophysiology.

3.00 talks about his invasive CPETs at the Brigham, has been doing these for about 7 years in ME/CFS:
Vascular abnormalities found in both ME/CFS and LC - disproportionately in women:
1. Preload failure/insufficiency - low pressure is feeding the right heart when doing upright exercise
2. (in a subset) Impaired oxygen extraction by muscle at peak exercise

They find a very high prevalence of small fibre neuropathy (diagnosed by skin biopsy). The small fibre nerves mediate pain but also autonomic function and therefore blood vessel tone and so blood flow.
5.00 So one hypothesis is there is impaired blood flow due to problems with autonomic nervous system.

5.40 Second hypothesis, has gained traction over the last 9 months, from their work and collaborators in Amsterdam, is that the muscle mitochondria plays a role in impaired oxygen extraction by muscle.

So, the study is to address these hypotheses, and see if one or both of the hypotheses are true.
All participants have PEM; 50% have poor oxygen extraction at peak exercise and 50% do not
Day 1 - Blood drawn -> Plasma - proteomics, metabolomics; Muscle biopsy; Whole blood to Maureen Hansen to look at PBMCs.
Day 7 - Non-invasive CPET to precipitate PEM.
Day 8 - repeat of Day 1

10.00 Question about how results might be translated to the clinic
Treatment of neuromuscular dysfunction is very different to mitochondrial problems.
Neuromuscular dysfunction - they have treated with drugs such as pyridostigmine (Mestinon), a myasthenia gravis drug.
Mitochondrial problems - there are some treatments for genetic mitochondrial myopathies.
[So really have to find what the problem is]

14.00 The study is underway. 8 muscle biopsies done over the last month out of a planned 50 participants; collaborators are receiving samples.
 
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Hutan said:
Day 1 - Blood drawn -> Plasma - proteomics, metabolomics; Muscle biopsy; Whole blood to Maureen Hansen to look at PBMCs.
Day 2 - Non-invasive CPET to precipitate PEM.
Day 3 - repeat of Day 1
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I think it is Day 1, Day 7, Day 8.

Here are excerpts from the transcript regarding the testing protocol, by day. It was not clear to me when exactly the invasive CPET is carried out. i.e. Was it on day 1 or 2 after the sample collection, or was it some time in the past. The muscle biopsies will be sent to collaborators in Amsterdam.
Text below is from transcript, edited for formatting.

Day 1. On day one, they have some baseline blood drawn,
* we're sending plasma for proteomics to SomaLogic,
* we are sending plasma to collaborator in Montreal, Alain Moreau, who is doing transcriptomics,
* and we are doing metabolomics at Metabolon.

Day 8. So there will be a variety of blood-borne biomarkers that will be obtained both on day one and as I'll tell you about day eight, which is the last day of the study.

Day 1. The other thing we do on day one is a muscle biopsy. It's frozen so that we can interrogate live mitochondria later.
Day 1. So all that's done on day one, that's a
* muscle biopsy done by one of our interventionalists
* and the blood, which is plasma for the omics that I just mentioned.
* Additionally, we're sending whole blood to Dr. Maureen Hanson at Cornell for interrogation of peripheral blood mononuclear cells, which may give us some further insight into the mitochondrial function,

Day 7. So on day seven, they return and they do semi-exhaustive exercise.
* It's not meant to be too onerous, but what we're attempting to do is precipitate a little bit of PEM the next day. Of course, our patients are aware of that. It's a non-invasive cardiopulmonary exercise test.
* We purposely create a shallow workload, meaning they go about twice as long as they did for a previous clinically indicated invasive CPET. And again, that's meant to increase the exercise burden a bit and precipitate PEM the next day.

Day 8. And the next day they return for the very same things they get on the baseline day.
* So another needle muscle biopsy, frozen, sent to our collaborators
* and all the bloodborne omics.

So what we're doing is based on the initial invasive CPET, is determining all the patients, by definition, and it's an inclusion criterion, have the clinical phenomenon of PEM.
Half of the patients have poor oxygen extraction at peak exercise and half of them do not.
So we're asking the question, does the invasive CPET identification of poor oxygen extraction enrich the possibility of having mitochondrial dysfunction?
 
A Muscle Biopsy Study to Understand the Molecular Mechanisms of PEM
The Heart of the Matter
  • Post-exertional malaise (PEM) is a debilitating symptom of ME/CFS with an unknown cause.
  • Systrom, the Director of The Ronald G. Tompkins Harvard ME/CFS Collaboration, has designed a study to help better understand the relationship between poor oxygen extraction, vascular abnormalities, and mitochondrial dysfunction and how they might relate to PEM.
  • The study team will explore molecular changes that occur with PEM through proteomics, metabolomics, and transcriptomics conducted on blood samples and analysis of mitochondrial function completed on muscle biopsies.
  • This study is ongoing, placing it in the “Recruitment, Data Collection” stage of the research process.
A Muscle Biopsy Study to Understand the Molecular Mechanisms of PEM
Post-exertional malaise (PEM) is a characteristic feature of ME/CFS that is also a requirement for diagnosis. As a debilitating symptom, it’s important to understand what drives PEM so we can develop treatments that will alleviate or eliminate crashes. Dr. Systrom, the Director of The Ronald G. Tompkins Harvard ME/CFS Collaboration, has designed a study to do just that.

Dr. Systrom’s previous work using invasive cardiopulmonary exercise tests (iCPET) has identified vascular abnormalities in ME/CFS patients, including preload failure and impaired oxygen extraction. Delving deeper into impaired oxygen extraction, there are two major schools of thought on what might drive it: a vascular abnormality called small fiber neuropathy that ultimately leads to blood flow not getting properly directed to exercising muscle, or muscle mitochondrial dysfunction.

Current methods of identifying PEM aren’t able to differentiate between blood flow abnormalities and mitochondrial dysfunction, so this muscle biopsy study is designed to investigate potential molecular mechanisms underlying PEM. The study has three groups of participants, based on results from a previously conducted iCPET: 10 controls that don’t experience PEM, 20 ME/CFS patients that exhibit poor oxygen extraction at peak exercise, and 20 ME/CFS patients that don’t show poor oxygen extraction.

To better understand the molecular mechanism of PEM in people with ME/CFS and any potential connection between vascular abnormalities, mitochondrial dysfunction, and impaired oxygen extraction, the muscle biopsy study will conduct analyses of muscle biopsies and blood samples, including proteomics, metabolomics, and transcriptomics. These samples will be taken both before and after an exercise test (a non-invasive CPET) that will induce PEM to see if the team will be able to identify changes in the blood markers and mitochondrial function in the muscle biopsies when the participant is experiencing PEM.

Ultimately, the goal is to understand more about the molecular mechanism of PEM to inform future clinical practices. Current treatment of vascular dysfunction and mitochondrial dysfunction are quite different, so identifying factors contributing to poor oxygen extraction in ME/CFS patients has the potential to improve clinical management of the disease.

Stage-2-recruitment-9-26-24-1024x85.png

Dr. Systrom’s muscle biopsy study is currently underway, having completed about 15% of its target enrollment. Therefore, the project is in the “Recruitment, Data Collection” stage of the research process.
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Full video and transcript (easier to read than YOutube) also at link
A Muscle Biopsy Study to Understand the Molecular Mechanisms of PEM - Open Medicine Foundation Canada
 
"suggest that we have an acquired mitochondrial problem. It's likely not a genetic form."

"The baseline studies suggest we have a decrease in what's called mitochondrial biomass […] the number of mitochondrial in the skeletal muscle."

"And this is very, very different from the genetic form of mitochondrial myopathy." "Our patients have really the opposite finding, patients with ME and Long Covid. They have a decrease in the total number of mitochondria, whereas the genetic forms we know from the help of our collaborator Bob Naviaux at UCSD, that the opposite occurs in genetic forms. In genetic forms there's a primary decrease in the function of the mitochondria, the electron transport chain is dysfunctional, and as a result there's an increase in biomass… an increase in the number of mitochondria. One could view that as a compensatory mechanism"

"we also have emerging data from Baylor about the electron transport chain function. And it appears that it can go one of two ways. It can be decreased in addition to the decreased biomass in ME and long Covid and the various complexes 1 through 4 - those are the ones we can see with a frozen muscle biopsy, can be decreased. And when that happens […] there is impairment of systemic oxygen extraction at peak exercise." "some of the patients have this defect in function and a decrease in biomass - one could view that as a double whammy" "But there is also a subset of patients who appear to have a compensatory increase in electron transport chain function"
 
"what we've identified for a long time now is this issue of impaired O2 extraction, so oxygenated RBC in both ME and LC during incremental exercise and peak exercise are just fine . . . '

"But in a subset of patients something additionally happens and that's in paradox in O2 uptake and utilization, and really in the differential diagnosis, there is blood flow abnormalities at a micro vascular level, so small blood vessels, and there are a lot of potential reasons for that. But the other possibility for that is that there is intrinsic mitochondrial dysfunction, and an important point for patients, docs and healthcare providers to know is that the treatments, at least for these currently are totally different, blood flow abnormalities on the one hand, maybe related autonomic nervous system dysfunction, and then intrinsic mitochondrial dysfunction . . . the current treatments are quite different and ultimately what we're hoping for is precision medicine, so we can see an individual patient, and our biomarker quest identify these subsets of patients and treat them properly, get them better"
 
The standout in my mind is the 5 min poster presentation on preliminary findings in muscle capillary basement membrane thickening.

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I suspect this is what Grigor is referring to here.

Grigor said:
As a patient rep working closely with biomedical researchers here in the Netherlands, I can confidently say they do see signs of real damage in the body and the findings align with what we see elsewhere. Yes, it's preliminary, for the moment unpublished, and the research is still developing, but dismissing it just because the studies are small doesn’t mean there’s nothing there.
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This could tie up with the acquired mitochondrial disorder Systrom is describing above. Leading to fuel starvation (oxygen and various substrates) and variable attempts at mitochondrial compensations, alongside muscle fibre type shifts away from mitochondrial ox-phos dependency.

See also

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Thanks again!! I watched the first video - Anouk Slaghekke. That is an impressive presentation. It appears long covid and ME/CFS data really match each other in this measurement. I wonder what that implies…

It is also a pleasure to see someone so excited to be presenting.

after watching the 2nd video, I wonder how well @Jonathan Edwards, et al. recent Qeios paper fits with all this?
 
Thanks for recommending the muscle biopsy videos. I like that they were short presentations and really concise and wow, lots of interesting findings, some with good separation to controls, something we rarely see.

In the Wust presentation I loved seeing Systrom chair the session. I hope the Systrom and Wust projects are sharing best practices and for some parts help with replication of each others findings where possible - that would speed up the field having another distinct cohort to compare the most distinct findings against for replication purposes. Is that too much to hope for?
 
wigglethemouse said:
Thanks for recommending the muscle biopsy videos. I like that they were short presentations and really concise and wow, lots of interesting findings, some with good separation to controls, something we rarely see.

In the Wust presentation I loved seeing Systrom chair the session. I hope the Systrom and Wust projects are sharing best practices and for some parts help with replication of each others findings where possible - that would speed up the field having another distinct cohort to compare the most distinct findings against for replication purposes. Is that too much to hope for?
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wiggle,

Yeah, when I watched the video I was wondering what were the discussions between Dr. Systrom and Dr. Wurst, etc...

... one of those times it's exciting to be a scientist.
 
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