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
Click to expand...
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.
Click to expand...
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
 
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