From the Desk of Dr. Danielle Meadows
Vice President of Research Programs & Operations
Today, I’m happy to share another update on a study that I introduced back in November 2024 in an interview with Dr. Systrom. The study is still going on, but in this case, we’re able to share some exciting preliminary data. We can’t draw any conclusions from preliminary results, but it’s an interesting first look at the kind of information we can get from this study.
The Heart of the Matter
- Dr. Systrom, the Director of The Ronald G. Tompkins Harvard ME/CFS Collaboration, and his team are studying the relationship between poor oxygen extraction, vascular abnormalities, and mitochondrial dysfunction and how they might relate to post-exertional malaise (PEM).
- Preliminary analysis of baseline muscle biopsy samples indicates that people with ME/CFS have a reduced mitochondrial biomass, roughly correlating to the number of mitochondria.
- Some people also show altered electron transport chain activity (or mitochondrial function), which would have important implications in clinical management of the disease if the finding is supported moving forward.
- This study is ongoing, placing it in the “Recruitment, Data Collection” stage of the research process.
Update: A Muscle Biopsy Study to Understand the Molecular Mechanisms of PEM
In my November interview with Dr. David Systrom, Director of The Ronald G. Tompkins Harvard ME/CFS Collaboration, we talked about his investigation into the molecular underpinnings of post-exertional malaise (PEM). If you missed the interview or want to watch it again, you can view it here: A Muscle Biopsy Study to Understand the Molecular Mechanisms of PEM.
An initial examination of some of the muscle biopsies collected at baseline (before exertion) indicates that people with ME/CFS have an acquired mitochondrial problem, which looks clearly different from genetic forms of mitochondrial dysfunction. So far, people with ME/CFS are showing reduced mitochondrial biomass, which roughly corresponds to a lower number of mitochondria. In addition, some patients also have a defect in mitochondrial function, as seen in the electron transport chain analysis. The current hypothesis is that this combination of reduced biomass and altered function correlates with poor oxygen extraction and worse symptoms.
If these preliminary findings are reinforced going forward, this can have important implications for the treatment of symptoms that are associated with ME/CFS. Impaired oxygen extraction might be explained by blood flow abnormalities or mitochondrial dysfunction, which have completely different treatment strategies. Therefore, this study has the potential to identify mitochondrial dysfunction in a subset of patients, which can then inform the clinical management of their ME/CFS.
These preliminary data are based only on a portion of the total number of participants targeted for the project, as the study is still ongoing, falling in the “Recruitment, Data Collection” stage of the research process.
If you would like to be considered for participating in research opportunities like this, please consider joining our OMF StudyME Registry.
Watch the new video interview with Dr. Systrom below.
Click Here to Read the Video Trancript
Video Transcript:
Danielle Meadows, PhD: Hi, everyone! I am joined here today by Dr. David Systrom, the Director of Open Medicine Foundation’s Ronald G. Tompkins Harvard ME/CFS Collaboration. And I’m really trying to follow up with him today on his work on a muscle biopsy study, which we actually talked about in an interview that we shared over the winter. So welcome, Dr. Systrom.
David Systrom, MD: Thank you very much, Danielle. I’m happy to return and give everyone a bit of an update on the project.
Danielle Meadows, PhD: Awesome. As a quick recap of what we talked about over the winter, Dr. Systrom is conducting a study that’s looking at the molecular changes that occur with post-exertional malaise in people with ME/CFS and Long COVID that also meet ME/CFS criteria.
We know from existing research that people with ME/CFS exhibit physiological differences when experiencing PEM, which can be measured through a two-day cardiopulmonary exercise test. But this study is really trying to expand on that knowledge to understand what’s happening on that second day at a molecular level and in the muscle itself.
To start us off today, could you give us a brief update on where the study stands now?
David Systrom, MD: Sure. We have human studies approval to study a total of 50 patients. Forty of those patients have either ME/CFS by classic IOM criteria or are patients with Long COVID who meet the IOM criteria for ME/CFS. So, it’s before and after largely 2020 with acquired symptoms. An important part of that old IOM criteria is the presence of post-exertional malaise, which you just mentioned, Danielle.
So, the ultimate goal of this study is to better understand the muscle physiology and any role that the mitochondrion may have in precipitating post-exertional malaise.
We have targeted 40 patients with some form of post-exertional malaise and an additional 10 patients with fatigue and various diseases such as heart failure or pulmonary hypertension, but no post-exertional malaise.
Where we stand right now is we are about two-thirds of the way through the study, and patients are tolerating dual thigh muscle biopsies quite well. Our interventional team is fabulous and keeps them comfortable.
What I’m going to discuss today in the way of preliminary results is the baseline muscle biopsy. So that’s the one done on day one, before an exercise perturbation, which is designed to precipitate a little post-exertional malaise.
Danielle Meadows, PhD: Awesome, thank you so much. As you mentioned, we’re doing this follow-up interview today because you have some really interesting preliminary data that we want to share. So, can you give a short summary of what you’re seeing from these baseline muscle biopsies so far?
David Systrom, MD: Yeah. The preliminary findings suggest that we have an acquired mitochondrial problem. It’s likely not a genetic form—it’s acquired—and the signals that precipitate it I think are under active investigation.
Broadly speaking, we think there’s often autoimmunity and associated inflammation, and those things are bad for mitochondria. So that’s a hypothesis.
But the baseline studies suggest that we have what’s called a decrease in mitochondrial biomass. Maybe a simpler term would be the number of mitochondria in the skeletal muscle.
This is very, very different from the genetic form of mitochondrial myopathy. Those would be patients often identified in childhood with strong family histories and a well-defined either nuclear or mitochondrial genetic defect.
Our patients have really the opposite finding. In patients with ME and Long COVID, they have a decrease in the total number of mitochondria, whereas the genetic forms, we know from 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 mitochondrion. The electron transport chain is dysfunctional, and as a result there’s an increase in biomass, or an increase in the number of mitochondria. One could view that as a compensatory mechanism to help stoke the power plant in the muscle and preserve the ability to exercise.
But what we’ve got in a preliminary way with almost 30 patients is the opposite: a decrease in the number of mitochondria, or the biomass.
Within those categories of up or down biomass, 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. The various complexes I through IV—those are the ones we can see with a frozen muscle biopsy—can be decreased.
When that happens, what we know is, there is impairment in systemic oxygen extraction at peak exercise. That’s from a related, but it’s a clinical invasive cardiopulmonary exercise test. We know from the exercise testing that there is a subset of patients, predominantly women, who have impaired oxygen extraction. It contributes to symptoms and a decrease in the so-called VO2 max.
So, when we look at the electron transport chain itself in ME and Long COVID, some of the patients have this defect in function and a decrease in biomass. One could view that as a double whammy. Presumably the two things contribute to worse symptoms.
But there is also a subset of patients who appear to have a compensatory increase in electron transport chain function. So, in a way, you could say the primary defect might be a decrease in mitochondrial number—different from genetic forms—and some patients are able to rev up the function of the mitochondrion in a compensatory fashion. So, it’s diametrically opposed to the genetic forms.
Danielle Meadows, PhD: Awesome, thank you. So maybe I’ll try to put it in my own words and you can correct me if I get anything wrong here. It sounds like what you’re seeing is that people with ME/CFS have this reduced mitochondrial biomass in the muscle even at baseline, which is the samples that we’re looking at right now. And that roughly might correlate to reduced energy production or worse symptoms. We don’t yet know exactly what’s causing this, but there’s a hypothesis that the cells are receiving stress or danger signals in some sort from the body, and this is kind of their adaptation to those signals. Does that sound right?
David Systrom, MD: That’s right. I guess “adaptation” might imply—
I agree with everything, Danielle. Adaptation might imply to some that it’s a favorable response.
So, I think what we’re seeing in a preliminary fashion is that in ME and Long COVID, there appears to be a primary defect in the biogenesis of mitochondria—meaning the numbers are fewer.
And then some patients additionally have decreased function, and they are the ones we really identify with poor oxygen extraction and a depressed VO2 max and presumably worse symptoms.
There is another subset, however, who maybe in response to the decreased biomass do increase their function of the individual mitochondria. And that I would view as a favorable adaptive phenomenon.
Danielle Meadows, PhD: That’s a great nuance. Speaking of nuances, I think we talk about mitochondrial dysfunction in ME/CFS research a lot. And so it’s really interesting. What is kind of fascinating about this preliminary data is that you’re seeing a level down of that mitochondrial dysfunction with the electron transport chain sometimes being defective in some of the mitochondria when you’re seeing that in a physiological sense as well, with the poor oxygen extraction. But then there’s the subset that, like you’re saying, is adapting better. So that’s a really, really interesting finding, I think, that you’re seeing.
David Systrom, MD: Yeah, exactly. And I think maybe just taking one giant step backwards—what we’ve identified for a long time now is this issue of impaired oxygen extraction.
So, oxygenated red blood cells, for the most part in both ME and Long COVID, during incremental exercise and at peak exercise—they’re just fine. They’re going out the aorta, the big pipeline out to the exercising muscle. But then in a subset of patients, something additionally happens, and that is impaired oxygen uptake and utilization.
And really, the differential diagnosis there is blood flow abnormalities at a microvascular level—so, small blood vessels. And there are a lot of potential reasons for that. But the other possibility is that there is intrinsic mitochondrial dysfunction.
And an important point for patients and doctors to know—healthcare providers—is that the treatments for these things, at least currently, are totally different. Blood flow abnormalities on the one hand—and maybe related autonomic nervous system dysfunction—and then intrinsic mitochondrial dysfunction, either number or function.
The current treatments are quite different. And ultimately what we’re hoping for, obviously, is precision medicine. So, we can see an individual patient and with our biomarker quest identify these subsets of patients and treat them properly—get them better.
Danielle Meadows, PhD: What a wonderful way to wrap that up with some clinical relevance. I love that. So thank you so much for taking the time to provide an update on your research and share some really exciting results so far.