A “unifying” hypothesis of the mechanisms, triggers, and risk factors for myalgic encephalomyelitis (ME), is gaining support. Further evaluation and development of a potential drug depend on funding.
Key points you should know:
- Pharmacologist Klaus Wirth and immunologist Carmen Scheibenbogen describe myalgic encephalomyelitis (ME) as a complex of impaired blood flow and self-perpetuating mitochondrial damage.
- Their hypothesis is an extremely comprehensive effort to explain the onset of ME through various triggers as well as its wide range of symptoms.
- Central to the complex hypothesis is a disruption in calcium-sodium metabolism in skeletal muscle cells.
- Most aspects of the German scientists’ model are supported by findings in people with ME, experimental data and established physiology, but one key element — and the overall mechanism of the disease — has not been proven yet.
- Wirth is developing a drug that, in his assessment, would target ME’s central mechanism. Clinical trials would help determine whether the hypothesis holds. Patient groups in Germany are lobbying for funding.
It all began by chance. In 2018, German pharmacologist Klaus Wirth stumbled across a regional TV report featuring a person with myalgic encephalomyelitis (ME). At the time, Wirth knew little about this enigmatic disease. The brief report, however, was enough to spark his curiosity.
In the following days, the medical doctor and adjunct professor at Goethe University Frankfurt dove into the subject, scouring websites and scientific databases. One paper stood out: a study led by immunologist Carmen Scheibenbogen, head of Berlin’s University Hospital Charité Fatigue Center. Intrigued, Wirth reached out.
What began as an exchange of ideas has since blossomed into a sustained scientific collaboration. Its centerpiece is an ambitious “unifying hypothesis” of the pathophysiology of ME. First published in 2020 and refined since, this hypothesis is an extremely comprehensive attempt to explain the disease’s origins, triggers, risk factors, and full spectrum of symptoms.
As Wirth told The Sick Times, “severe ME/CFS is an acquired, self-perpetuating mitochondrial damage of the skeletal muscles.” At his startup Mitodicure, he is developing a compound that could target the disease’s potential central mechanism.
The company is planning clinical trials to evaluate the compound’s effectiveness and to validate the underlying hypothesis. While evidence exists for many individual pieces of this complex mechanism, testing an intervention targeting the suspected central pathway may lead to a definitive answer.
The hypothesis also has support in the patient community. “Klaus Wirth was the first to come up with a therapeutic idea that tackles the problem at its root — the cardinal symptom, [post-exertional malaise (PEM)],” said Birgit Gustke, a ME advocate and former chair of the German patient organization Fatigatio.
Calcium overload in skeletal muscle
According to this complex framework, ME can emerge as a distinct disease from a range of different triggers. One common trigger is COVID-19.
SARS-CoV-2 can attack the endothelium, the cellular lining inside blood vessels designed to regulate the vascular system and prevent blockages. SARS-CoV-2 also causes immune activation, which can slow blood flow through the capillaries, the smallest blood vessels, reducing oxygen delivery to muscles, the heart, and the brain.
In ME, these microcirculatory issues remain even after triggers, such as persistent virus fragments or microclots, subside. The hallmark of ME is post-exertional malaise (PEM), marked by a worsening of symptoms after exertion, often delayed by up to 72 hours. PEM causes structural damage in skeletal muscle, as demonstrated by Dutch physiologist Rob Wüst, and is fundamentally distinct from exhaustion or deconditioning caused by inactivity.
“Klaus Wirth was the first to come up with a therapeutic idea that tackles the problem at its root — the cardinal symptom, [post-exertional malaise (PEM)]
Birgit Gustke, ME advocate and former chair of Fatigatio
“The key question is why this damage occurs in muscle,” Wirth said. In their hypothesis, he and Scheibenbogen identified disrupted ion exchange in muscle cells as the underlying cause.
Calcium ions are essential electrolytes; they regulate muscle contraction, blood clotting, nerve signals, and enzyme functions. When muscles contract, calcium ions flood the cell’s internal fluid. In healthy individuals, these ions are swiftly cleared through rest, partly due to an exchange of sodium ions. But this recovery mechanism may fail in people with ME.
In response to disturbance from infection or other triggers, the heart rate increases, further lowering capillary pressure. When the blockage from microclots, virus fragments, or immune cells clears and blood flow suddenly returns, an ion pump in the membrane of muscle cells becomes hyperactive, expelling protons while importing sodium ions — now in excess.
Simultaneously, low oxygen reduces ATP, the cell’s primary energy carrier. This low ATP impairs the functioning of a second ion pump that expels sodium in exchange for potassium and works hardest during muscle contraction.
These disrupted pumps push sodium inside the cell to abnormally high levels. This is where the central mechanism for the researchers’ hypothesis comes in: calcium overload. According to the hypothesis, a transporter called NCX then expels the extra sodium by shifting from its typical direction. But that shift causes “calcium overload,” which “can directly damage cells,” Wirth explained.
When sodium in the cell hits a critical level and triggers NCX to switch into reverse mode, PEM sets in, he said.
Excess calcium damages mitochondria — the cell’s powerhouse. In response, the mitochondria release molecules derived from oxygen, called reactive oxygen species, which further deplete ATP, disrupt the pumps’ functioning, and worsen circulation in muscle blood vessels.
In this way, mitochondrial damage becomes a “vicious cycle,” as Wirth puts it. ME becomes a self-perpetuating disease as the pool of intact mitochondria needed for cellular repair gradually declines. “A bedridden patient can hardly escape this anymore,” Wirth said.
The role of autoantibodies
Among international ME researchers, Carmen Scheibenbogen is also a leading expert on autoantibodies — antibodies that mistakenly target the body’s own tissues. In the study her team conducted that first drew Wirth’s attention, she treated 10 post-infectious people with ME with immunoadsorption — a blood filtration procedure that removes certain autoantibodies. Most patients showed at least temporary, marked improvement.
Wirth, a former senior researcher at Sanofi, has studied how Beta-2 receptors regulate blood flow in both brain and muscles. In their ME hypothesis, autoantibodies may affect the sodium–potassium pump by blocking the Beta-2 receptors that stimulate this pump. The same blocked receptors may also be related to small fiber neuropathy, often reported in ME.
Other factors could worsen these pathways, including orthostatic stress from circulatory dysfunction and persistent adrenaline release due to pain.
Scheibenbogen and Wirth’s hypothesis suggests the body attempts to compensate for skeletal muscle energy deficit by releasing hormones that widen blood vessels. This response may overshoot: These signaling molecules then spill into the bloodstream — an effect observed in menstrual cramps and mast cell activation syndrome — and further reduce circulating blood volume.
These signals can reach multiple organs, contributing to pain, cramps, and spasms, as well as mental exhaustion, irritability and the cognitive dysfunction characteristic of ME.
Overall, in this hypothesis, “a range of triggers and disease-sustaining processes ultimately funnel into a single, shared mechanism,” Scheibenbogen told The Sick Times. She said the causes of reduced blood flow “are likely not uniform,” and the autoantibodies detected in a subgroup of people with ME may impair autonomic regulation.
The state of evidence
“The concept of modulating ion transport is fascinating,” Norwegian biochemist Karl Johan Tronstad, a professor of biochemistry and molecular biology at Bergen University, told The Sick Times. He described the hypothesis as “a thoughtful attempt” to weave still-limited evidence into a coherent disease model. Still, he cautioned that several core elements remain at an early theoretical stage, even if grounded in established physiology.
Data supports many crucial components of the hypothesis: impaired capillary blood flow, altered brain energy metabolism, damaged mitochondria, persistent endothelial dysfunction, and elevated muscle sodium correlating with reduced handgrip strength have all been reported in people with Long COVID and ME, although sometimes only in small studies. Experimental research also supports central mechanisms, such as NCX reversal under sodium overloading.
However, proof is still lacking for a key element — calcium overload in ME patients — and for the full interplay of the mechanism. In one of their papers, Wirth and Scheibenbogen note a practical challenge: current imaging techniques can’t capture calcium overload in human subjects. But they argue that findings in Rob Wüst’s post-exercise biopsy study “can only be explained by calcium overload.”
Only a small number of scientists worldwide have engaged closely with the hypothesis. One is David Systrom, a physician and director of the Advanced Cardiopulmonary Exercise Testing Program at Harvard University. “I am a big fan of the work that they are doing and I think it could lead to good things,” he told The Sick Times, calling the hypothesis “quite tenable.”
However, Systrom said that he finds the mechanism convincing for a “subset of patients with ME.” As he explained, “not everybody has the impaired oxygen extraction during exercise that is typical of mitochondrial damage.”
However, Wirth argues the hypothesis could apply more broadly. Circulatory disturbances do not always result in visible mitochondrial damage, he said, and mitochondria may be compromised even when oxygen extraction appears normal. These issues need further research.
Systrom supports the Germans’ aim of testing the hypothesis rapidly through therapeutic studies: “I am a firm believer that we need to take what we have in basic science and rapidly apply it in randomized clinical trials.”
I am a firm believer that we need to take what we have in basic science and rapidly apply it in randomized clinical trials.
avid Systrom, physician and director of the Advanced Cardiopulmonary Exercise Testing Program at Harvard University
New therapeutic approaches
Wirth does not expect a single breakthrough drug to cure all ME patients. “In the end, it is very likely that severely ill patients will need multiple medications” to address different risk factors and triggers alongside the suspected central mechanism, he said.
The search for a drug targeting the central mechanism of ME led Wirth back to earlier pharmacological work. Reviewing a list of compounds, Wirth identified a candidate that had already shown in testing that it can increase both cerebral and muscular blood flow without lowering blood pressure. According to Wirth, it may also interrupt the “vicious cycle” of disrupted ion homeostasis — halting sodium overload and, in turn, presumed calcium overload.
Wirth landed on the compound he calls “MDC 002.” On its website, Mitodicure describes MDC 002 as “an orally applicable small molecule” that stimulates both the sodium-potassium pump and the sodium-calcium exchanger NCX in skeletal muscle.
Advocate Gustke, like others with ME in Germany, wants to see the compound tested in trials. When she first met Wirth in 2019 at an event at the Charité’s Fatigue Center, his hypothesis immediately struck a chord: “It was the first time I thought: This is how it might all fit together.”
To her, the hypothesis may explain what her body goes through during PEM. “I always felt this couldn’t simply come from the muscles. It felt like a systemic collapse — something originating in the cells.”
Such impressions cannot replace scientific evidence. But for Gustke, the time it takes to organize the necessary studies is hard to bear. “We know there won’t be a therapy overnight,” she said. “At the same time, we are in contact with so many people who are fighting for their lives. To ignore that there might be a drug — that’s unbearable.”
The German Ministry of Research has already received numerous letters and emails urging it to fund clinical studies with this compound.
Ricarda Piepenhagen, founder of the German patient advocacy group Nicht Genesen (“Not Recovered”), is among those lobbying policymakers to support Mitodicure. She argues that Wirth and Scheibenbogen’s approach could mark a turning point: “We may finally have something that can help people out of bed,” she said.
But she criticized what she sees as a lack of urgency, saying biomedical research is still not taken seriously enough. “Too often, policymakers rely on advice shaped by psychosomatic perspectives,” Piepenhagen said.
Perhaps that is why Mitodicure has struggled for years in its search for funding — despite the German Federal Government having funded Long COVID and ME research for several years. It also declared a “research decade for post-infectious diseases,” backed by €500 million ($589 million) over the next 10 years.
Other trials test autoantibody treatments
Wirth must still raise significant private capital to conduct four-week toxicology studies even before advancing to the first phase of clinical trials. Venture capital funds — even semi-public ones — have so far been reluctant to invest in ME.
Yet research into autoimmunity has gained traction in animal studies. Mouse studies, including one by Jeroen den Dunnen of Amsterdam University Medical Center reproduced Long COVID symptoms in mice by injecting them with autoantibodies from peoples’ blood—evidence of their role in the disease mechanism. The Amsterdam University study and one from Belgian researchers have been peer-reviewed; the others are pre-prints.
We may finally have something that can help people out of bed.
Ricarda Piepenhagen, founder of a German patient advocacy group
In Germany, therapeutic research along these lines is advancing. In early 2025, Scheibenbogen’s team reported another case series on immunoadsorption. Twenty patients with ME after COVID-19 underwent five sessions to remove Beta-2-adrenergic autoantibodies from their plasma. Fourteen of the twenty showed marked improvements in overall condition and core ME symptoms. The study, however, lacked a control group, leaving open the possibility of a placebo effect.
Now, three randomized controlled trials in Germany and one in the Netherlands aim to determine whether — and if so, which — patients benefit from having autoantibodies removed from their blood. The University of Amsterdam is still recruiting participants, while the German trials have already wrapped up. No results have yet been released from a study at University Medical Center Mainz involving 40 people with Long COVID, or from a trial at Hannover Medical School that enrolled 60 patients with COVID-associated ME.
Researchers from Charité medical school — in a study not led by Scheibenbogen — presented preliminary findings at last week’s international ME/CFS conference in Berlin. In the trial, 45 participants underwent five sessions of immunoadsorption, while 20 received a sham treatment. Researchers tracked fatigue severity over 60 days using the Chalder Fatigue Scale. According to the preliminary data, there was no statistically significant difference between the treatment and placebo groups.
But criticism of the study design surfaced during the conference itself. The neurologists leading the trial had not specifically recruited subjects with confirmed autoantibodies. Charité biochemist Birgit Sawitzki noted that some participants, according to the preliminary data,“were benefiting tremendously.”
A subgroup analysis, which has not yet been conducted, may ultimately reveal whether a certain subset of people with ME did in fact respond to the treatment. Especially since, in contrast to those findings, a new case series from Scheibenbogen’s research group — which also presented preliminary results at the conference — painted a different picture: Of the 15 participants with ME and detectable autoantibodies, 7 appeared to respond to immunoadsorption, with improvements in their overall condition. However, the study lacked a control group.
Even if trials do confirm a benefit, it may prove temporary. In Scheibenbogen’s case series, patients’ conditions deteriorated again after three to six months — a pattern researchers anticipated. The procedure removes circulating autoantibodies, but beta-cells remain, producing new autoantibodies over time. To address this, Scheibenbogen and colleagues are preparing clinical trials of approved drugs aimed at Beta-cells, in an effort to prevent renewed autoantibody production.
All of this will help determine whether she and Wirth are correct when they write in their latest paper on the hypothesis: “ME/CFS is no more an enigmatic disease.”
Martin Rücker is an investigative science reporter based in Berlin, Germany. For several years, the freelancer has been reporting on the gaps in care for people with Long COVID and ME. You can follow Rücker on X, Bluesky, LinkedIn, and Instagram.
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