McGregor et al. (2019)
- Authors: Neil R. McGregor, Christopher W. Armstrong, Donald P. Lewis, Paul R. Gooley
- Institutes: Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne; Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biochemistry Institute; CFS Discovery, Donvale Medical Centre.
- Publisher: Diagnostics
- Link: DOI
Summary
This research provides a potential biological explanation for the “crash” experienced during PEM. It suggests that exertion triggers a hypermetabolic state in ME/CFS patients, causing their bodies to wastefully excrete vital molecules—including those needed for cellular regulation (acetate) and energy (purines)—through their urine. This process is linked to evidence of muscle breakdown and leaky gut. The resulting lack of key molecules like acetate (hypoacetylation) could disrupt a vast range of cellular activities, offering a reason for the widespread symptoms of PEM. These findings offer specific biochemical targets for future research into diagnostics and treatments and provide a scientific basis for why graded exercise may be physically harmful for patients.
What was researched?
This study investigated the biochemical changes in the blood and urine of ME/CFS patients to identify metabolic signatures associated with the severity of post-exertional malaise (PEM) experienced in the previous seven days. The researchers aimed to understand the underlying pathophysiology of PEM, a core symptom of the illness.
Why was it researched?
While PEM is a defining characteristic of ME/CFS, very little is known about its biological basis. Previous research indicated that ME/CFS patients have dysregulated energy metabolism, including problems with glycolysis (breaking down sugar for energy) and purine metabolism (related to ATP, the cell’s energy currency). This study was designed to specifically link these previously observed biochemical anomalies to the acute experience of PEM.
How was it researched?
This was an observational study analyzing blood and urine samples from 46 ME/CFS patients and 26 age- and sex-matched healthy controls. The ME/CFS group was further divided into 35 patients who had experienced PEM within the last 7 days (the “PEM group”) and 11 who had not. Researchers used questionnaires to score PEM severity and frequency, and metabolomics (the large-scale study of small molecules) to analyze the biochemical differences between the groups.
What has been found?
The study found that the severity of PEM in the last 7 days was associated with a “hypermetabolic event” characterized by the increased excretion of multiple metabolites in the urine. Key findings included increased urinary excretion of methylhistidine (a marker for muscle protein breakdown), mannitol (a marker for intestinal barrier dysfunction or “leaky gut”), and acetate. The primary biochemical change linked to PEM severity was a significant drop in the serum level of hypoxanthine, a crucial component of purine metabolism needed for energy production. These findings point towards a state of hypoacetylation (low acetate availability) and dysregulated energy production during PEM.
Discussion
The authors acknowledge several limitations, including the small study size and the potential for recall bias from using self-reported symptom questionnaires. The study was designed as an exploratory investigation to generate a hypothesis, rather than to test a pre-existing one. Therefore, the findings need to be confirmed in larger, multi-center studies that can further validate the identified biochemical changes.
Conclusion & Future Work
The authors conclude that PEM is associated with significant disruptions in glycolysis, acetylation, and purine metabolism. This suggests a state of hypoacetylation occurs, which can profoundly impact cellular functions, including gene expression and enzyme activity. The researchers call for future studies to directly evaluate acetylation processes and their consequences in ME/CFS patients to better understand the mechanisms of PEM and develop appropriate therapies.