Sharma et al. (2025)
- Authors: Sayan Sharma, Lynette D. Hodges, Katie Peppercorn, Jemma Davis, Christina D. Edgar, Euan J. Rodger, Aniruddha Chatterjee, Warren P. Tate.
- Institutes: Department of Pathology and Molecular Medicine, Dunedin School of Medicine, University of Otago; School of Sport, Exercise and Nutrition, College of Health, Massey University; Department of Biochemistry, School of Biomedical Sciences, University of Otago.
- Publisher: International Journal of Molecular Sciences
- Link: DOI
Summary
This research provides molecular evidence that the abnormal response to exercise in ME/CFS involves changes to how genes are regulated. By tracking DNA modifications before and after exercise, the study identified specific, dynamic shifts in gene activity related to the immune system, inflammation, and blood vessel function that occur during PEM. This confirms that PEM has a distinct biological basis, moving us closer to a potential objective test to diagnose the condition and monitor its severity. Understanding these specific pathways also opens up new avenues for developing targeted treatments.
What was researched?
This study investigated how the DNA of ME/CFS patients is epigenetically modified during post-exertional malaise (PEM). Researchers used a two-day cardiopulmonary exercise test (CPET) to induce PEM in five patients and tracked changes in their DNA methylation patterns at three time points: before exercise, 24 hours after the first exercise, and 48 hours after the start of the study.
Why was it researched?
PEM is the hallmark symptom of ME/CFS, but the molecular processes that cause it are not well understood. Previous studies by the authors suggested that DNA methylation, a process that controls gene activity, is a sensitive indicator of biological changes during ME/CFS relapses. This study aimed to use a controlled exercise stressor to precisely map these epigenetic changes as PEM develops, hoping to find molecular signatures that could explain the symptom and potentially be used for diagnosis.
How was it researched?
This was a longitudinal precision medicine study involving five female ME/CFS patients and two healthy female controls. All participants performed a maximal effort CPET on two consecutive days to induce PEM. Blood samples were collected before the first test (0h), 24 hours later (before the second test), and 48 hours after the start (24h after the second test). The researchers then used Reduced Representation Bisulphite Sequencing (RRBS) to analyze and compare the DNA methylation patterns in immune cells from these samples over time.
What has been found?
ME/CFS patients showed a deterioration in cardiopulmonary function on the second day of exercise, which was not seen in the healthy controls. The analysis identified 205 unique, ME/CFS-specific changes in DNA methylation that occurred in response to exercise, with 98% of these changes being exclusive to the patient group. These epigenetic alterations followed distinct patterns over the 48-hour period and were linked to genes involved in endothelial function, inflammation, and immune regulation.
Discussion
The authors noted that despite the ME/CFS patients having similar clinical profiles, they showed considerable individual variation (heterogeneity) in both their physiological and epigenetic responses to the exercise. However, the overall dysfunctional pathways affected were similar across the patients. In stark contrast, the two healthy controls showed very similar, almost identical, epigenetic responses to each other, highlighting that the changes observed in the ME/CFS group were disease-specific.
Conclusion & Future Work
The study concludes that PEM is associated with dynamic and specific epigenetic changes in genes related to stress and immune functions. These findings reveal potential molecular signatures that could be significant for both diagnosis and understanding the mechanisms behind ME/CFS. The authors suggest future work should integrate these epigenetic findings with other molecular data (like RNA and protein levels) and investigate cell-free DNA in plasma as another source for potential biomarkers.