People with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) showed multiple maladaptive proteomic responses to exercise compared with matched sedentary controls, a new study found.

ME/CFS is a disabling chronic illness defined by profound fatigue for at least 6 months, post-exertional malaise (PEM), and unrefreshing sleep, along with cognitive impairment and/or orthostatic intolerance. The symptoms must be moderate to severe in intensity and present at least 50% of the time.

The new plasma profiling study focused on PEM, an exacerbation of the individual’s symptoms following physical, mental, or emotional exertion. The authors assessed correlations of levels of 6361 unique proteins with patient-reported symptom data gathered before, during, and after 2 days of maximal cardiopulmonary exercise testing (CPET). Compared with 53 healthy people who were similarly sedentary — to control for the effects of deconditioning — 79 individuals with ME/CFS showed sustained immune, metabolic, and neuromuscular dysregulation following the first CPET.

The exertion also disrupted T- and B-cell signaling, interleukin-17 pathways, and mitochondrial metabolism. In those with ME/CFS, the protein signatures correlated with severity of symptoms, such as muscle pain and sleep disturbance, and impaired exercise performance. The study was published in the December 2025 issue of Molecular & Cellular Proteomics.

In women, there were strong correlations between PEM severity post-exercise and coagulation-related proteins, while in men, the associations were with proteins involved in protein folding and the endoplasmic reticulum stress response during recovery.

“Fundamentally, the ME/CFS patient’s response to exercise is very different and very impaired….These are objective changes in the bodies of these patients that correspond with what the patients are saying,” study co-author Katherine A. Glass, PhD, research associate at Cornell University, Ithaca, New York, told Medscape Medical News.

Study Series Shows a ‘Profound, Disrupted Response to Exercise’

This paper is the latest in a series of studies from the Cornell research team of the same participant group. One published in 2023 showed delayed recovery from exercise, while another in 2024 showed impaired cardiopulmonary and metabolic responses in 2-day CPET testing.

“The whole body of work on this very well-characterized cohort is showing that there is this very profound, disrupted response to exercise. And again and again, we find the largest changes are from immediately post-exercise to 24 hours later, which we call the ‘recovery period’ from exercise because the healthy controls have recovered, but patients have not. And it does correlate with the symptom severity data, where patients are reporting that they have increases in post-exertional malaise,” Glass said.

Asked to comment, Leonard H. Calabrese, DO, head of Clinical Immunology and vice-chair of the Department of Rheumatologic and Immunologic Diseases at the Cleveland Clinic in Cleveland, told Medscape Medical News that the study was “very nice work that helps elucidate the profound and complex immuno-metabolic disruption that occurs in people who have PEM following physical exertion….It’s not one thing, but a network of disruptions.”

However, Calabrese pointed out that “it really doesn’t give us insight into any of the other forms of PEM, namely following intellectual stress and psychological stress. We still have huge gaps in our knowledge about PEM induced by nonphysical exertion triggers.”

Clinical Implications: Pacing Advised to Avoid PEM

Clinically, Calabrese said, “Graded exercise for people who have PEM is not good. On the other hand, doing nothing is not good either.” Instead, he recommends — as do most ME/CFS experts — the practice of pacing, in which patients learn to carefully manage their activity levels to limit the number and severity of PEM “crashes” while remaining as active as possible.

His approach is to help patients “understand the merits of pacing in all domains that are triggering their episodes of PEM and to help empower them that they have some control over this.”

Calabrese said he refers all of his patients — including those with ME/CFS, fibromyalgia, and other infection-associated chronic conditions — to the “robust” educational resources on the website of the Salt Lake City-based Bateman Horne Center, including specific information on pacing as part of overall patient management. He also gives patients handouts based on the information posted there.

Both Glass and Calabrese lament the fact that there is no optimally validated screening tool for PEM, although Calabrese routinely uses the short form of the DePaul Symptom Questionnaire. Glass is currently part of a National Institutes of Health committee that aims to strengthen the common data elements for ME/CFS studies specifically relating to PEM.

In addition to the DePaul tool, Calabrese also uses several different screening questionnaires for pain and for quality of life. Importantly, as a starting point with patients who have multiple symptoms, he always asks “What bothers you the most?”

Glass, who had ME/CFS and is now in remission, noted of the condition, “It’s so incredibly difficult because when you rest too much, you get worse, and then when you do too much, even a tiny bit too much, you get worse, and then you can no longer maintain the same baseline….I think post-exertional malaise really is the biggest challenge that both researchers and clinicians need to address for the patient.”

The research was funded by several National Institutes of Health grants and the Amar Foundation. Glass and Calabrese reported having no relevant disclosures.

Miriam E. Tucker is a freelance journalist based in the Washington, DC, area. She is a regular contributor to Medscape Medical News, with other work appearing in the Washington Post, NPR’s Shots blog, and Diatribe. She is on X @MiriamETucker and BlueSky @miriametucker.bsky.social.