Post-exertional malaise (PEM) is the hallmark symptom of ME/CFS: an exacerbation of symptoms triggered by physical or mental exertion that is often disproportionate to the activity. While PEM has long been recognized as central to ME/CFS, the molecular mechanisms underlying this debilitating response have remained largely unknown.

A recent paper from the Center, published in Molecular & Cellular Proteomics, provides a comprehensive look at what happens at the protein level when people with ME/CFS experience PEM. The work was led by first author and Center investigator Arnaud Germain, a postdoctoral research associate in the Hanson Lab. The paper has also been featured in an article on Medscape.

What Was Done

The study used a powerful aptamer-based proteomic assay (the SomaScan 7K) to measure 6,361 unique plasma proteins in 132 individuals (79 ME/CFS cases, 53 age/BMI-matched sedentary controls). The design included two maximal cardiopulmonary exercise tests (CPET) separated by 24 h, enabling the investigators to chart the molecular aftermath of exertion and recovery.

By comparing ME/CFS to sedentary controls rather than healthy active individuals, the team could distinguish disease-specific alterations from changes simply due to physical  deconditioning, a key approach that differentiates this study from others.

Key Findings

Our analysis revealed widespread proteomic changes following exertion, with the most dramatic alterations occurring in ME/CFS participants during the 24-hour recovery period—precisely when PEM symptoms typically emerge.

Immune System Dysfunction:

• Suppression of T and B cell signaling
• Reduced IL17 and cell-cell communication pathways

Metabolic Disruption:

• Up-regulation of glycolysis/gluconeogenesis pathways, consistent with mitochondrial stress and impaired immune recovery
• Disrupted associations between protein levels and physiological performance (VO₂max, ventilatory anaerobic threshold) in ME/CFS compared to controls

Clinical Correlations:

• Correlations between immune-related proteins and symptom severity, including muscle pain, recurrent sore throat, and lymph node tenderness

Sex Differences:

• Sex-stratified analyses revealed distinct molecular responses in females and males, emphasizing the critical importance of considering sex as a biological variable in future research

Key Insights

For Patients: This research provides molecular validation for what ME/CFS patients have long known—that their bodies respond abnormally to exertion. The recovery phase in ME/CFS is characterized by prolonged, maladaptive molecular responses rather than a healthy return to baseline. This data provides scientific backing for clinical recommendations around pacing and avoiding activities that trigger PEM.

 For Researchers: The findings reveal that immune, metabolic, and neuromuscular pathways remain dysregulated in ME/CFS long after exertion ends. The study also demonstrates that women and men with ME/CFS may exhibit different molecular pathophysiology, emphasizing the need to account for sex differences in future studies.

 For the Field: This work provides a rich molecular dataset and a foundation for mechanistic follow-up. The longitudinal dynamic profiling approach may also serve as a model for investigating other disorders featuring exertion intolerance (e.g., Long COVID).

Access the Research

The full manuscript is now available in Molecular & Cellular Proteomics:

Germain A, Glass KA, Eckert MA, Giloteaux L, Hanson MR. Temporal dynamics of the plasma proteomic landscape reveals maladaptation in ME/CFS following exertion. Molecular & Cellular Proteomics (2025). doi: https://doi.org/10.1016/j.mcpro.2025.101467

The associated dataset can be accessed on the journal’s website and on mapMECFS.