Linking Exercise Limitation Phenotypes to Muscle impairments in ME/CFS using non-invasive methods
Reduced exercise capacity, exhaustion, muscle weakness and post-exertional malaise (PEM) are characteristic symptoms of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). However, the underlying causes of these symptoms are not yet fully understood.
Exercise testing has shown that some patients receive insufficient oxygen delivery to their muscles, while others extract less oxygen from the blood. This suggests that multiple mechanisms may contribute to exercise intolerance in ME/CFS.
This project aims to improve understanding of muscle abnormalities associated with exercise limitation and PEM. The researchers use non-invasive techniques—including Magnetic Resonance Imaging (MRI) and Near-Infrared Spectroscopy (NIRS)—to investigate muscle function and develop clinically relevant biomarkers that can be used in both research and clinical practice. The findings will contribute to a deeper understanding of the pathophysiology of ME/CFS and may support the development of new, personalised treatment strategies.
Objective
The aim of this project is to better understand the mechanisms underlying exercise limitation and PEM in ME/CFS and to develop reliable, patient-friendly tools for assessing muscle function.
Recent studies at Harvard University have identified distinct muscle-level abnormalities using invasive exercise tests, suggesting that different biological mechanisms may cause exercise intolerance in different patient subgroups. To translate these findings into clinical practice, there is a need for accurate, non-invasive measurement techniques.
Approach / Method
The project consists of two complementary sub-studies that address key research questions formulated in collaboration with patient representatives, who remain actively involved throughout the project.
Sub-study 1: International collaboration with Harvard Medical School
This study investigates the relationship between different forms of exercise limitation and specific skeletal muscle changes. The researchers re-analyse existing muscle samples and data from invasive exercise tests to identify muscle-level abnormalities associated with reduced performance and PEM.
Sub-study 2: Observational study in the Netherlands
This study includes 80 ME/CFS patients with varying levels of disease severity and 20 healthy controls, all drawn from the Dutch NMCB biobank. The main objectives are to:
- Validate invasive findings by analysing new muscle biopsies from a separate ME/CFS cohort and confirming changes observed in Sub-study 1.
- Test and validate non-invasive techniques—including MRI, 31P-Magnetic Resonance Spectroscopy (31P-MRS), and NIRS—to assess muscle structure, mitochondrial function, and oxygen uptake, and to identify reliable muscle biomarkers.
- Investigate the relationship between exercise limitation, PEM, and muscle abnormalities.
Patients participating in the second substudy will undergo four assessments (measurement points) that vary in their burden. These include: an MRI scan to assess muscle composition and a muscle biopsy, a 31P-MRS scan during brief, light exercise to determine muscle mitochondrial function, and NIRS measurements during brief, light exercise to measure oxygen diffusion capacity in the muscles. And, optionally, a CPET for patients with mild to moderate symptoms, followed by questionnaires.
Collaboration Partners
This project is part of the Dutch ME/CFS Cohort and Biobank (NMCB). Analyses are conducted in the Netherlands with active collaboration and expertise exchange between:
- VU University Amsterdam
- Harvard Medical School (USA)
- Myolab
- Other national and international research groups within the NMCB consortium
The project team works in a multidisciplinary and international context, combining expertise in physiology, imaging, and muscle biology.
Patient representatives from various national organisations—MECVS Nederland and the ME/cvs Vereniging—are actively involved in all phases of the research, from study design to dissemination.
Expected Results
The project should provide insights into exertional problems in ME/CFS. It will also provide non-invasive diagnostic tools. These can be applied in research, care, and the early diagnosis of muscle abnormalities in ME/CFS. By better understanding the causes of various exertional problems in ME/CFS, targeted treatments can be developed that match the characteristics of individual patients.