A characteristic symptom complex in ME/CFS is post-exertional malaise (PEM). This condition follows physical exertion, cognitive exertion, or what is called “orthostatic stress” (a failure of the autonomic nervous system to properly balance heart rate and blood pressure when a person is upright for very long). Typically, PEM appears 12 – 72 hours after these physical, cognitive, or orthostatic stressors. The symptoms include increased fatigue, difficulty thinking (“brain fog”), as well as increased aching of the muscles.
Since PEM follows physical exertion, it is possible that abnormalities in the muscles may trigger the condition. We propose to examine at the molecular level the response of muscles to physical stress, in people with ME/CFS and in healthy people. This evaluation might give us insight into mechanisms of disease as well as suggestions for biomarkers and potential drug targets for treatment of PEM in ME/CFS patients.
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Background
This clinical research focus will discover and understand the multi-omic signature of the skeletal muscle from patients with ME/CFS both at rest and eventually during their recovery from mild to moderate muscular stress. Comparisons will be made to the multi-omic signatures of healthy volunteers also at rest, during recovery from muscular stress, and during immobilization. These comparisons will come from samples made available from our United Kingdom (UK) colleagues at the Universities of Birmingham and Nottingham. Our hypothesis is that the inflammation-related recovery mechanisms become dysfunctional in the ME/CFS disease, and this dysregulation causes a delayed recovery of muscle after exertional stress (Post-exertional Malaise, PEM). We intend to focus on genomics, proteomics, and ultrastructural features of skeletal muscle cells (as shown in the figure). Of particular interest are the mitochondria and their role in energy production and resolution of the inflammation that is generated by muscular stress and exercise. It is both possible and even likely that clues for potential biomarkers for PEM will be revealed in these highly detailed studies.
One of the most prominent symptoms - in addition to fatigue - that is included in the diagnostic criteria for ME/CFS is Post-exertional Malaise (PEM). These symptoms worsen after physical, cognitive, or emotional effort. 
Typically in those patients who can participate in exercise, when challenged to exceed their usual exercise tolerance limit, these ME/CFS patients can often perform to a normal or slightly reduced compared to normal extent. However in those ME/CFS patients who can consider to attempt a follow up challenge, PEM has usually appeared within 24-72 hours of the initial challenge. In their follow up challenge, these ME/CFS patients cannot achieve nearly a comparable effort shown in their initial challenge. Our hypothesis is that these exercise challenges naturally lead to cytokine-associated myofibrillar damage, which is described as “soreness” in normal volunteers and resolves within 24 - 48 hours. In ME/CFS patients, the reparative process is in some way dysfunctional and the reparative processes are seriously delayed, which causes an extreme exaggeration of symptoms that can last for hours, days, or even months. Genomic, proteomic, phospho-proteomic, ultrastructural, or mitobiogenetic biomarkers will be identified to distinguish this process in normal volunteers when compared to those processes in ME/CFS patients. As shown in the figure above, it is likely that mitochondria are central to this energy and reparative process.
Patient Studies
The ME/CFS patients will be those who have been seen and evaluated by highly trained and experienced clinicians familiar with making the diagnosis and successfully treating ME/CFS patients. Standard questionnaires describing the phases of disease and phenotype of disease will be cataloged for these patients. Most, if not all, of these patients will have been evaluated by iCPET to ensure that cardiopulmonary diseases are not mimicking ME/CFS. Most often these iCPET evaluations will be consistent with “preload” failure. Many, if not all, will also have received neuroimaging evaluations intended to discern if any neuroinflammation or more specifically, microglial cell activation is present.
In the initial studies, we will focus on open skeletal muscle biopsies on these patients performed by a plastic surgeon. These muscle tissues will be deeply evaluated by multiple modalities including high throughput RNASeq at MGH, high throughput proteomics, phospho-proteomics, and metabolomics performed at PNNL, ultrastructural morphology at MGH, and other biogenesis evaluations at MGH. In selected muscle samples, thin slices will be challenged by tryptophan (Trp) to evaluate the presence of a “molecular trap”, which is a hypothesis, that might explain many of the phenomena seen in ME/CFS patients. These stable isotope metabolites will be evaluated in the Bergquist laboratory at the Uppsala University.
Normal Volunteer Studies
Comparison studies with age and lifestyle matched controls are essential to best discern any subtle differences in genomics, proteomics, phospho-proteomics, metabolomic, and ultrastructural analyses seen in the skeletal muscle samples from ME/CFS patients. It is very important that age, level of activity, and immobility are critical basic features requiring comparative control. These samples will come from our collaborations at the University of Birmingham and the University of Nottingham, who are highly skilled in precise studies of normal volunteers evaluating age, inflammation, and immobilization. These studies are also required to precisely control physiology and metabolic responses. This relationship is a fabulous opportunity provided to the ME/CFS Collaboration because of these unique resources.
Participation in the Studies
These are very complex studies. For this MGH and BWH study in ME/CFS patients, which is currently under review by the MGH/Partners Harvard Institutional Review Board, enrollment is not yet possible. Since these studies include muscle biopsies, the review process can be complicated and prolonged. It is clear that over the course of time, various projects will be involved in open enrollment, others pending open enrollment, and others that have been closed and are under analysis. This situation suggests a fluid process and it is our intent to develop a separate portion of this website to announce opportunities for patient volunteers to be updated readily for any studies that are currently enrolling within the ME/CFS Collaboration. Any patients who have interest in a study will be able to register and participate as well as provide feedback regarding their experience.
