Skeletal Muscle Dysfunction. The Harvard ME/CFS Collaboration at Harvard-Affiliated Hospitals

John Mac · Sep 18, 2019

Research proposal

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.

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.
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http://endmecfs.mgh.harvard.edu/skeletalmuscle/

NelliePledge · Sep 18, 2019

Yes this is what the British researchers at Nottingham and Birmingham will be involved in

Andy · Sep 18, 2019

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.
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ETA: Meant to say something about this quote - the second paragraph looks like investigations will be impressively thorough.

jpcv · Sep 23, 2019

I think there is a group of Italians who have been studying the muscle in patientes with ME.
It seems thet this was a very promisisng field of research a few decades ago but somehow the interest faded away

Mithriel · Sep 23, 2019

ME became CFS and the psychiatrists took over. The researchers who had been working on me for years were sidelined and grants dried up.

I know I keep harping on about it, but it looks, and is often stated as fact, that avenues like muscle and enteroviral involvement were explored and abandoned because they didn't lead anywhere but there have been lots if interesting results never followed up.

The cardiac involvement is something we could have done with being proved or disproved and cell membrane issues in particular, but it suited the narrative that we are just deconditioned and to imply that all that work was done but showed nothing.

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Skeletal Muscle Dysfunction. The Harvard ME/CFS Collaboration at Harvard-Affiliated Hospitals

John Mac Senior Member (Voting Rights)

NelliePledge Moderator Staff Member

Andy Committee Member

jpcv Established Member (Voting Rights)

Mithriel Senior Member (Voting Rights)

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Skeletal Muscle Dysfunction. The Harvard ME/CFS Collaboration at Harvard-Affiliated Hospitals

John Mac Senior Member (Voting Rights)

NelliePledge Moderator Staff Member

Andy Committee Member

jpcv Established Member (Voting Rights)

Mithriel Senior Member (Voting Rights)

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