From viral persistence to complex immune studies to tissue sampling to assessing heavy-duty immune treatment trials and large treatment trials, long COVID researchers are doing things the ME/CFS community has wanted to happen for decades.
Including an exercise stressor has proved so valuable in ME/CFS that it is now considered a core research practice
On the flip side, Long COVID researchers have acknowledged that early on, they could have paid more attention to ME/CFS and post-infectious disease findings.
Even now, though, the long COVID field is mostly ignoring the most effective tool in the ME/CFS research playbook – adding an exertion stressor to a study to get at core elements of the disease.
Exertion Intolerant Disease
From the beginning, ME/CFS has been characterized by an intolerance of exertion. Its closest historical antecedent – neurasthenia – was described as producing chronic mental and physical exhaustion, easy fatigability after minor effort, poor concentration, etc.
The ME/CFS field learned over 20 years ago that adding an exercise stressor wasn’t just helpful – in many cases, it was mandatory. The normal baseline results, which perplexed patients, doctors, and researchers – and gave rise to psychological interpretations of the disease – were quickly replaced by penetrating insights once an exertion stressor was applied.
Exertion studies show that people with ME/CFS are often running on empty.
Adding exercise stressors made sense and, in fact, was probably inevitable. It was the ME/CFS field, after all, that introduced the term “postexertional malaise” to the medical field in 1991. Komaroff’s 1996 study documented the unique exertion challenges people with ME/CFS face when it found they were significantly more functionally impaired than people with congestive heart failure, type II diabetes mellitus, heart attack, and multiple sclerosis. The Institute of Medicine’s 2015 report underscored the core role exertion plays when it proposed calling the disease “systemic exertion intolerance disease (SEID)“.
Never before had a disease been so characterized by an inability to tolerate exertion. Never had it been so necessary to understand what happens during and after exertion. Using exercise studies to help understand ME/CFS was an innovation that was waiting to happen, and it didn’t take long.
The Workwell Foundation’s 2-day ME/CFS exercise test results sealed the deal. The results may have shocked exercise physiologists, but they didn’t shock people with ME/CFS. The idea that exercise one day inhibited one’s ability to generate energy the next day flew in the face of decades of research but made perfect sense to people with ME/CFS.
“A Crack in the Foundation”: Workwell, Exercise Intolerance and Chronic fatigue Syndrome (ME/CFS)
Using an exertion stressor enabled researchers to get a core factors in the disease.
Beginning in the late 1990s, ME/CFS researchers began using exercise stressors to understand HPA axis functioning and cytokine levels. During the 2000s, brain imaging and gene expression studies revealed abnormal patterns of brain activation and blood-flow regulation and a dramatic upregulation of stress, sensory, and immune genes.
It was if a curtain obscuring ME/CFS had been pulled. By the 2010s, using an exertion stressor to better understand ME/CFS had become a core ME/CFS research design feature.
Exertion is such a core feature of ME/CFS studies that, in an attempt to spare ME/CFS patients the effects of intense exercise, Canadian researchers have been using an inflatable cuff to mimic the changes produced during exercise.
Recent studies indicate that adding exercise greatly expands our understanding of ME/CFS. They include a gene expression study that found increased platelet activation, a proteomic study that demonstrated metabolic impairments, immune overactivation, and ER stress response, a urine metabolomic study that uncovered a dramatically diminished metabolic response, and a plasma metabolomics study that highlighted changes in lipid and energy-related pathways.
The Failure to Engage Findings
Some ME/CFS exercise studies suggest that a failure to engage on a molecular level plays a role.
Exercise studies are producing fundamental insights into the pathophysiology of ME/CFS that are, despite the enormous funding gap between the two diseases, arguably far outstripping what we’ve learned about long COVID. Consider the findings suggesting that, besides being dysregulated in a number of ways, ME/CFS patients’ systems are simply failing to engage on a molecular level when stressed by exercise.
- Gene expression – Exercise produced “altered functional gene networks” in healthy controls but produced no significant changes in ME/CFS patients.
- circRNA – Exercise produced an increase in circRNA in healthy controls but not in people with ME/CFS.
- Metabolites – Exercise produced an explosion in altered urine metabolites (n=400) in healthy controls, but produced no significant change in ME/CFS patients’ metabolites 24 hours after exercise later.”
- Proteins – Exercise produced reduced protein production in extracellular vesicles 15 s after exercise, reduced protein expression (63 vs 178), and a delayed increase in proteins in ME/CFS patients.
One Study
Exercise produced many results that were opposite to expectations.
Check out the dramatic changes – all abnormal – that exercise produced in Che’s recent ME/CFS study “Heightened innate immunity may trigger chronic inflammation, fatigue and post-exertional malaise in ME/CFS“. It found that exercise produced
- Increased citrate levels
- No change in phosphate levels
- elevated analytes in the S100 family and Class B/2 signaling pathways
- Increased levels of C1R and complement factor H-related protein 4 (CFHR4)
- Acyl-carnitine levels fall
- High tri and diglyceride levels
- Higher than normal linoleic acid and possibly high 12,13-diHOME levels
- Elevated ORN:CIT and ARG:CIT ratios prior to exercise; reduced ORN:CIT and ARG:CIT ratios after exercise
- Lower KYN: TRP ratios before exercise; increased KYN: TRP ratios after exercise
- Kynurenic acid (KYNA) to KYN KAT) activity ratios higher before exercise and decreased after exercise
- Higher levels of retina-specific copper amine oxidase (AOC2) and copper homeostasis protein cutC homolog (CUTC)
- Reduced pre- and post-exercise levels of tetranectin (CLEC3B)
These findings suggested that exercise disrupted the citric acid cycle, impaired beta-oxidation of fatty acids, impacted the urea cycle energy production cycle, produced lipid abnormalities, disrupted the extracellular matrix homeostasis, worsened gut dysbiosis, activated the complement system, knocked the redox system off balance, and dysregulated tryptophan-serotonin-kynurenine pathways.
Long COVID
Postexertional malaise (PEM) is considered a core symptom in long COVID and is being used by the RECOVER and NIH-funded studies to differentiate the ME/CFS-like long COVID cohort from other types of long COVID. Numerous cardiopulmonary studies have also documented a similar cardiovascular response exists in ME/CFS and long COVID.
In some areas, the small ME/CFS field is outstripping the much larger long COVID field.
Despite the similarities between the two diseases, I found just six long COVID studies that used exercise to explore other aspects of long COVID pathophysiology. Three were done by researchers who had worked with ME/CFS researchers or who had been funded by ME/CFS groups.
The findings were strikingly similar to those found in ME/CFS: lipid dysregulation, a shift towards glycolysis, problems with fatty acid metabolism, inflammation, blood vessel dysfunction, impaired muscle bioenergetics, and mitochondrial dysfunction.
Adding a new component – exercise – to a research study is not easy, but it is now routinely being done in ME/CFS and is an opportunity not to be missed. Indeed, more commonly including exertion stressors in long COVID studies could conceivably shorten the search for answers by years. The possibilities are enormous.
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