One of the dangers facing the long-COVID research field was an over-emphasis on immune functioning and an under-emphasis on metabolism and energy production. While exercise studies showed up pretty early in chronic fatigue syndrome (ME/CFS), it took the field a while to incorporate them. Indeed, some of the findings were so striking that they were largely discarded by outside exercise physiologists.
The findings from Systrom’s recent invasive exercise studies and Naviaux’s and others’ early metabolic studies helped, though, make these key research arenas in ME/CFS. Because long COVID, to all appearances, is probably immune driven, one could see these areas being neglected and one could argue that they are relative to the work being done in ME/CFS, but they are steadily showing up – and, at times, are producing eye-opening results.
The study, “Muscle abnormalities worsen after post-exertional malaise in long COVID“, did something simple but brilliant that we haven’t seen in ME/CFS or FM before. Given the exertion problems, it’s always seemed that something has to be going on in the muscles, and indeed both fibromyalgia and ME/CFS studies (often miserably small) suggest something is, but no one has ever put that idea to the test; i.e. nobody has, to my knowledge, tested how the muscles responded to an exercise challenge until now.
This smallish study (25 long COVID/24 healthy controls) study did. It took muscle biopsies from long-COVID patients (none of whom had been hospitalized) and healthy controls (people who’d recovered from COVID-19) – put them on a bike and exercised them to exhaustion (it doesn’t take long :)) using a CPET protocol – and then took another round of muscle biopsies and compared them.
Led by Rob Wust, an exercise physiologist and mitochondrial researcher, the study was funded by a variety of sources including the Patient-Led Research Collaborative for Long COVID and the Solve M.E.’s 2022 Ramsay Grant Program (!).
The primary aim of that Ramsay Grant was “to unravel the origins of muscle pain, extreme muscle fatigue and post-exertional malaise in patients with long-covid”. I would say the researchers made a good step in that direction. Score a big win for Solve M.E. and their Ramsay Grant program.
Cardiopulmonary Exercise Test (CPET)
First came a standard CPET analysis which assessed how well the participants responded to exercise. The results were pretty typical: the long-COVID patients were clearly inhibited in their ability to produce energy (VO2 max, peak power output). They also exhibited problems moving air in and out of their lungs. The ability to move air in and out is critically important during exercise to remove waste products like CO2 and to supply the muscles with the oxygen that drives our chief source of energy – the aerobic energy production system in our mitochondria.
It was interesting, therefore, to see lower maximal ventilation (a reduction in the ability to pump normal amounts of air at peak exercise) and lower maximal end-tidal pressure of CO2 (PETC02), suggesting that hyperventilation may have been present. This suggests that the long-COVID patients may have been removing too much CO2 from their blood. Too low or too high of anything is damaging, and low CO2 levels can produce many of the symptoms found in long COVID and ME/CFS.
CO2 levels have only recently been assessed in ME/CFS, but the results have been striking. One study found that hypocapnia (low CO2 levels) was far more common in ME/CFS than postural orthostatic tachycardia syndrome (POTS), and other studies have found hypocapnia in long COVID. The biggest exercise study ever in ME/CFS found more problems with “gas exchange” and strange breathing patterns than anything else.
The authors of that study, though, proposed that the real problem probably lay in poor oxygen intake from the muscles and/or problems with blood delivery to them.
The near-infrared spectroscopy readings in the present long-COVID study indicated a reduction in “peripheral O2 extraction” was present; i.e. the muscles of the long-COVID patients weren’t taking up as much oxygen (read energy) as were the muscles of the healthy controls (recovered COVID-19 patients).
All these findings jive with those found in ME/CFS and the reduction in O2 extraction using near-infrared spectroscopy provides a nice validation of Systrom’s invasive exercise findings indicating that problems with oxygen extraction are present.
That was all good, but it was just the prelude to what came next.
Muscle Structure and Function
Next, digging into their biopsies, they assessed muscle structure and functioning. The problems with oxygen (read “energy”) extraction could have been due to reduced levels of blood vessels at the muscles that impaired flows of oxygen-rich blood to the muscles, but that wasn’t the problem, or at least it wasn’t the main problem: capillary density and capillary-to-fiber ratio were similar.
(A trend (p<.08) to reduced low capillary to fiber ratio, and the fact that the ratio was correlated with VO2 max, suggested something might be going on, though.)
Digging deeper into muscle structure, the Dutch researchers found a higher proportion of highly fatigable glycolytic fibers in the long-COVID patients and a lower cross-sectional area of fatigue-resistant type I fibers in females.
Also known as type-II, or fast-twitch, muscle fibers, glycolytic muscle fibers are muscle fibers that work great at producing short bursts of energy (think sprinting) but are horrible at endurance.
These muscle fibers don’t use oxygen (or the mitochondria) to produce energy; instead, they use a process called glycolysis, which produces energy anaerobically. Not only does glycolysis produce much less energy than aerobic energy production but it leaves behind a substance called lactate, which produces muscle fatigue and pain if not quickly removed.
Systrom, Workwell, Visser, and others have found indications that the aerobic energy production we rely on for the vast majority of our energy is to some degree broken in ME/CFS and long COVID – resulting in a greater dependence on anaerobic energy production or glycolysis. This could help explain why physical exertion is so fatiguing in people with these diseases.
This finding of an increased incidence of glycolytic, or fast-twitch, muscle fibers in the long-COVID patients fits in well with this hypothesis, as does a 2009 ME/CFS study that found increased levels of these “fatigue-prone, energetically expensive” muscle fibers in ME/CFS. Likewise, a 2022 Colorado exercise study suggested increased levels of fast-twitch muscle fibers were present in long COVID.
It was no surprise, given all that, that, ounce for ounce, the muscles of the long-COVID patients weren’t producing as much energy as the recovered COVID-19 patients.
Lower levels of an enzyme, succinate dehydrogenase (SDH), involved in both parts of ATP production in the mitochondria – the citric acid cycle and the electron transport chain – once again made sense given the emphasis on glycolysis (which takes place outside the mitochondria) and the reductions in muscle energy production.
Summing up the section on muscle structure and function, the authors proposed that the lower exercise capacity found in long COVID was in part due to a relative overabundance of “highly fatigable” glycolytic (fast-twitch) muscle fibers and reduced mitochondrial activity, possibly in concert with reduced blood flows to the muscles and hyperventilation during exercise.
Digging Deeper: Mitochondrial Activity and Metabolism
That was all to the good, but with so many illuminating findings staring them in the face, why stop there? They dug deeper and assessed changes in muscle biopsies as well as metabolic signatures in the blood after exercise to see if exercise was taking a hammer to mitochondrial energy production and metabolism.
Interestingly, a maximal exercise test one day reduced the ability of both groups of patients to generate energy the next, but the groups separated when it came to succinate dehydrogenase (SDH), with SDH activity increasing in the recovered patients but significantly decreasing in the long-COVID patients. SDH activity had been normal pre-exercise, but the reduced SDH activity after exercise found in the long-COVID patients suggested that exercise had reduced mitochondrial activity and levels.
Muscle metabolism took a big hit. Similar results between the long COVID patients and healthy controls would have resulted in clear circles but almost all the circles associated with the citric acid and glycolytic pathways – were either light or dark blue – indicating lower levels of these metabolites were present.
The blood metabolomics diagram – which showed a mixture of red (high metabolite levels) and blue (low metabolite levels) – was different. It showed high levels of glycolytic metabolites – suggesting that the glycolytic anaerobic pathway (as suspected) had been activated – but low levels of metabolites associated with the Krebs or citric – suggesting (as suspected) that aerobic energy production had been inhibited by the exertion.
Even at rest, mitochondrial deficiencies turned up with lower levels of several key metabolites (including glutamate, FAD+, alpha-ketoglutarate, and citric acid) associated with the citric acid or Krebs cycle. Note that the goal of the Krebs cycle is to provide FAD+ and NADH to the electron transport chain (which then produces ATP). Alpha-ketoglutarate and citric acid are intermediate metabolites in that cycle. Robert Phair’s Itaconate Hypothesis predicts they will be low in ME/CFS, and so they were in the muscles of long-COVID patients.
The reduced ratio of citric acid (produced in the mitochondria by the Krebs cycle) to lactate (produced by glycolysis outside the mitochondria) in the skeletal muscle indirectly validated the increased levels of glycolytic fast-twitch muscle fiber, indicating that the anaerobic energy production pathway was being emphasized more in the long-COVID patients.
Likewise, lower concentrations of creatine – a key player in energy production, particularly during intense exercise – in the muscles of the long-COVID patients suggested that problems with energy production, particularly during exercise, were present. Some people have used creatine as a post-exertional malaise buster in ME/CFS and creatine has been proposed for use in long COVID as well.
Other findings suggested problems with lipid synthesis, and high levels of oxidative stress may be present.
The idea that microclots could be blocking blood flows to the muscles and other organs has captured a lot of attention. The study did indeed find amyloid proteins (strangely shaped, difficult-to-break-down proteins) in greater concentrations in the skeletal muscle of long-COVID patients but they did not appear to be blocking blood flows.
Resia Pretorius – the originator of the microclot hypothesis – reacted to that finding with alarm stating “”That means the microclots can actually have traveled through the damaged vasculature into the muscle. What is scary, but possibly very significant, is that this might be happening in other tissues as well.”
Nor did they find evidence of low muscle oxygen levels (hypoxia). Still, it was not clear why increased levels of amyloids were found in the long-COVID patients or what effect they might be having.
Digging down into the structure of the muscle fibers, they found that a larger percentage of long-COVID patients displayed necrotic (dead) muscle fibers (36%) after exercise while 80% (!) displayed atrophied muscle fibers after exercise (up from 50% before exercise). It appeared that exercise had induced macrophage (CD68+) and CD3+ T-cells to invade the muscles – something Akiko Iwasaki said is rarely seen in healthy muscles and could indicate an autoimmune response had occurred.
Despite the evidence of immune cell infiltration, they failed to find a reason for it. High levels of oxidative stress could have fragmented the mitochondria – drawing the immune cells in, but neither it nor signs of muscle breakdown were found. Nor did the SARS-CoV-2 virus appear to be responsible: similar levels of the SARS-CoV-2 nucleocapsid protein were found in both groups.
Their conclusion that “factors other than viral persistence” are responsible for the muscle damage found clashes with the hypothesis that viral persistence is triggering long COVID. That might not be a bad finding for post-infectious illnesses like ME/CFS, though, which would be faced with figuring out which viruses or pathogens were persisting. In any case, the reason for the exercise-induced muscle fiber atrophy remained a mystery.
Finally, this study used an accelerometer to assess step counts. It found that while the long-COVID patients were rather sedentary (~4,000 steps/day), they weren’t bedbound, and deconditioning could not explain the results; indeed, the muscle atrophy associated with deconditioning was not found.
All in all, this muscle study found evidence of problems at virtually every turn and cemented the idea that intense exercise is harmful. The study findings – which are getting quite a bit of attention – should help doctors and others realize that exercise prescriptions are not the answer. (One wonders what the RECOVER Initiative with their exercise clinical trial is thinking…)
Lead researcher, Rob Wust told the Guardian, “It’s really confirming that there is something inside the body going wrong with the disease. It damages your muscles, it worsens your metabolism, and it can explain why you feel muscle pain and fatigue up to weeks after the exercise,”.David Putrino from Mt. Sinai told NPR “I don’t think the messaging has been strong enough. It is very clear that this is not a typical response to exercise.”
While noting that a gradual exercise prescription can help after the appropriate medical interventions have helped, David Systrom stated “You cannot simply ask these patients to go to the gym and fix the problem.” For his part, David Putrino prescribes what’s called “autonomic rehabilitation“. .
The breadth of the findings – from tissues starved for energy and depleted mitochondria impressed one of he study authors. Braeden Charlton called the energy depletion “very profound“, said “We see this at basically every parameter that we measure.” and stated that “The mitochondria are operating at a severely reduced capacity compared to healthy people,”
The authors noted that post-exertional malaise is specific for long COVID and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), and proposed that a similar pathophysiology exists in these two illnesses.
Note that despite the fact that the exercise produced post-exertional malaise in every long-COVID patient, “considerable heterogeneity” showed up in the test results. A similar pattern in ME/CFS suggests that several pathways can produce the same conclusion: reduced energy production and PEM.
- This is the kind of extensive study that we – people with chronic fatigue syndrome (ME/CFS), fibromyalgia (FM), and allied diseases – hoped that long COVID would trigger. The first test of how the muscles of long-COVID patients responded to exercise found problems at every turn.
- Powered, in part, by a Ramsay Grant from the Solve ME/CFS Initiative, the study’s exercise test found evidence of reduced energy production, problems with “ventilation” (moving air in and out of the lungs efficiently), low CO2 levels, and problems with oxygen utilization – all of which have been found in ME/CFS.
- Digging into muscle structure, a higher proportion of highly fatigable glycolytic, or fast-twitch, muscle fibers could help explain why exercise is so difficult in long COVID. (A similar result has been found in ME/CFS.)
- It was no surprise, given all that, that, ounce for ounce, the muscles of the long-COVID patients weren’t producing as much energy as the recovered COVID-19 patients. Lower levels of an enzyme, succinate dehydrogenase (SDH), pointed, once again, to reduced mitochondrial activity in the muscles of the long-COVID patients.
- Exercise only made things worse. Evidence of damaged and dying muscle tissue was found in about a third of long-COVID patients. Muscle and blood metabolomics studies found reductions in metabolites associated with aerobic energy production and an increased emphasis on the dirty and inefficient anaerobic energy production system.
- Other findings suggested problems with lipid synthesis and high levels of oxidative stress may be present. All these findings jive with what we know about ME/CFS and all emphasis the damaging effects of exercise.
- With no evidence of increased coronavirus proteins in the muscles, the authors took an axe to a popular hypothesis when they concluded that “factors other than viral persistence” are responsible for the muscle damage. Finally, the step counts of the participants indicated that the muscle problems found could not be due to deconditioning.
- Two major muscle studies by the Open Medicine Foundation, one of which includes a 2-day cardiopulmonary exercise test (CPET), will tell us even more about this potentially key area of ME/CFS pathophysiology.
Major ME/CFS Muscle Studies Underway Courtesy of the Open Medicine Foundation
The Open Medicine Foundation has two major muscle studies underway under the guidance of David Systrom and Wenzhong Xiao. One consists of a deep, deep dive (genomics, proteomics, metabolomics, phospho-proteomics, ultrastructural analysis, mitobiogenetic markers) into muscle samples from ME/CFS patients.
The next study will go even further than this long-COVID study and take muscle samples before and after a two-day CPET exercise test. Among other things, it will also assess levels of citrate synthase (which Systrom has found depleted in ME/CFS before), gene expression, metabolites and proteins in the muscles, as well as mitochondrial functioning, cytokine, gene expression, metabolites, and proteins in the blood. Given what we just saw with the long-COVID study, this is a timely study indeed.
Studies suggest that energy production is impaired in long COVID but we didn’t know if the muscles themselves were impacted. It appears they are. The first test of how the muscles of long-COVID patients responded to exercise found problems at every turn.
Powered in part by a Ramsay Grant from the Solve ME Initiative, the study’s exercise test found evidence of reduced energy production, problems with “ventilation” moving air in and out of the lungs efficiently, low CO2 levels, and problems with oxygen utilization – all of which have been found in ME/CFS.
Digging into muscle structure a higher proportion of highly fatigable glycolytic or fast-twitch muscle fibers could help explain why exercise is so difficult in long COVID. (A similar result has been found in ME/CFS.)
It was no surprise, given all that, that, ounce for ounce, the muscles of the long-COVID patients weren’t producing as much energy as the recovered COVID-19 patients. Lower levels of an enzyme, succinate dehydrogenase (SDH), pointed, once again, to reduced mitochondrial activity in the muscles of the long-COVID patients.
Exercise only made things worse. Evidence of damaged and dying muscle tissue was found in about a third of long-COVID patients. Muscle and blood metabolomics studies found reductions in metabolites associated with aerobic energy production and an increased emphasis on the dirty and inefficient anaerobic energy production system. Other findings suggested problems with lipid synthesis and high levels of oxidative stress may be present.
With no evidence of increased coronavirus proteins in the muscles, the authors took an axe to a popular hypothesis when they concluded that “factors other than viral persistence” are responsible for the muscle damage.
Finally, the step counts of the participants indicated that the muscle problems found could not be due to deconditioning.
Two major muscle studies by the Open Medicine Foundation, one of which includes a 2-day cardiopulmonary exercise test (CPET), will tell us even more about this potentially key area of ME/CFS pathophysiology.
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Nothing excites me more than exercise studies – particularly studies that take their findings to the next level. This study – the first to really test the muscles – did that and its results confirm what virtually everyone with ME/CFS/Long COVID instinctively feels – something has gone very wrong with the muscles. If covering the results of exercise studies appeals to you please support us in a manner that works for you.