Preprint Skeletal muscle properties in long COVID and ME/CFS differ from those induced by bed rest, 2025, Charlton, Wust et al

[Nightsong]

Abstract:
Patients with long COVID and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) suffer from a reduced exercise capacity, skeletal muscle abnormalities and post-exertional malaise (PEM), where symptoms worsen with cognitive or physical exertion. PEM often results in avoidance of physical activity, resulting in a lower aerobic fitness, which may contribute to skeletal muscle abnormalities.

Here, we compared whole-body exercise responses and skeletal muscle adaptations after strict 60-day bed rest in healthy people with those in patients with long COVID and ME/CFS, and healthy age- and sex-matched controls. Bed rest altered the respiratory and cardiovascular responses to (sub)maximal exercise, while patients exhibited respiratory alterations only at submaximal exercise. Bed rest caused muscle atrophy, and the reduced oxidative phosphorylation related to reductions in maximal oxygen uptake.

Patients with long COVID and ME/CFS did not have muscle atrophy, but had less capillaries and a more glycolytic fibers, none of which were associated with maximal oxygen uptake. While the whole-body aerobic capacity is similar following bed rest compared to patients, the skeletal muscle characteristics differed, suggesting that physical inactivity alone does not explain the lower exercise capacity in long COVID and ME/CFS

Link | PDF (MedRxiv preprint, May 2025, open access)

 

[Nightsong]

The major finding of the present study is that acute exercise responses and skeletal muscle alterations in long COVID and ME/CFS differ from those caused by bed rest-induced deconditioning per se. Despite similar whole body exercise capacity in both patient groups and participants after bed rest, the pulmonary and cardiovascular responses to acute exercise were distinct. Bed rest induced severe muscle atrophy, which was not observed in patients with long COVID or ME/CFS.

Instead, both patient groups displayed a lower proportion of type I fibers, whereas only patients with ME/CFS exhibited lower capillary-to-fiber ratios and type I specific atrophy. Further, the lower oxidative phosphorylation capacity in both patient groups did not correlate with VO2max, in contrast to bed rest participants, suggesting that physiological impairments distinct from inactivity drive reduced exercise capacity in patients.

These findings challenge the notion that deconditioning is the primary driver of reduced exercise capacity in long COVID and ME/CFS. Rather, our observations suggest intrinsic skeletal muscle abnormalities contribute to limited exercise capacity, including reduced capillary supply relative to muscle fiber size and mitochondrial impairments

Patients with long COVID and ME/CFS displayed higher proportions of type IIa/IIx fibers, and signs of intrinsic mitochondrial dysfunction, observations that were not seen following bed rest. These findings indicate that the lower exercise capacity in patients with long COVID and ME/CFS is not solely due to physical inactivity; therefore rehabilitation strategies for patients should consider that patients with ME/CFS and long COVID are not simply deconditioned, and should be treated as unique cases with alternative rehabilitation strategies.

 

[Utsikt]

Most patients could have told you this years ago, but it’s good to finally have some confirmation (assuming their interpretations are valid)!

 

[Utsikt]

The bedrest cohort was ~10 years younger than the other groups, and had a slightly lower BMI.

Not sure it makes much of a difference?

 

[Utsikt]

The healthy controls and patients with long COVID and ME/CFS were all vaccinated against SARS CoV2 at the time of measurements, while the bed rest study was conducted before the COVID pandemic. Patients with long COVID developed symptoms prior to vaccination, and met the Canadian Consensus Criteria for ME/CFS. Patients with ME/CFS were already diagnosed with ME/CFS before the COVID pandemic, and were therefore ill for a significantly longer time relative to long COVID patients. Both patient groups displayed mild symptoms, as is implied by their willingness and ability to undergo exercise testing. Patients with long COVID and ME/CFS displayed large interindividual differences in daily step count (range: 733-8609 steps/day; Table 1).

All LC patients had ME/CFS (CCC). The bedrest group was done before the pandemic, so they knew about this when they got the response from the BPS-lobby to their other paper.

 

[EndME]

I'm hoping that this is just one result of their ME/CFS study. Otherwise it would appear that the majority of the findings of their Long-Covid study could not be replicated and as such as aren't mentioned?

Edit: I think this is only a subset analysis of some of the data of the ME/CFS study.

 

[V.R.T.]

I'm hoping that this is just one result of their ME/CFS study. Otherwise it would appear that the majority of the findings of their Long-Covid study could not be replicated and as such as aren't mentioned?

Perhaps they have released this part first to head off the inevitable BPS criticism.

 

[EndME]

I'm hoping that this is just one result of their ME/CFS study. Otherwise it would appear that the majority of the findings of their Long-Covid study could not be replicated and as such as aren't mentioned?

Since this is only data after one exercise test and the ME/CFS study had two, I think it's fair to suggest that more papers will be coming out that will include more data, including the data that had sparked some interest following the LC study. Since in the LC study there were differences between the results of the first and second CPET it would be interesting to know how those different results would all look here .

 

[EndME]

Perhaps they have released this part first to head off the inevitable BPS criticism.

Maybe so, but those can just adapt their criticism to it's "pacing/limiting activity" etc, i.e. that it's reconditioning rather than it being pure deconditioning. Are there any things in the paper that wouldn't be explained by differing activity patterns?

 

[Utsikt]

Maybe so, but those can just adapt their criticism to it's "pacing/limiting activity" etc, i.e. that it's reconditioning rather than it being pure deconditioning. Are there any things in the paper that wouldn't be explained by differing activity patterns?

I believe the muscle composition was different from both bedrest and HC.

 

[EndME]

I believe the muscle composition was different from both bedrest and HC.

Yes, but that in itself would be explainable by differing activity patterns as differing activity patterns can cause differing muscle composition (so to what extent and could it cause the differences observed here is my question). Bedrest for 2 months needn't have the same impacts as pacing for 1 year or longer. I don't know much, but wouldn't a shift in glycotic fiber from type 1 to 2 also be explainable by ME/CFS patients doing short bursts of things they manage to do but a lack of endured efforts? I know these authors are careful with their work, so it would be awesome to know what exactly can't be explained by different activity patterns. Of course the same question as always remains: How does this relate to PEM and ME/CFS?

 

[Mij]

Methodology:
The study involved skeletal muscle biopsies and assessments of whole body exercise responses, comparing: -Long COVID patients -ME/CFS patients -Healthy controls before and after bed rest

Findings suggest unique muscle pathology in Long COVID and ME/CFS
https://twitter.com/user/status/1919843135720452118

 

[Hutan]

The bedrest cohort was ~10 years younger than the other groups, and had a slightly lower BMI.

There are also massive differences in the % of females: 8/24 in the bedrest group, around 50% in the patient groups. I don't know if they did an analysis separating people by sex. 8 females in the bedrest cohort would limit statistically valid comparisons.

 

[Grigor]

Since this is only data after one exercise test and the ME/CFS study had two

What are you basing it on that ME had 2? I thought both had one?

 

[Creekside]

Yes, but that in itself would be explainable by differing activity patterns as differing activity patterns can cause differing muscle composition

Emotional state (stress, choosing to be inactive for research rather than being prevented from being active by ME) could also have an effect on muscle composition. Do muscles normally undergo some pattern of contractions (microcontractions?) to maintain their healthy state? If so, emotional state and neurological dysfunction and sleep patterns could affect muscle properties.

They could compare the muscle tissues of people who are inactive due to various reasons, such as being in a body cast, or severely depressed, or whatever. Finding a difference between a subset and some HCs doesn't mean that everyone who isn't in that subset is the same as those HCs.

 

[Sean]

Patients with long COVID and ME/CFS did not have muscle atrophy,

Now that is interesting.

 

[Snow Leopard]

Now that is interesting.

De-conditioning isn't the same as atrophy.

So long as the person maintains some sort of weekly or day to day activity (rather than being completely bedbound), they will maintain enough muscle to do those tasks.

 

[EndME]

What are you basing it on that ME had 2? I thought both had one?

Sorry, you're correct. I had misremembered things. But there should at least be multiple measurements for the ME/CFS group (and LC group), before exercise testing and after exercise testing and other measurements (amyloid staining, metabolimics etc) are also not present, so I'm assuming there is more to come, especially since the LC study had more patient data than there is for the ME/CFS cohort here (some of which might be valuable including comorbidities).

If I'm understanding things correctly the second muscle biopsy for the bed-rest group was taken before the second exercise test. Whilst for the ME/CFS and LC group they have 2 different muscle biopsies. It isn't clear to me which one they used though and they had previously reported that they looked different, so I'm assuming they are using the first one to match the situation of the bed-rest cohort?

 

[Utsikt]

If I'm understanding things correctly the second muscle biopsy for the bed-rest group was taken before the second exercise test.

Correct. It was taken on day 55. The exercise test was done ln day 60.

Whilst for the ME/CFS and LC group they have 2 different muscle biopsies.

Where does it say that they took two? I can’t find any info on the timing of the biopsies from the patients.

 

[EndME]

Correct. It was taken on day 55. The exercise test was done ln day 60.

Where does it say that they took two? I can’t find any info on the timing of the biopsies from the patients.

The LC data is from the LC study that was already published and discussed here. The ME/CFS data is from a grant that had a similar setup as the LC study, with before and after measurements. The bed-rest data is from one of their earlier studies. To me it looks like they are just getting some of their data together here in one paper (given the replies by Garner and others) and then hopefully we'll get some more detailed data on ME/CFS elsewhere.