Muscle abnormalities worsen after post-exertional malaise in long COVID (Appelman, Wust et al 2024)

[Murph]

https://www.nature.com/articles/s41467-023-44432-3

• Article
• Open access
• Published: 04 January 2024

Muscle abnormalities worsen after post-exertional malaise in long COVID​

• Brent Appelman
• Rob C. I. Wüst

Nature Communications volume 15, Article number: 17 (2024) Cite this article

Abstract​

A subgroup of patients infected with SARS-CoV-2 remain symptomatic over three months after infection. A distinctive symptom of patients with long COVID is post-exertional malaise, which is associated with a worsening of fatigue- and pain-related symptoms after acute mental or physical exercise, but its underlying pathophysiology is unclear. With this longitudinal case-control study (NCT05225688), we provide new insights into the pathophysiology of post-exertional malaise in patients with long COVID. We show that skeletal muscle structure is associated with a lower exercise capacity in patients, and local and systemic metabolic disturbances, severe exercise-induced myopathy and tissue infiltration of amyloid-containing deposits in skeletal muscles of patients with long COVID worsen after induction of post-exertional malaise. This study highlights novel pathways that help to understand the pathophysiology of post-exertional malaise in patients suffering from long COVID and other post-infectious diseases.

 

[Murph]

This seems like a major paper. They looked at muscle during PEM and found a ton of weird things going on.

It's the sort of visible, structural finding that people can understand. And it is logical in a very simple way even a lay person can grasp: ah, they can't move their muscles because something is wrong with the muscle.


Look at the necrosis they see here in panel B. Muscle cells are just dying in a spectacular fashion after exercise.:

 

[Murph]

This is the exact kind of study we need more of:

Looking before and after intense exercise to see what PEM does. And taking muscle biopsies.

It's getting good coverage: https://www.theguardian.com/world/2...should-avoid-intense-exercise-say-researchers

 

[Murph]

This paper swings the argument away from vascular explanations for long covid / mecfs/ pem and toward metabolic / structural ones.

They had a genuine look for clots and for problems with capillary density, etc, and just didn't find them.

What they did find is amyloid deposits in the muscle (the green dots below).

I just hope we don't now emulate alzheimers and spend 20 years fussing over amyloid deposits without fixing anything!

 

[SlamDancin]

Nice. Matches my experience or at least what I imagine muscle necrosis feels like. They should do a bigger study with an ME/CFS group

 

[Murph]

A weird and interesting thing about this study that may crack open soething important.

They found uncontrolled muscle breakdown when they took photos of the muscles. 36% of patients had necrosis. But they didn't find the classic marker of necrosis: creatine kinase (CK). CK levels in the blood were normal.

That is weird.

A previous study found low CK in serum was a marker of severe mecfs.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6627354/

Could it be that we simply have low CK in our muscles, so when they break down we don't get much CK In serum??? or is there something else happening?

 

[SWAlexander]

Muscle abnormalities worsen after post-exertional malaise

Creatine kinase results are too low in most people who have been confined to bed rest for extended periods.

For me, it is not only COVID that causes muscle weakness.
I experienced the same muscle weakness for over 3 years after sepsis in 2016.

Some other thoughts are interesting - findings on brain MRI (in particular corpus callosum)...

https://discovermednews.com/visuosp...-neuroimaging-after-covid-19/#google_vignette

 

[bertiedog]

I think this is definitely exciting (from Twitter yesterday)

Rob Wüst

@RobWust
·
21h
Replying to @EleanorDavin and @NatureComms
We are now seeing if something similar happens in patients with ME, and hope to include muscle biopsies from patients with severe ME as well in the near future

11:49 am · 4 Jan 2024
·
1,824
Views


Sorry I couldn't do a better copy of his post as I don't know how to do it!
Pam

https://twitter.com/i/web/status/1742875925358748131

 

[SWAlexander]

https://twitter.com/i/web/status/1742878359367926249

Rob Wüst @RobWust
·
13h

That’s the next study

 

[SlamDancin]

Awesome line of research. Not all have muscle problems but for me it’s been critical to my recovery to focus on muscle health.

One interesting supplement I’m trying is 20-hydroxyecydesterone (20-HE). It’s a natural plant steroid that according to a new study may not work through steroid receptors but through MAS receptor (part of the angiotensin system). It works similar to Angiotensin 1,7, sorta the counterpart to Angiotensin II, except it’s way cheaper. It’s being taken through clinical trials by a company trying to get it approved for muscle wasting conditions.

BIO101 stimulates myoblast differentiation and improves muscle function in adult and old mice

 

[SWAlexander]

Awesome line of research.

Is it really necessary to reinvent the wheel?
How is it possible that all these previous scientific discoveries were not recognized in everyday medical practice long ago?
I'm referring to all the References in both links:
https://link.springer.com/article/10.1007/bf00294431
https://www.sciencedirect.com/science/article/abs/pii/S0140673684918713

 

[andyguitar]

It's the sort of visible, structural finding that people can understand. And it is logical in a very simple way even a lay person can grasp: ah, they can't move their muscles because something is wrong with the muscle.


Look at the necrosis they see here in panel B. Muscle cells are just dying in a spectacular fashion after exercise.:

If these muscle cell changes are also present in me/cfs it might explain why some have found benefit from taking Branched Chain Amino Acids. Should have posted that a while ago. Forgot.

 

[Murph]

I emailed Rob Wust to ask how you get high necrosis without lots of ck splashing around. Could it be simply that the cells had very little ck to start with? I asked.

To his credit, he replied. Here's his response.

Thanks for this. We were puzzled about this too, but we think that either we haven’t measured this at the right time (we would love to ask these very sick people back in the lab multiple times, but that’s logistically difficult), but another important aspect is that the creatine levels in skeletal muscle in these patients were already very low (see the results in our paper). Lastly, we don’t know how extensive the muscle damage really is, as our biopsies were only the size of a single grain of rice.

These are possible reasons of our findings.

Best wishes,

Rob


Here's the creatine thing he mentions. very low in muscle (blue) but high/normal in blood (red):

 

[SWAlexander]

Could it be simply that the cells had very little ck to start with? I asked.

I wonder if there is a SMN1 and SMN2 genes problem, called "Spinal Muscular Atrophy (SMA)"
Summary posted: https://swaresearch.blogspot.com/2024/01/spinal-muscular-atrophy-sma.html

If it is genetic and SMN1 is missing, no supplements would work, a Lab-Dr. once told me.

 

[SlamDancin]

I emailed Rob Wust to ask how you get high necrosis without lots of ck splashing around. Could it be simply that the cells had very little ck to start with? I asked.

To his credit, he replied. Here's his response.

Thanks for this. We were puzzled about this too, but we think that either we haven’t measured this at the right time (we would love to ask these very sick people back in the lab multiple times, but that’s logistically difficult), but another important aspect is that the creatine levels in skeletal muscle in these patients were already very low (see the results in our paper). Lastly, we don’t know how extensive the muscle damage really is, as our biopsies were only the size of a single grain of rice.

These are possible reasons of our findings.

Best wishes,

Rob


Here's the creatine thing he mentions. very low in muscle (blue) but high/normal in blood (red):
View attachment 53316

Any chance Creatine supplementation would make it to the muscles and help?

 

[SWAlexander]

Any chance Creatine supplementation would make it to the muscles and help?

We should ask Rob Wüst.

I would first check if there is a defense block by Immunoglobulins (cytokines) to the muscle cells.

For over two years now, I have experienced aggressive cytokine reactions every time I take a new supplement or use the one I have not taken for a while.

 

[Murph]

Any chance Creatine supplementation would make it to the muscles and help?

Hrd to know. it's already high in blood, so will making it even higher n blood lift levels in muscle? maybe?

 

[SlamDancin]

@Murph So I got an idea of where to start reading and the first paper that caught my eye gives an interesting starting point. Like Alexander was saying maybe we want to reach out to the Dr with some of this. Check it out, from 1988.

​

Extracellular creatine regulates creatine transport in rat and human muscle cells​

Muscle cells do not synthesize creatine; they take up exogenous creatine by specific Na+-dependent plasma membrane transporters. We found that extracellular creatine regulates the level of expression of these creatine transporters in L6 rat muscle cells. L6 myoblasts maintained for 24 hr in medium containing 1 mM creatine exhibited 1/3rd of the creatine transport activity of cells maintained for 24 hr in medium without creatine. Down-regulation of creatine transport was partially reversed when creatine-fed L6 cells were incubated for 24 hr in medium lacking creatine. Down-regulation of creatine transport occurred independently of amino acid and glucose transport. Furthermore, the down-regulation of creatine transporters by extracellular creatine was slowed by inhibitors of protein synthesis. These results suggest that creatine induces the expression of a protein that functionally inactivates the creatine transporters. Regulation of creatine transport by extracellular creatine also was observed in L6 myotubes and in cultures of human myoblasts and myotubes. Hence, the activity of creatine transport represents another site for the regulation of creatine homeostasis.

Rapamycin is a protein synthesis inhibitor

 

[SWAlexander]

I have been talking about this for a long time:
https://forums.phoenixrising.me/thr...-appelman-wust-et-al-2024.91340/#post-2452424

I wrote in detail about:

Is ME CFS Spinal Muscular Atrophy (SMA):​

https://swaresearch.blogspot.com/2024/01/is-me-cfs-spinal-muscular-atrophy.html​

Now this:

Myalgic encephalomyelitis/chronic fatigue syndrome from current evidence to new diagnostic perspectives through skeletal muscle and metabolic disturbances​

Abstract​

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a demanding medical condition for patients and society. It has raised much more public awareness after the COVID-19 pandemic since ME/CFS and long-COVID patients share many clinical symptoms such as debilitating chronic fatigue. However, unlike long COVID, the etiopathology of ME/CFS remains a mystery despite several decades' research. This review moves from pathophysiology of ME/CFS through the compelling evidence and most interesting hypotheses. It focuses on the pathophysiology of skeletal muscle by proposing the hypothesis that skeletal muscle tissue offers novel opportunities for diagnosis and treatment of this syndrome and that new evidence can help resolve the long-standing debate on terminology.
https://onlinelibrary.wiley.com/doi/10.1111/apha.14122
See also:

Supporting Information​