Review Disuse-Induced Muscle Fatigue: Facts and Assumptions, 2024, Sergeeva et al.

[SNT Gatchaman]

Disuse-Induced Muscle Fatigue: Facts and Assumptions
Sergeeva, Xenia V.; Lvova, Irina D.; Sharlo, Kristina A.

Skeletal muscle unloading occurs during a wide range of conditions, from space flight to bed rest. The unloaded muscle undergoes negative functional changes, which include increased fatigue. The mechanisms of unloading-induced fatigue are far from complete understanding and cannot be explained by muscle atrophy only.

In this review, we summarize the data concerning unloading-induced fatigue in different muscles and different unloading models and provide several potential mechanisms of unloading-induced fatigue based on recent experimental data. The unloading-induced changes leading to increased fatigue include both neurobiological and intramuscular processes. The development of intramuscular fatigue seems to be mainly contributed by the transformation of soleus muscle fibers from a fatigue-resistant, “oxidative“ “slow” phenotype to a “fast” “glycolytic“ one. This process includes slow-to-fast fiber-type shift and mitochondrial density decline, as well as the disruption of activating signaling interconnections between slow-type myosin expression and mitochondrial biogenesis.

A vast pool of relevant literature suggests that these events are triggered by the inactivation of muscle fibers in the early stages of muscle unloading, leading to the accumulation of high-energy phosphates and calcium ions in the myoplasm, as well as NO decrease. Disturbance of these secondary messengers leads to structural changes in muscles that, in turn, cause increased fatigue.

Link | PDF (International Journal of Molecular Sciences) [Open Access]

 

[Jonathan Edwards]

I think they mean muscle fatiguability.

 

[Turtle]

Disuse-Induced Muscle Fatigue: Facts and Assumptions
Sergeeva, Xenia V.; Lvova, Irina D.; Sharlo, Kristina A.

Skeletal muscle unloading occurs during a wide range of conditions, from space flight to bed rest. The unloaded muscle undergoes negative functional changes, which include increased fatigue. The mechanisms of unloading-induced fatigue are far from complete understanding and cannot be explained by muscle atrophy only.

In this review, we summarize the data concerning unloading-induced fatigue in different muscles and different unloading models and provide several potential mechanisms of unloading-induced fatigue based on recent experimental data. The unloading-induced changes leading to increased fatigue include both neurobiological and intramuscular processes. The development of intramuscular fatigue seems to be mainly contributed by the transformation of soleus muscle fibers from a fatigue-resistant, “oxidative“ “slow” phenotype to a “fast” “glycolytic“ one. This process includes slow-to-fast fiber-type shift and mitochondrial density decline, as well as the disruption of activating signaling interconnections between slow-type myosin expression and mitochondrial biogenesis.

A vast pool of relevant literature suggests that these events are triggered by the inactivation of muscle fibers in the early stages of muscle unloading, leading to the accumulation of high-energy phosphates and calcium ions in the myoplasm, as well as NO decrease. Disturbance of these secondary messengers leads to structural changes in muscles that, in turn, cause increased fatigue.

Link | PDF (International Journal of Molecular Sciences) [Open Access]

Important stuff. But how could an unloading moment be found in ME/CFS an LC when you're not diagnosed for 3 or 6 months or even much later, if al all?

Some passages read as if it is about ME/CFS. Happening not just in space, but in my own body, as down to earth as it gets.

Could the NIH have been close to an unloading moment?

@Hutan related Lipkin talking about a sister of a patient volunteer, acting as a HC, who developed LC after the first visit?

 

[Kitty]

But how could an unloading moment be found in ME/CFS an LC when you're not diagnosed for 3 or 6 months or even much later, if al all?

It may not be directly relevant, as substantial numbers of people with ME don't really unload their muscles. They might be able to do less, but unless they're severely ill they often have to carry on as best they can. Their activity pattern doesn't resemble bed rest, space flight, or immersion at all.

 

[SNT Gatchaman]

I look forward to Rob Wüst et al's upcoming investigation of ME/CFS, following their LC study. I hope he will talk about preliminary findings in a couple of weeks at the UniteToFight conference. As I recall, the LC study showed fibre-type shift as a prominent feature along with small fibre atrophy, but succinate dehydrogenase was highlighted as a difference.

It should also be noted that in a number of experiments, under conditions of space flight and “dry” immersion, it was shown that atrophy of “slow” type fibers is more pronounced than atrophy of “fast” fibers, which can also contribute to an increase in muscle fatigue

We only included individuals with severe long COVID, but the observed abnormalities are not reflective of physical inactivity. Accelerometer data indicated that the long COVID patients were not bed-ridden, and had an average step-count of ~4000 steps/ day. While our cohort might have displayed sedentary behavior, physical inactivity itself does not cause postexertional malaise and is linked with muscle atrophy and a lower mitochondrial SDH activity, which we did not observe in our cross-sectional analysis.

I think the last line there is saying that lower SDH activity was not observed (at baseline), because they did show more atrophy (worse after exercise challenge, including in some of the HCs).



The abstract for Rob Wüst's previous Capillary rarefaction during bed rest is proportionally less than fibre atrophy and loss of oxidative capacity (2022, Journal of Cachexia, Sarcopenia and Muscle) includes —

After just 6 days of bed rest, fibre atrophy (—23.2 ± 12.4%, P < 0.001) and reductions in capillary-to-fibre ratio (C:F; 1.97 ± 0.57 vs. 1.56 ± 0.41, P < 0.001) were proportional in both muscles as reflected by a maintained capillary density. Fibre atrophy proceeded at a much slower rate between 6 and 55 days of bed rest (—11.6 ± 12.1% of 6 days, P = 0.032) and was accompanied by a 19.1% reduction in succinate dehydrogenase stain optical density (P < 0.001), without any further significant decrements in C:F (1.56 ± 0.41 vs. 1.49 ± 0.37, P = 0.459). Consequently, after 55 days of bed rest, the capillary supply–oxidative capacity ratio of a fibre had increased by 41.9% (P < 0.001), indicating a capillarization in relative excess of oxidative capacity. Even though the heterogeneity of capillary spacing (LogR SD) was increased after 55 days by 12.7% (P = 0.004), tissue oxygenation at maximal oxygen consumption of the fibres was improved after 55 days bed rest. Daily centrifugation failed to blunt the bed-rest-induced reductions in fibre size and oxidative capacity and capillary rarefaction.

 

[Sean]

It may not be directly relevant, as substantial numbers of people with ME don't really unload their muscles. They might be able to do less, but unless they're severely ill they often have to carry on as best they can. Their activity pattern doesn't resemble bed rest, space flight, or immersion at all.

This. Nothing about the deconditioning claim adds up. It is both internally and externally inconsistent. Not that such features have ever stopped or even slowed down the unfalsifiable psychosomatic gravy train.

 

[Turtle]

The paper would explain creaky gym squats.
I really hope too Rob Wüst et all have real news soon. He mentioned on X: "There's a whole lot more going on than PEM".
That small sentence goes through my mind at least once a day. More about muscle changes in ME/CFS could be "a whole lot". Other things; I keep guessing.
I'm hoping for something that will convince doctors to pay real attention to ME/CFS. (If their ego's will let them).

The NIH study (Deep Phenotyping) did not find differences in muscle oxygenation between groups, isn't that weird? Some members here seem to have found those differences, or am I wrong about that?
I tried to find another word for unloading, didn't work yet, but just "taking the load of" might do for now (for me).
Changes in blood volume, OI, metabolic changes, less aerobic energy etc could that lead to muscle changes, in stead of an unloading period?
I was in bed for just 3 days, but in 3 decades after that I haven't been in bed for one whole day.

 

[Medfeb]

The NIH study (Deep Phenotyping) did not find differences in muscle oxygenation between groups, isn't that weird? Some members here seem to have found those differences, or am I wrong about that?

I wondered the same. How would this fit in with Systrom's finding of impaired systemic oxygen extraction. only thing i can imagine is that the O2 that's there is not being used so no more delivered but I'm not sure that makes sense

 

[SNT Gatchaman]

The NIH study (Deep Phenotyping) did not find differences in muscle oxygenation between groups, isn't that weird? Some members here seem to have found those differences, or am I wrong about that?

I believe I was showing significant differences in muscle oxygenation (using the Moxy Monitor), however the technology is consumer grade, albeit used in research. You can overcome some of the inherent limitations in physics/design compared to very expensive equipment*, eg by calibrating to ischaemia / reperfusion with arterial occlusion. I don't have the equipment or inclination for that at this stage, but it may not be necessary if the raw data are hugely different from HCs; and the rates of deoxygenation and recovery in oxygenation may be the more pertinent finding. @Kiwipom has my device now and when up to it she will do a few measurements.

With luck it may be able to be incorporated into a local study in order to get some better n for patients and HCs. Even if that is practicable, it would report some time after the Wüst study. There are already related publications on sedentary patients, eg people with paraplegia/quadriplegia on cycle ergometers (via electrical stimulation), so we have some positive control data to compare.

---
* continuous wave NIRS, vs frequency domain or time-domain. See The use of near-infrared spectroscopy in understanding skeletal muscle physiology: recent developments (2011, Philosophical Transactions of the Royal Society A: Mathematical, Physical and Engineering Sciences)

 

[Turtle]

I believe I was showing significant differences in muscle oxygenation (using the Moxy Monitor), however the technology is consumer grade, albeit used in research. You can overcome some of the inherent limitations in physics/design compared to very expensive equipment*, eg by calibrating to ischaemia / reperfusion with arterial occlusion. I don't have the equipment or inclination for that at this stage, but it may not be necessary if the raw data are hugely different from HCs; and the rates of deoxygenation and recovery in oxygenation may be the more pertinent finding. @Kiwipom has my device now and when up to it she will do a few measurements.

With luck it may be able to be incorporated into a local study in order to get some better n for patients and HCs. Even if that is practicable, it would report some time after the Wüst study. There are already related publications on sedentary patients, eg people with paraplegia/quadriplegia on cycle ergometers (via electrical stimulation), so we have some positive control data to compare.

---
* continuous wave NIRS, vs frequency domain or time-domain. See The use of near-infrared spectroscopy in understanding skeletal muscle physiology: recent developments (2011, Philosophical Transactions of the Royal Society A: Mathematical, Physical and Engineering Sciences)

Thanks for your answer.
I would have loved to join you down under in the moxy measurements.
But I'm pretty sure the user guide is more than one page and if an i-phone is used I'm lost.
In kitchen appliances I win, just by using logic. In I-phone and other complicated things my brainfog wins.
I even lost my own introduction here. Serendipity will make me stumble on it someday.
In copy, cut, paste the copy ends up in the belly of the beast (computer) but it won't come out.

Glad you and people around you are doing the measurements. I think it could be of utmost importance.
ME/CFS, to me, feels as running on "empty". When you could measure that the rest of the researchers will follow, I hope.

 

[Turtle]

I don't have the equipment or inclination for that at this stage, but it may not be necessary if the raw data are hugely different from HCs; and the rates of deoxygenation and recovery in oxygenation may be the more pertinent finding.

It probably will be the more pertinent finding, would be my guess. Shunting in Systroms CPET's seem to go that way.
The core business of the body needs the blood and the oxygen, no room for extracurricular activities and those activities could do the most damage to the muscles
(and other cells?) And that could cause PEM?
Availability of blood and oxygen could that be the core problem?
But I'm only a layperson, who am I to guess. I do it anyway because scientist don't have that many theories. I had 3 decades of thinking about it and experiencing it.
Please fire away with comments and thoughts!!! All of us together might find more; at least we know how it feels.

 

[bobbler]

The paper would explain creaky gym squats.
I really hope too Rob Wüst et all have real news soon. He mentioned on X: "There's a whole lot more going on than PEM".
That small sentence goes through my mind at least once a day. More about muscle changes in ME/CFS could be "a whole lot". Other things; I keep guessing.
I'm hoping for something that will convince doctors to pay real attention to ME/CFS. (If their ego's will let them).

The NIH study (Deep Phenotyping) did not find differences in muscle oxygenation between groups, isn't that weird? Some members here seem to have found those differences, or am I wrong about that?
I tried to find another word for unloading, didn't work yet, but just "taking the load of" might do for now (for me).
Changes in blood volume, OI, metabolic changes, less aerobic energy etc could that lead to muscle changes, in stead of an unloading period?
I was in bed for just 3 days, but in 3 decades after that I haven't been in bed for one whole day.

Do you mean you actually hear a creak?

Has anyone else noticed this? when i directly exercise certain muscles then when they are at the end of their whatever /out if whatever they I get 3 tugs in quick sequence. Like someone is pulling a rope straight letting it bend then tugging it again. Timing wise like three raps at a door.

it was demonstrated perfectly when I once got a personal trainer and at end of what had for her been a trying to be very gentle session she tried to stretch out my leg muscles for me and my hamstring did that and of course because she was on top of said muscle she felt it and it freaked her out until I said: yes THATS ME/CFS calmly

it is, I just assume there is a word for when muscles do this

and assume we might know what it is?