Consequences of sarcolemma fatigue on maximal muscle strength production in patients with ME/CFS, 2023, Retornaz et al.

Sly Saint

Sly Saint

Senior Member (Voting Rights)
Highlights
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    Does force failure result from sarcolemma fatigue in Myalgic Encephalomyelitis patients?
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    Two groups of Myalgic Encephalomyelitis patients with or not M wave alterations were compared.
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    Maximal handgrip strength and M wave in forearm muscle were simultaneously measured.
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    Post-exercise changes in Maximal handgrip strength and M wave were positively correlated.
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    The post exercise sarcolemma fatigue measured could be the cause of muscle failure in these patients.
Abstract
Background
Myalgic encephalomyelitis is an invalidating chronic disease often associated with exercise-induced alterations of muscle membrane excitability (M wave). No simultaneous measurements of maximal isometric force production and sarcolemma fatigue in the same muscle group have been previously reported. We hypothesized that M wave alterations could be partly responsible for the reduced muscle force present in this invalidating disease.
Methods
This retrospective study compared two groups of patients who presented (n = 30) or not (n = 28) alterations of M waves evoked by direct muscle stimulation during and after a cycling exercise bout. The maximal handgrip strength was measured before and after exercise, concomitantly with electromyogram recordings from flexor digitorum longus muscle. The patients also answered a questionnaire to identify eventual exacerbation of their clinical symptoms following the exercise test.
Findings
The M wave amplitude significantly decreased in muscles and the M wave duration significantly increased in the group of patients with M wave alterations after exercise. Resting values of handgrip were significantly lower in patients with exercise-induced M-wave alterations than in patients without M-wave abnormalities. In patients with exercise-induced M-wave alterations, handgrip significantly decreased after exercise and the changes in handgrip and M wave were positively correlated. The frequency of post-exertion malaise, increased fatigue, myalgia, headache and cognitive dysfunction was significantly higher in patients with M-wave alterations and variations in handgrip after exercise.
Interpretation
These data suggest that post-exercise sarcolemma fatigue often measured in patients with myalgic encephalomyelitis could be the cause of muscle failure.

https://www.clinbiomech.com/article/S0268-0033(23)00186-9/fulltext
 
Another study finding some differences between patients with shorter/longer disease duration. I don't really understand what sarcolemma fatigue is, but it doesn't read as if these differences are simply the result of adaptation.
 
The sarcolemma is the muscle cell's plasma membrane. While cell membrane covers the entire components of a cell, plasma membrane covers only the cell's organelles. Some main differences between the two are the fact that the plasma membrane encloses the organelles, whereas the cell membrane encloses the entire cell.

Blausen_0801_SkeletalMuscle.png
 
The bigger picture of how the brain controls muscle contraction. The nerve cell's axons connect to a structure called the neuromuscular junction, which transmits the signals to the sarcolemma, which is excitable and can propagate it across the cell.

a-vector-of-motor-neuron-function.jpg
 
Any comment @Jonathan Edwards?

Am I the only one who thinks this is really interesting? It seems that this might be a useful diagnostic test that also helps get us closer to understand the problem. It also aligns with the old description of PEM as postexertional muscle weakness.

Why I think this is important: the sarcolemma is where the problem is in certain other neuromuscular disorders, like muscle dystrophies. It's also just downstream of neuromuscular junctions which are affected by myasthenia gravis. It also raises the question of whether this problem in skeletal muscles is related to the neurovascular dysregulation that is believed to exist by Systrom et al (as far as I understand, this would be primarily dependent on smooth muscles functioning properly).
 
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From https://link.springer.com/article/10.1007/s00421-017-3788-5:

Rodriguez-Falces and Place said:
Whereas the Na+/K+ pump-induced hyperpolarization of the membrane has been the prevailing hypothesis for M-wave potentiation for the past decades (McComas et al. 1994), evidence from in vitro studies agree that the fatigue induced increase in extracellular K+ concentration leads to an increase in the duration of intracellular action potentials (Lüttgau 1965; Hanson 1974; Metzger and Fitts 1986; Lännergren and Westerblad 1987). Our recent observations in humans also favor the hypothesis that, during fatiguing contractions, the transmembrane action potential increases itsduration (Rodriguez-Falces and Place 2017b).

The effect of muscle fiber conduction velocity on M-wave properties has also attracted the attention of investigators. There is consensus that a fatigue-induced decrease in conduction velocity results in an increase in the duration (i.e., broadening) of the M wave (Bigland-Ritchie et al. 1982). The effect on M-wave amplitude is more controversial. On theoretical grounds, a decrease in velocity alone (without concomitant changes in the transmembrane potential.
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Jammes et al wrote said:
We confirmed in ME/CFS patients the observations by Sharma et al. in patients with amyotrophic lateral sclerosis (Sharma et al., 1995a; Sharma and Miller, 1996) and multiple sclerosis (Sharma et al., 1995b) who have reported that muscle fatigue in these patients resulted from alterations of muscle membrane.
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But that isn't the opinion of Sharma 1995a who wrote:

The lack of decline in CMAP amplitude during exercise was similar in ALS and controls; this result suggests that the origin of fatigue was not at the myoneural junction or in the muscle membrane. Since there was a tendency toward less metabolic change during exercise in patients, their increased fatigability was not due to metabolic inhibition of the contractile process.
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Other studies at the time, utilising supramaximal twitch interpolation to measure 'central activation failure' eg central fatigue, found clear evidence of that in ALS patients, as well as patients with mitochondrial diseases and peripheral neuropathies. Restated, the same finding of central fatigue in ME/CFS patients was found in mitochondrial myopathies, muscular dystrophies and peripheral neuropathies.

Anyway, the dispute between Jammes and Sharma may be clarified by comments by Rodriguez-Falces & Place:

The use of the M wave to study fatigue‑induced changes in muscle sarcolemmal membrane excitability. For clarity, a distinction must be made between the terms “neuromuscular propagation” and “sarcolemmal membrane excitability”. As shown in Fig. 6a, M waves are initiated by action potentials that begin in the motor axons after application of an electrical stimulus. Thus, the changes in the M-wave properties are assumed to reflect alterations in neuromuscular propagation between the site of initiation (nerves) and the site of recording (muscle fibers) (Enoka and Stuart 1992). Therefore, there are three events (each located in a different site, see Fig. 6a) that can result in impaired neuromuscular propagation during fatiguing contractions (1) increase in the recruitment threshold of axons, (2) failure in the transmission at the neuromuscular junction, and (3) impaired sarcolemmal membrane excitability. According to this, reduced sarcolemmal membrane excitability represents only one of the possible contributors to impaired neuromuscular propagation. Yet, most authors agree that, among the three factors mentioned above, sarcolemmal membrane excitability is the most critical for the electrical activation of the muscle (Bigland-Ritchie et al. 1982; Lännergren and Westerblad 1987). Indeed, although it is well-documented that axonal hyperpolarization may occur during fatiguing contractions (Vagg et al. 1998; Burke 2002), the fact that most researchers stimulate the muscle with a supramaximal stimulus reduce the probability that some axons remain inactive when the stimulus arrives. On the other hand, failure of electrical transmission across the neuromuscular junction is dependent on the activation frequency (Thesleff 1959) and has only been demonstrated in animal studies using repetitive nerve stimulation (Krnjevic and Miledi 1958). Thus, it is not clear whether the motoneurone firing rates typical of human voluntary contractions are sufficiently high or are sustained at high levels long enough to result in neuromuscular block (Bigland-Ritchie et al. 1982).
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The above points out one of the key problems of the supramaximal twitch interpolation approach - it relies on a short stimulus rather than a sustained stimulus and thus only really tests whether there is neuromuscular blockage through other means, rather than a transient decline in impaired sarcolemmal membrane excitability or a decline in force output over time due to metabolic availability (supramaximal twitch interpolation relies on maximal motor unit recruitment and measures primarily use of anaerobic glycolysis, compared to maximal aerobic metabolism that occurs at stimulus levels that does not recruit all available motor units.

They also state that the M-wave has strong limitations as a measure of sarcolemmal excitability:

The transmembrane action potential cannot be recorded directly under in vivo conditions; rather, sarcolemmal excitability is generally assessed indirectly, from changes in the properties of the M wave (Fowles et al. 2002). Unfortunately, M-wave characteristics may be influenced by multiple factors other than the transmembrane action potential, such as those listed in Sect. 3. For this reason,
the practice of drawing conclusions about sarcolemmal membrane excitability based on M-wave properties should be treated with caution (Keenan et al. 2006). To work around this limitation, the first step is to analyze separately the first and second phases of the M wave
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The Jammes et al. manuscript is not clear on the specific methodology of measuring the M-wave amplitude.
 
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Kitty said:
Another study finding some differences between patients with shorter/longer disease duration. I don't really understand what sarcolemma fatigue is, but it doesn't read as if these differences are simply the result of adaptation.
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The differences in disease duration aren't that great:
The mean disease duration was 58 months (4.8 years) in those with M wave alterations, and 76 months (6.3 years) in those without. I can't tell what the numbers after the means are - maybe standard deviation? If so, there's quite a lot of overlap.
 
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Hutan said:
The differences in disease duration aren't that great
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I did wonder whether that might be the case, but I can't read numbers and statistics very well (dyscalculia).

I suppose it's one of those things that has to be noted if you find it, because if it's also found in larger follow-up studies it could be something—but equally it may not be anything at all. Could even be some kind of measurement artefact, given what Snow Leopard has said.
 
(please don't feel any need to rush to reply Snow Leopard)
Snow Leopard said:
They also state that the M-wave has strong limitations as a measure of sarcolemmal excitability:
For this reason, the practice of drawing conclusions about sarcolemmal membrane excitability based on M-wave properties should be treated with caution
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The authors of the 2023 paper seem to acknowledge that measurements of M-waves shouldn't be compared between participants, that absolute numbers aren't terribly useful. It's the change in the waves in an individual that they suggest is useful. For example, if the placement of the electrodes stays the same, that's taking out that source of variability.

I did see in the Rodriguez-Falces and Place paper that the temperature of the muscle can have an effect, I think it was consistent with what was seen here - a decrease in M-wave amplitude. I wonder if it's possible that an increase in muscle temperature due to the cycling might be having an effect?
Another factor, the increase in intramuscular temperature during a contraction, is known to have a depressing effect on M-wave amplitude (Rutkove, 2000).
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I found this study interesting and wrote about it in my recent news article (Substack)

Here is what I wrote:


Research into Muscle Dysfunction
Consequences of Sarcolemma Fatigue on Maximal Muscle Strength Production in Patients with ME/CFS was published Aug 3, 2023 and discusses muscle fatigability issues in patients who have ME. This study used 58 participants who fulfilled the International Consensus Criteria (ICC). It discussed possible causes for the muscle fatigability issue including:

“Muscle failure called “peripheral fatigue” may result from a failure of different metabolic processes such as the imbalance between oxygen demand and supply, the reduced excitation–contraction coupling, and the impaired muscle membrane excitability due to the altered flux of potassium through the sarcolemma… may have also a central origin resulting from a reduced central motor command to muscles…”

This research points to how this muscle issue could be used as a biomarker:

See article here: https://colleensteckelmeiccinfo.substack.com/p/news-2023-august-05

“In conclusion, this study suggest that post-exercise sarcolemma fatigue often measured in ME/CFS patients could be the cause of muscle failure and MHGS [Maximal handgrip strength] measurement constitutes a good index of global muscle performance and fatigability in ME/CFS patients. This simple and unexpansive method could represent a potential screening tool.”

If I understood this correctly, there were two different patterns within this patient group. They compared 30 patients with and 28 without electromyography (EMG) abnormalities. EMG is a technique for evaluating and recording the electrical activity produced by skeletal muscles.

This difference between the two groups may be a result of issues with placement of the electrodes. The paper states this as a limitation: “we cannot give absolute normal or abnormal values of M wave configuration due to the variability of skin electrodes position and skin conductivity between patients.”

FYI - Sarcolemma is the plasma membrane of the muscle cell.

Note: The original description of ME included “muscle fatigability”. And the IC Primer states that patients have a “pathological low threshold of physical and mental fatigability in response to exertion.”

This lack of stamina in the muscles has also been suggested as a biomarker in the 2021 Hand grip strength and fatigability: correlation with clinical parameters and diagnostic suitability in ME/CFS paper. “Repeat HGS [hand grip strength] assessment is a sensitive diagnostic test to assess muscular fatigue and fatigability and an objective measure to assess disease severity in ME/CFS.”

This is a promising area of research which I think could be moved into the clinical area if doctors were aware to look. I do a grip strength test as part of my yearly physical (my doctor offers more in depth screening than most practices). I can see (and feel) the decline in muscle function as I repeat the hand grip test during the physical.
 
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