Altered muscle membrane potential and redox status differentiates two subgroups of patients with chronic fatigue syndrome: Jammes et al Apr 2020

[Sly Saint]

Abstract
Background
In myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), altered membrane excitability often occurs in exercising muscles demonstrating muscle dysfunction regardless of any psychiatric disorder. Increased oxidative stress is also present in many ME/CFS patients and could affect the membrane excitability of resting muscles.

Methods
Seventy-two patients were examined at rest, during an incremental cycling exercise and during a 10-min post-exercise recovery period. All patients had at least four criteria leading to a diagnosis of ME/CFS. To explore muscle membrane excitability, M-waves were recorded during exercise (rectus femoris (RF) muscle) and at rest (flexor digitorum longus (FDL) muscle). Two plasma markers of oxidative stress (thiobarbituric acid reactive substance (TBARS) and oxidation–reduction potential (ORP)) were measured. Plasma potassium (K+) concentration was also measured at rest and at the end of exercise to explore K+ outflow.

Results
Thirty-nine patients had marked M-wave alterations in both the RF and FDL muscles during and after exercise while the resting values of plasma TBARS and ORP were increased and exercise-induced K+ outflow was decreased. In contrast, 33 other patients with a diagnosis of ME/CFS had no M-wave alterations and had lower baseline levels of TBARS and ORP. M-wave changes were inversely proportional to TBARS and ORP levels.

Conclusions
Resting muscles of ME/CFS patients have altered muscle membrane excitability. However, our data reveal heterogeneity in some major biomarkers in ME/CFS patients. Measurement of ORP may help to improve the diagnosis of ME/CFS.

https://translational-medicine.biom...mpaign=BSCN_2_DD01_CN_bmcso_article_paid_XMOL

 

[Andy]

Subjects aged ≥ 18-years referred to our hospital for the diagnosis of chronic fatigue were recruited between April 2018 and June 2019. Inclusion criteria included: at least 6 months of chronic fatigue and at least four symptoms of inability as required for the diagnosis of ME/CFS [1, 2].

The references are CCC and IOM.

 

[cassava7]

To the best of my knowledge, the three largest groups of ME/CFS patients in France are Pr Authier's in Paris, Dr Ghali's in Angers, and that of Dr Retornaz and Pr Jammes in Marseille. The latter two are the only ones to research ME in France (Authier instead works with EUROMENE). Very glad to see seemingly good research from them

 

[wigglethemouse]

Not going to comment on the conclusions.

But can someone with some statistics background comment on why it is valid to draw a straight line in these graphs. So many papers I see like this, where a few extra data points, or removal of a few points, could cause a different slope and hence different conclusions. When I see data is spread so much like in this case my intuition tells me more data points are needed before drawing conclusions. Thoughts?

 

[ME/CFS Skeptic]

There was no control group so I guess the main finding is that the subgroup of ME/CFS patients with abnormal muscle membrane excitability have significantly higher markers of oxidative stress than the other ME/CFS group with normal muscle membrane excitability.

 

[Penelope McMillan]

Not going to comment on the conclusions.

But can someone with some statistics background comment on why it is valid to draw a straight line in these graphs. So many papers I see like this, where a few extra data points, or removal of a few points, could cause a different slope and hence different conclusions. When I see data is spread so much like in this case my intuition tells me more data points are needed before drawing conclusions. Thoughts?
View attachment 10670

I can't claim to understand the software they used, but if you simply look at the data points, there is a rough alignment with the direction of the solid lines.
There are plenty of data points outside the 95% confidence dashed lines, but the bottom left and top right corners of the plots are emptier than the top left and bottom right.
I am not disagreeing that more data points would make a stronger case. But these seem to be enough to suggest a trend that is perhaps worth following up with replications.

 

[Penelope McMillan]

I am a little lost here. Is there any information on differences between the two groups other than the muscle membrane excitability grouping?
Some ME studies have indicated that differences found tended to correlate with length of illness or with comorbid fibromyalgia or some other identifiable illness grouping.

I am wondering, as I tend to do with exercise provocation studies, what the PEM/PENE status of the participant was before the provocation.
For example, is the difference simply between those who were well rested before the study and those who were not? Would a retest two days later then find that all participants had abnormal results?

Thoughts, please!

 

[Snow Leopard]

I am wondering, as I tend to do with exercise provocation studies, what the PEM/PENE status of the participant was before the provocation.
For example, is the difference simply between those who were well rested before the study and those who were not? Would a retest two days later then find that all participants had abnormal results?

This is an interesting question, but this (and prior studies from this group) do not answer this question.

The study was seemingly designed to examine possible causes for M-wave alterations, rather than why some patients had measurable differences and others did not.

The authors state they have no explanation for the differences (the mention of post-polio was of interest to me).

However, the intergroup differences between oxidative abnormalities could not result from age and/or sex differences as reported in healthy subjects by Fano et al. [28] because in our study these parameters were similar in the two groups. Furthermore, the comorbidities present in group 2 patients cannot explain the absence of marked oxidative damage. Indeed, high levels of oxidative stress are often measured in patients with ankylosing spondylitis [29] or Lyme disease [30], these comorbidities being present in six of our patients. Additionally, fatigue that leads to physical deterioration is another important symptom that is observed in 90% of patients with post-polio syndrome, probably resulting from spine frontal horn motor neuron damage during acute poliovirus infection [31]. However this comorbidity was only reported in one of our patients. We therefore have no satisfactory explanation for the intergroup differences observed here.

It is important to note several things, the first is peak heart rates were low in both groups, 151 and 148 BPM (both +-3), which is low for 43-47 year old participants. VO2Peak was also low, at 67%, 63% of predicted VO2Max. (an increase in max heart rate from 150 to 175 BPM leads to a big increase in cardiopulmonary output)
The group with M wave differences had slightly higher performance, were slightly younger, and had been ill for slightly longer, but none of these differences were considered significant. Most participants would have been exercising for a total of 5-6.5 minutes given the peak workload and ramping rate.

(A slower ramping rate and higher peak workload can mean much longer times on the bike, a real world example: during the 2 day CPET, I was still on the bike for over 8 minutes after exceeding my anerobic threshold. Due to a slower ramp time: 15 watt/min and peak power:270 watt)

The key point however is that the level of fatigue induced in these participants is not uniform and thus a more severe exercise challenge (or prior PEM) could potentially induce measurable changes in the other participants.

Taking a step back, the authors do not explain what M-waves are. M-waves are reflex responses caused by surface electrical stimulation of sensory nerve fibres (stemming from muscle spindles which sense muscle stretch and are counterbalanced by gamma motor neuron drive). Alterations of M-waves therefore suggest peripheral alterations in sensory nerve fibre sensitivity, and/or a difference in number (of) and location of active motor units.

A popular (but wrong) hypothesis by psychiatrists and neurologists (who don't understand exercise physiology) is that CFS is merely a central disorder of effort perception. But change in effort perception during activity is entirely related to change in neural drive and is not affected by peripheral afferents. (note that effort baseline itself can be biased due to a variety of psychological factors, including a sense of pain at baseline and hence it is the not the baseline that is important to consider, but the rate of change of effort perception during activity)
The reason why this is a flawed hypothesis, is that such a disorder would lead to proprioceptive error, since movement is reliant on prediction of force and location based on neural drive (our nervous system is too slow to do this in real time) and hence a flaw in effort perception would lead to an error in positioning and our sense of effort would quickly be corrected through feedback. Unless there is also an alteration in muscle spindle sensitivity at the same time, but a central disorder of sensitivity to muscle spindle afferents would lead to a disorder of muscle tone due to a disorder of gamma motor neuron drive.

The current study is interesting because they compared stimulation of afferents in quadriceps muscles (which were use strongly during the exercise protocol) and compared them to toe muscles.

In group 1, M-wave alterations were present in both the exercising (RF) and resting (FDL) muscles. More specifically, the M-wave amplitude and length and the conduction time were affected in RF whereas only the M-wave amplitude varied in FDL. The kinetics of the M-wave changes in group 1 are shown in Fig. 1: compared to resting values, significant changes in M-wave amplitude (F value > 12) occurred close to the end of exercise and often progressed until the end of the recovery period. A significant increase in M-wave duration (F = 4.42) only occurred in RF. In group 2, the M-wave amplitude tended to increase in RF (F = 10.24) with no change in duration or conduction time. No M-wave change occurred in FDL (Table 2 and Fig. 2).

M-wave amplitude increases suggest a peripheral increase in sensitivity of Ia sensory Fibres. The fact that this occurred in both the quadriceps and toe muscles suggests vascular origins (perhaps related to increased circulation of oxidative stress related products). But this amplitude increase itself doesn't necessarily suggest additional fatigue, whereas the increased duration and conduction time of the M-wave suggest increased fatigue and (potentially) altered muscle unit recruitment due to fatigue. (see the references cited in the study, including prior ME/CFS studies).