[CFS]: Abnormally fast muscle fiber conduction in the membranes of motor units at a low-level static force load, Klaver-Krol et al, 2021

Full title: Chronic fatigue syndrome: Abnormally fast muscle fiber conduction in the membranes of motor units at a low-level static force load

Paywall, https://www.sciencedirect.com/science/article/abs/pii/S1388245721000122

 

I'm keen to read this once I have access.

Note that an increase in conduction velocity is often associated with increased temperature. Which suggests that patients could be working (relatively) harder than controls.

(note, I'm assuming factors like muscle fibre length are effectively controlled by controlling for height, and sex etc.)

Trained individuals are also able to quickly recruit motor units with higher conduction velocities.
Higher muscle fiber conduction velocity and early rate of torque development in chronically strength-trained individuals
https://journals.physiology.org/doi/full/10.1152/japplphysiol.00025.2018

And just to be clear, a change in motor unit recruitment patterns on the 2nd CPET is a central part of my hypothesis for explaining the 2 day CPET findings.

 

Have you written about your hypothesis anywhere - I'm interested in reading?

I believe Systroms iCPET studies are really key to explaining issues with exercise. I just wish he had $$$ to dig deeper into omics to see what makers changed. I'm hoping Nath has done this in his exercise studies and will report later this year.

 

I have commented, even on the thread about Systrom's most recent study.
https://www.s4me.info/threads/unexp...xtraction-2019-by-melamed-systrom-et-al.11176

I am not a fan of his methodology, as they are ignoring the first ventilatory threshold (which is the most repeatable physiological threshold) and focusing on VO2peak which is subject to too many performance biases. They make a big deal about hyperventilation as a possible cause even though their results don't really support it. Hyperventilation is actually normal past the second ventilatory threshold, due to respiratory compensation due to reduced blood PH. Much ado was made about O2 dissociation curves and the Bohr effect due to hyperventilation, when the math suggests the effect on diffusion in the muscle is marginal at the physiological pressures they measured.

I instead focus on the reduction in workrate at the first ventilatory threshold aka the gas exchange threshold - this threshold has metabolic significance, namely it is the nonlinear point of oxygen extraction versus carbon dioxide output.
I note however, that the lower workrate on the second day is NOT consistently associated with a delay or reduction in VO2 kinetics (as would be predicted by the hyperventilation hypothesis) see the summary table here:
https://me-pedia.org/wiki/Two-day_cardiopulmonary_exercise_test

But back to the gas exchange threshold, this point occurs in exercise where there is a ramped increase in power output. Interestingly it does not consistently occur in fin swimming where participants increase cadence, but not necessarily increase power output. Which is to say that this ventilatory threshold is an artefact of a ramped exercise protocol (the same can be said of related 'anerobic threshold' - it does not simply occur beyond a particular heart rate threshold, it is an artefact of the balance between workrate and motor unit recruitment!)

This is a hint not to look at it purely on a metabolic level, but on a physiological level.
There are several phenomena to consider:
1. Muscle fibres utilising less oxygen due to a build up of inhibitory metabolites or poorer O2 diffusion
2. A reduction of force output due to metabolic kinetic limitations (or peripheral neurological fatigue) leads to an alteration in the recruitment of motor units, typically measured as a reduction in EMG and MMG frequency and an increase in EMG amplitude as more motor units are recruited.
3. The build up of metabolites due to the shift in metabolism in the muscle fibres or the same due to an increase in higher threshold motor units (that in turn have poorer diffusion of O2 since they are connected to muscle fibres that are situated further away from capillaries) leads to an increase in stimulation of Type III and IV muscle afferents. These afferents feed back in several ways, the first is the sensations associated with fatigue, the second is any spinal and supraspinal inhibitory feedback. This spinal and supraspinal feedback due to muscle afferents is the primary cause of "central fatigue". These afferents inhibit corticospinal excitability in particular, likely though GABAergic mechanisms. (note that it is adrenergic mechanisms that increase corticospinal excitability). During a ramped exercise protocol (such as a CPET), the individual will necessarily have to increase the upstream drive (which will be perceived as increased effort on the Borg scale) and which can alter the pattern of motor units recruited and it will shift the balance between ventilatory rates and workrate. The latter of which I believe is the primary purpose of "central fatigue". Eg it is not to protect against muscle damage (because empirically, it doesn't prevent such damage), nor prevent peripheral fatigue (because it doesn't prevent that either), nor maintain some sort of body-wide homeostasis (because the effect is only concerned with the muscles that are in use, rather O2 or glucose availability in the brain or elsewhere).
Autonomic functions (such as heart rate and blood pressure) in turn lag behind the changes in ventilation and motor drive.

Of the points 1-3, which comes first? It is a bit of a chicken or egg type question, but the result is the combination of these effects feeding into one another leads to a clear transition point, known as the gas exchange threshold, or the (first) ventilatory threshold.

Lastly, on the topic of "central fatigue", the same pattern as measured by electrophysiological stimulation (supramaximal twitch interpolation) in CFS patients is also found in patients with muscular dystrophy, peripheral neuropathies and central neuropathies (MS). Hence, regardless of underlying defects, the remaining motor units/muscle fibres still have to work hard and this stimulates the type III/IV afferents leading to "central fatigue" being predominant, even in conditions that clearly have peripheral disease. This suggests clear coupling between peripheral factors and "central fatigue".

I want to vary the 2 day CPET protocols so that it is no longer maximal (in terms of VO2) and I want to shift away from the ventilatory threshold to a EMG/MMG threshold. The impact of blocking the Type III/IV afferents is an obvious step, but the tricky and rewarding bit is going beyond this and discovering which metabolites are stimulating the receptors and how to target their levels in patients.

 

Do you believe what happens in me/cfs is what is thought to be the mechanism behind post polio syndrome?

„The new weakness of PPS appears to be related to the degeneration of individual nerve terminals in the motor units. A motor unit is formed by a nerve cell (or motor neuron) in the spinal cord or brain stem and the muscle fibers it activates. The polio virus attacks specific neurons in the brain stem and spinal cord. In an effort to compensate for the loss of these motor neurons, surviving cells sprout new nerve-end terminals and connect with other muscle fibers. These new connections may result in recovery of movement and gradual gain in power in the affected limbs. ...“


I believe it makes total sense (unfortunately).

 

I don't think it is quite that simple, because not all ex-poliomyelitis patients develop it. The delay for decades isn't fully explained by the "overuse" explanation, nor the fact that electrodiagnostic methods have inconsistent results. I wonder if there is more to it than the notion of natural decline of 'fragile' spinal axons.

Guillain-Barré syndrome often leaves residual symptoms very similar to CFS and PPS in a significant minority of patients, despite apparent neurological recovery (as measured using electrodiagnostic methods). I guess this could be partly explained by GBS being the result of peripheral or more distal axonal damage, compared to the anterior horn in poliomyelitis (GBS can also have sensory consequences, but there are purely motor axonal variants). Both GBS and poliomyelitis cause a very similar acute flaccid paralysis, the difference being that it is almost always bilateral in GBS and usually unilateral in poliomyelitis. There are some signs of disturbed immune system regulation or abundance of particular t-cells, though there is a lack of study and replication. (sound familiar?)

 

Looking at the conclusion to this paper

is the central neural deregulation bit trying to bring in a psych "central sensitisation" explanation for the findings?

Googling "disturbed muscle membrane function" gives results for studies on muscular dystrophy patients. Lipid rafts and calcium signalling also crop up, which are topics that I don't understand but various ME researchers have talked about (if I remember correctly). So it looks like there are more likely explanations for the findings other than a "central sensitisation" explanation, if that's what the authors are trying to introduce.

 

Not necessarily. I mean it might be if they don't understand what central fatigue is. I still don't have access to the paper, so...

 

I was sent this document from a lecture about fibromyalgia by the lead author. It was in Dutch so this is a Google translation. Images are missing but the text explains the same.

 

From the document

 

Effects, or resulting symptoms, that should be explored are: abnormal muscle tightness, abnormal aching and abnormal weakness after muscle use/exertion. This tightness can range from aching to spasm. For me this can take days of recovery involving careful stretching, massage and gentle movement. Muscles need to move and work to be healthy but working them in a body with long term ME produces contradictory, dysfunctional results.

 

Has anyone managed to read the full manuscript of this yet?

 

The article has been published. Haven't read it yet!

https://www.sciencedirect.com/science/article/pii/S1388245721000122?dgcid=author

 

Would this explain why muscle wasting is rarely reported in pwME (at least in those who are not very severe)?

 

It has always puzzled me that I am not more unfit than I am, that I have not lost more muscle mass or put on more weight. In the first twenty years or so of my ME when I still had periods of relative remission, if I was well enough to do things, I could do things approaching my premorbid level of fitness.

More recently, in the last six or seven years, I have become less fit and do not see periods of remission, this seems to have been since orthostatic intolerance has become as much a limiting factor as PEM.

 

Spot on.

Many years ago, my ME/CFS went into almost complete remission overnight. At the time, I was mild and working about 4 hours per day. After this 'remission', I returned to working full-time hours without any problems within a few days.

The deconditioning hypothesis is complete nonsense.

 

It took me nearly 20 years to get over severe muscle pain with these problems, and only after I learned a lot more about pacing.