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PEM - is it axon damage?

Discussion in 'General ME/CFS Discussion' started by Kimsie, Jan 23, 2015.

  1. Kimsie

    Kimsie Senior Member

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    I have been considering a hypothesis that PEM is actually a type of axon damage in the brain due to either a lack of NAD or an inability to change NMN to NAD.

    Axons are the long part of the nerve that runs from one synapse to the next, sort of the telephone wire of the nerve that the signals run through. Damage to axons has been found to be associated with ME/CFS, and damage to the axons has been found when nicotinamide mononucleotide (NMN) builds up due to insufficient activity of nicotinamide mononucleotide adenylyltransferase 2 (NMNAT2) (but no one is connecting those two ideas, until now, as far as I know).

    So I am hypothesizing that the inhibition of the electron transport causes the lack of available ATP (which is one of the substrates of NMNAT) during periods of mental or physical activity leads to a buildup of NMN in the neurons, which damages the axons. Perhaps PEM is a temporary manifestation of the damage but by repeating the process which leads to PEM and not allowing for enough healing the damage can become worse and worse.

    By taking time out for complete rest periods you allow your body and brain to decrease the buildup of NMN in the neurons because the ATP can be shunted over to NMNAT during the rest periods, and this avoids the damaging PEM.

    Of course this is just a hypothesis and I don’t have any idea if it is correct but I think it has some interesting aspects.
     
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  2. Hip

    Hip Senior Member

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    How would the axon damage occur so quickly (PEM often occurs within hours of exertion), and how would it heal itself so quickly (you can recover from PEM within a day or two)?
     
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  3. Kimsie

    Kimsie Senior Member

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    If it was a small amount of damage or maybe it causes inflammation in the axon?
     
  4. cfsStevew

    cfsStevew

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    I thought it was increased inflammation switching on the 'sickness response' in the brain, possibly combined with mitochondrial malfunctioning from running out of ADP...and other peripheral issues cause by the inflammation...sounds vague cos it is...
     
  5. adreno

    adreno PR activist

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  6. Hip

    Hip Senior Member

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    I think the switching on of sickness behavior stands a good chance of explaining post-exertional malaise (PEM).

    ME/CFS symptoms are very similar to sickness behavior, and some researchers think that this disease is underpinned by chronic sickness behavior. PEM is an exacerbation of ME/CFS symptoms, so this would simply make PEM an exacerbation of the existing state of sickness behavior in ME/CFS patients.

    Massive amounts of the cytokine IL-6 are released by the muscles during exercise, and IL-6 is one of the cytokines that precipitates sickness behavior.

    If the brain in ME/CFS is already in a state of sickness behavior, then this extra IL-6 from exercise might worsen the sickness behavior further, leading to what we experience as PEM.

    And note that when IL-6 was experimentally injected into healthy men, it caused fatigue and a reduced capacity to concentrate. 1



    Lactate may be another factor driving PEM. Lactate is also released by the muscles during exercise, and can cross the blood-brain barrier quite easily. Once in the brain, lactate induces release of all the major sickness behavior cytokines (IL-1β, IL-6 and TNF-α) from microglia (at least in a rat study). 1 So exercise-dervied lactate may be another factor increasing sickness behavior.


    So both IL-6 and lactate released by the muscles during exercise might be driving PEM.
     
    Last edited: Jan 28, 2015
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  7. nandixon

    nandixon Senior Member

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    Kimsie and merylg like this.

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