Elevated cfDNA after exercise is derived primarily from mature neutrophils, with a minor contribution of cardiomyocytes, 2023, Fridlich et al

Discussion in 'Other health news and research' started by SNT Gatchaman, Jul 30, 2023.

  1. SNT Gatchaman

    SNT Gatchaman Senior Member (Voting Rights)

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    Elevated cfDNA after exercise is derived primarily from mature polymorphonuclear neutrophils, with a minor contribution of cardiomyocytes
    Ori Fridlich; Ayelet Peretz; Ilana Fox-Fisher; Sheina Pyanzin; Ziv Dadon; Eilon Shcolnik; Ronen Sadeh; Gavriel Fialkoff; Israa Sharkia; Joshua Moss; Ludovica Arpinati; Shachar Nice; Christopher D. Nogiec; Samuel Terkper Ahuno; Rui Li; Eddie Taborda; Sonia Dunkelbarger; Zvi G. Fridlender; Paz Polak; Tommy Kaplan; Nir Friedman; Benjamin Glaser; Ruth Shemer; Naama Constantini; Yuval Dor

    Strenuous physical exercise causes a massive elevation in the concentration of circulating cell-free DNA (cfDNA), which correlates with effort intensity and duration. The cellular sources and physiological drivers of this phenomenon are unknown.

    Using methylation patterns of cfDNA and associated histones, we show that cfDNA in exercise originates mostly in extramedullary polymorphonuclear neutrophils. Strikingly, cardiomyocyte cfDNA concentration increases after a marathon, consistent with elevated troponin levels and indicating low-level, delayed cardiac cell death. Physical impact, low oxygen levels, and elevated core body temperature contribute to neutrophil cfDNA release, while muscle contraction, increased heart rate, b-adrenergic signaling, or steroid treatment fail to cause elevation of cfDNA. Physical training reduces neutrophil cfDNA release after a standard exercise, revealing an inverse relationship between exercise-induced cfDNA release and training level.

    We speculate that the release of cfDNA from neutrophils in exercise relates to the activation of neutrophils in the context of exercise-induced muscle damage.

    Highlights
    • The major source of elevated cfDNA in exercise is mature polymorphonuclear neutrophils
    • Physical impact and elevated core body temperature contribute to cfDNA elevation
    • cfDNA elevation has an inverse relationship to individual training level
    • A minor contribution of cardiomyocyte-derived cfDNA after extreme exercise

    Link | PDF (Cell Reports Medicine)
     
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  2. SNT Gatchaman

    SNT Gatchaman Senior Member (Voting Rights)

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  3. RedFox

    RedFox Senior Member (Voting Rights)

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    Dying heart cells? That sounds scary. But strenuous exercise is good for you. Do they just grow back?
     
  4. Andy

    Andy Committee Member

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    Interesting. I searched for studies looking for cell-free DNA in ME/CFS patients and found one that found no difference with controls, Analysis of 16S rRNA gene sequences and circulating cell-free DNA from plasma of chronic fatigue syndrome and non-fatigued subjects 2002 Vernon et al,

    and one that found elevated rates in patients, and one that found elevated rates, Mitochondrial dysfunction and the pathophysiology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) 2012 Booth et al
     
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  5. Hutan

    Hutan Moderator Staff Member

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    That's a short half-life

    Perhaps it would be necessary to look for differences in cell-free DNA immediately after exercise and/or during PEM.
     
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  6. Hutan

    Hutan Moderator Staff Member

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    So, a new technique to identify the source of cell free DNA. There might be issues if the cells of people with ME/CFS that then go on to release cell free DNA are not operating normally (and so are methylated unusually), but it still sounds interesting.
     
    Last edited: Jul 31, 2023
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  7. Hutan

    Hutan Moderator Staff Member

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    Those are massive increases in levels of cfDNA. The graded exercise test is just 12 minutes, a CPET. It's interesting that there was a lot of variation in fold change among the participants.

    Screen Shot 2023-07-31 at 12.21.18 pm.png

    These figures (1C and 1D) show the amount of cfDNA released by various cell types in a range of resting/exercise states. Sample sizes are low. I would really like to see this approach applied to people with ME/CFS. Among the cell type sources that are claimed to be assessed are vascular endothelial cells and colon cells. The cfDNA derived from neutrophils is shown in red. If this study is right, it really is remarkable just how much DNA is coming from the neutrophils in response to exercise (and they seem to be suggesting it's specifically a response to hypoxic conditions).

    What could that mean for a person with ME/CFS? Could PEM be a response to the loss of neutrophils? Or to the low oxygen levels?

    Is the sickness response that happens when someone has a fever a similar thing?

    How could a massive turnover of neutrophils be a good thing to happen in response to an exercise challenge?
     
  8. Hutan

    Hutan Moderator Staff Member

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    On the finding that physical impact seems to increase cf-DNA (whereas an increased heart rate does not)
    Could this, together with the finding that an increased body temperature increases cf-DNA, be why some people with ME/CFS prefer swimming over other exercising - less impact and less over-heating?

    They found lower levels of neutrophil cfDNA in trained individuals compared to untrained individuals.
     
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  9. SNT Gatchaman

    SNT Gatchaman Senior Member (Voting Rights)

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    Which I think relates to DNase activity. From Physical Exercise Promotes DNase Activity Enhancing the Capacity to Degrade Neutrophil Extracellular Traps (2022, Biomedicines) —

     
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  10. SNT Gatchaman

    SNT Gatchaman Senior Member (Voting Rights)

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    That paper also comments —

    So lipid dysregulation may impair control of cfDNA / NETs via DNases.
     
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