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 KaplanNir Friedman, Benjamin Glaser, Ruth Shemer, Naama Constantini, Yuval Dor*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

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, β-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.

Original languageAmerican English
Article number101074
JournalCell Reports Medicine
Volume4
Issue number6
DOIs
StatePublished - 20 Jun 2023

Bibliographical note

Publisher Copyright:
© 2023 The Author(s)

Keywords

  • ChIP-seq
  • chromatin
  • circulating cell-free DNA
  • exercise biology
  • fitness
  • inflammation
  • methylation
  • neutrophil extracellular traps
  • neutrophils
  • polymorphonuclear cells

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