Increased Circulating H3 Histone in Response to Repeated Bouts of Exercise Does Not Associate with Parallel Alterations of Cell-Free DNA

Abstract

Numerous studies have shown that cf nDNA significantly rises in stress caused by exercise. However, during nuclear decondensation, released DNA is followed by histones. Histones are also a common disease marker. After PAD4 mediated hypercitrullination extracellular H3Cit exhibits high toxicity contributing to tissue damage which, in cases of systemic inflammation, may lead to multiorgan failure and finally to death. We tested whether circulating histones rise in response to strenuous exercise. Eleven average-trained men performed three treadmill exercise tests to exhaustion at speed corresponding to 70% VO2max separated by 72 h of resting. Blood was collected before and just after each bout of exercise and plasma proteins were measured using enzyme-linked immunosorbent assay, whereas platelet activity was estimated with Light Transmission Aggregometry. Both, circulating histones and PAD4 raised in response to exercise. Plasma citrullinated histones increased from 3.1 ng/mL to 5.96 ng/mL (p = 0.0059), from 3.65 ng/mL to 6.37 ng/mL (p = 0.02), and from 3.86 ng/mL to 4.75 ng/mL (p = 0.033) after the first, second, and third treadmill run, respectively. However despite the parallel increase, no significant correlation between citrullinated histone and aggregation or cell-free nDNA was found. Furthermore, positive correlations of cf nDNA with aggregation and PAD4, lactate with aggregation, and lactate with citrullinated histone have been observed.

Exhaustive Exercise Increases Spontaneous but Not fMLP-Induced Production of Reactive Oxygen Species by Circulating Phagocytes in Amateur Sportsmen

“…In our previous studies, an exhaustive treadmill run executed according to the same protocol caused an increase in plasma cf n-DNA and citrullinated H3 histone in healthy average trained men and in those with type 1 diabetes [ 7 , 34 , 43 ]. These two biomolecules belong to the markers of neutrophil extracellular traps (NETs) formation [ 44 , 45 ], and it is believed that NETs formation is involved in the immune-metabolic response to strenuous exercise [ 6 , 46 ].…”

“…Moreover, these cells undergo degranulation, which results in increased levels of granular enzymes (e.g., myeloperoxidase) in circulating blood and post-exercise urine [ 3 , 5 ]. Relatively recently, it was found that a certain subset of neutrophils forms neutrophil extracellular traps (NETs) under the influence of exercise with subsequent increase in circulating cell-free nuclear DNA (cf-nDNA), antibacterial granular enzymes and cell-free citrullinated H3 histone [ 6 , 7 ]. Formation of NETs is accompanied by increased ROS production, which seems to be an essential mediator of this process [ 8 ].…”

Epigenetic Regulation of Inflammatory Responses in the Context of Physical Activity

“…Epigenetic changes after exercise are also stated in histone modifications. PA is found to moderate enzymes responsible for histone acetylation/deacetylation, circulating free citrullinated histones and histone acetylation levels [ 151 , 152 ]. Circulating histones are cytotoxic and may trigger an inflammatory response through TLRs [ 151 ].…”

“…PA is found to moderate enzymes responsible for histone acetylation/deacetylation, circulating free citrullinated histones and histone acetylation levels [ 151 , 152 ]. Circulating histones are cytotoxic and may trigger an inflammatory response through TLRs [ 151 ]. Extensive aerobic training causes the release of H3 histone into the bloodstream.…”

“…Extensive aerobic training causes the release of H3 histone into the bloodstream. Free circulating citrullinated H3 was correlated with the lactate level and increase of IL-10 after the bout [ 151 ].…”