The exercise-triggered release of extracellular vesicles into the circulation
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Abstract
Physical exercise induces acute physiological changes leading to massively enhanced cross-talk between cells, organs, and tissues. These acute alterations cause systemic adaptations which promote physical and mental health on a long-term. Though, the molecular basis underlying these bodily adaptations remains elusive. Extracellular vesicles (EVs) are cell-derived membranous entities which transport bioactive material and function as mediators of cell-cell-communication between several organs and tissues. EVs in the circulation increase upon diverse exercise interventions and are speculated to be involved in the physiological adaptation processes induced by regular physical exercise. However, knowledge on the dynamics, the origin, and the composition of EVs present in blood during and after exercise (ExerVs) is poor. In addition, the difficulties in EV-isolation from blood plasma represents a hurdle for the characterization of ExerVs.
Here, a detailed analysis of different ExerV subclasses to define their release kinetics and their origin was performed in an incremental cycling exercise setting involving 21 healthy male athletes. EV isolation via size exclusion chromatography (SEC), immuno-affinity capture as well as combination of SEC with density gradient centrifugation lead to enrichment of EVs from human plasma samples. Semi-quantitative analyses of ExerV dynamics in SEC-EVs and immuno-affinity captured EVs revealed elevations in a load-response related fashion. Phenotyping of ExerVs using two multiplexed analysis approaches directly in blood plasma or isolated SEC-EVs, CD9+EVs, CD63+EVs, and CD81+EVs revealed a panel of cellular marker proteins present on ExerVs. The results indicate that ExerVs originate from leukocytes, including lymphocytes (CD4+EVs, CD8+EVs), monocytes (CD14+EVs) and antigen presenting cells (MHCI+EVs, MHCII+EVs), as well as endothelial cells (CD105+EVs, CD146+EVs), and platelets (CD41b+EVs, CD62P+EVs). Impaired downstream analysis of proteomic content, nanoparticle tracking analysis, and imaging flow cytometry analysis of differentially isolated ExerVs demonstrated the need for further improvement of EV purity to gain deeper insights on actual concentrations and the composition of ExerVs.
Conclusively, various cell types of the circulatory system contribute to the exercise-triggered release of extracellular vesicles into the blood stream. This heterogeneous pool of ExerVs may be involved in signaling processes associated with coagulation, endothelial function and inflammation.