Early Days Yet in the Study of Extracellular Vesicle Signaling and Exercise
Cell signaling is vital to the metabolic and health benefits of exercise. Much of that signaling is carried by extracellular vesicles, tiny membrane-wrapped packages of molecules. Signaling taken as as a whole is a vast topic, and remains comparatively poorly mapped. Researchers are making incremental progress in the areas of greatest interest, those relating to response to cellular stress, in search of a basis for therapies that mimic some of the effects of calorie restriction, exercise, and other beneficial lifestyle choices and environmental factors.
The different physiological stimuli during physical exercise lead to an alteration of the extracellular vesicle (EV) landscape in blood. Research in humans was mainly focused on flow cytometric analysis of large EVs from platelets and endothelial cells, also called microparticles. The concentration of platelet microparticles increases during physical activity, starting at an early phase of exercise and reaching baseline few hours after the exercise session. Their release has been attributed to the activation of coagulative processes and shear stress. In contrast, abundance of endothelial microparticles varied between studies, but was reported as unchanged in most cases after exercise.
Recently, small extracellular vesicles (sEVs) have caught attention in the context of physical activity and an increasing number of studies addressed the release and their possible involvement in signaling pathways. Some studies in humans and rodents observed an immediate increase of sEVs after a single bout of physical exercise. One study found a direct reduction of total EV numbers, while detecting an increased population of muscle cell-derived EVs. Furthermore, elevation of resting EV levels were detected in response to long-term exercise interventions. sEVs released upon physical exercise (ExerVs) appear as a complex mixture of vesicles originating from platelets, endothelial progenitor, or endothelial cells, leukocytes, and muscle cells, which most probably varies depending on exercise mode and time of investigation.
Analysis of the protein cargo of ExerVs identified various proteins associated with key signaling pathways, including angiogenesis, immune signaling, and glycolysis. Additionally, the secretion and transport of myokines via ExerVs was suggested. Moreover, several studies found evidence for the transport of an altered miRNA panel via sEVs in response to exercise bouts or training. Some of the miRNAs carried by ExerVs belong to the group of myomirs indicating involvement of EVs in muscle regeneration processes following exercise. Functional analysis of ExerVs suggested contribution to cardio protection in ischemia / reperfusion-injury, hypoxia / reoxygenation-assays, tissue remodeling, endothelial function, as well as muscle remodeling and growth, potentially mediated by ExerV-cargo transported in response to exercise stimuli.
Overall, these studies provide evidence that sEVs are actively released into the circulation upon physical exercise and may function as mediators of different key signaling pathways, possibly involved in adaptation processes triggered by exercise.