Converging protective pathways: Exploring the linkage between physical exercise, extracellular vesicles and oxidative stress.

Physical Exercise (EXR) has been shown to have numerous beneficial effects on various systems in the human body. It leads to a decrease in the risk of mortality from chronic diseases, such as cardiovascular disease, cancer, metabolic and central nervous system disorders. EXR results in improving cardiovascular fitness, cognitive function, immune activity, endocrine action, and musculoskeletal health. These positive effects make EXR a valuable intervention for promoting overall health and well-being in individuals of all ages. These beneficial effects are partially mediated by the role of the regular EXR in the adaptation to redox homeostasis counteracting the sudden increase of ROS, the hallmark of many chronic diseases. EXR can trigger the release of numerous humoral factors, e.g. protein, microRNA (miRs), and DNA, that can be shuttled as cargo of Extracellular vesicles (EVs). EVs show different cargo modification after oxidative stress stimuli as well as after EXR. In this review, we aim to highlight the main studies on the role of EVs released during EXR and oxidative stress conditions in enhancing the antioxidant enzymes pathway and in the decrease of oxidative stress environment mediated by their cargo.

Plasma-derived extracellular vesicles released after endurance exercise exert cardioprotective activity through the activation of antioxidant pathways.

Cardiovascular diseases (CVD) can cause various conditions, including an increase in reactive oxygen species (ROS) levels that can decrease nitric oxide (NO) availability and promote vasoconstriction, leading to arterial hypertension. Physical exercise (PE) has been found to be protective against CVD by helping to maintain redox homeostasis through a decrease in ROS levels, achieved by increased expression of antioxidant enzymes (AOEs) and modulation of heat shock proteins (HSPs). Extracellular vesicles (EVs) circulating in the body are a major source of regulatory signals, including proteins and nucleic acids. Interestingly, the cardioprotective role of EVs released after PE has not been fully described. The aim of this study was to investigate the role of circulating EVs, obtained through Size Exclusion Chromatography (SEC) of plasma samples from healthy young males (age: 26.95 ± 3.07; estimated maximum oxygen consumption rate (VO2max): 51.22 ± 4.85 (mL/kg/min)) at basal level (Pre_EVs) and immediately after a single bout of endurance exercise (30' treadmill, 70% heart rate (HR) -Post_EVs). Gene ontology (GO) analysis of proteomic data from isolated EVs, revealed enrichment in proteins endowed with catalytic activity in Post_EVs, compare to Pre_EVs, with MAP2K1 being the most significantly upregulated protein. Enzymatic assays on EVs derived from Pre and Post samples showed increment in Glutathione Reductase (GR) and Catalase (CAT) activity in Post_EVs. At functional level, Post_EVs, but not Pre_EVs, enhanced the activity of antioxidant enzymes (AOEs) and reduced oxidative damage accumulation in treated human iPS-derived cardiomyocytes (hCM) at basal level and under stress conditions (Hydrogen Peroxide (H2O2) treatment), resulting in a global cardioprotective effect. In conclusion, our data demonstrated, for the first time, that a single 30-min endurance exercise is able to alter the cargo of circulating EVs, resulting in cardioprotective effect through antioxidant activity.

Tau Seeds in Extracellular Vesicles Induce Tau Accumulation in Degradative Organelles of Cells.

Clinical progression of tauopathies may result from transcellular propagation of pathogenic Tau seeds with the possible involvement of extracellular vesicles (EVs) as transport vectors. We established a cell model for investigating EV delivery of proteins, since the mechanism regulating EV cargo delivery to recipient cells is poorly understood. In our cell model, EVs are readily internalized and accumulate in degradative organelles (DOs). We then show for the first time that in this acidic compartment, profibrillogenic Tau delivered by EVs interacts with Tau expressed by the recipient cells and cause its accumulation by a process that involves the participation of autophagy. Thus, the degradative compartment of cells may represent the subcellular site initiating a cascade of events resulting in early hallmarks of tauopathies. These are characterized by seeded Tau accumulation, pathology-associated epitopes, DO stress, and cytotoxicity. The involvement of autophagy to this process and the relative accessibility of the degradative pathway for extracellular agents, support possible modes of intervention to slow down the progression of neurodegeneration.