Circulating Extracellular Vesicles: The Missing Link between Physical Exercise and Depression Management?

Abstract

Depression is associated with an increased risk of aging-related diseases. It is also seemingly a common psychological reaction to pandemic outbreaks with forced quarantines and lockdowns. Thus, depression represents, now more than ever, a major global health burden with therapeutic management challenges. Clinical data highlights that physical exercise is gaining momentum as a non-pharmacological intervention in depressive disorders. Although it may contribute to the reduction of systemic inflammation associated with depression, the mechanisms underlying the beneficial physical exercise effects in emotional behavior remain to be elucidated. Current investigations indicate that a rapid release of extracellular vesicles into the circulation might be the signaling mediators of systemic adaptations to physical exercise. These biological entities are now well-established intercellular communicators, playing a major role in relevant physiological and pathophysiological functions, including brain cell–cell communication. We also reviewed emerging evidence correlating depression with modified circulating extracellular vesicle surfaces and cargo signatures (e.g., microRNAs and proteins), envisioned as potential biomarkers for diagnosis, efficient disease stratification and appropriate therapeutic management. Accordingly, the clinical data summarized in the present review prompted us to hypothesize that physical exercise-related circulating extracellular vesicles contribute to its antidepressant effects, particularly through the modulation of inflammation. This review sheds light on the triad “physical exercise–extracellular vesicles–depression” and suggests new avenues in this novel emerging field.

Preliminary Investigations Into the Effect of Exercise-Induced Muscle Damage on Systemic Extracellular Vesicle Release in Trained Younger and Older Men

“…Endurance exercise has been shown to alter EV profiles ( Oliveira et al, 2020 ; Soares et al, 2021 ). Chronic exercise in murine models (3weeks swim training) was, for example, shown to significantly increase serum EV count ( Bei et al, 2017 ), whilst the modal size of EVs was unchanged.…”

The Role of Non-Coding RNAs in the Pathogenesis of Parkinson’s Disease: Recent Advancement

“…the PD cell model [204]. Simultaneously, circ_0070441 can directly bind to miR-626, thereby indirectly regulating IRS2 expression, and its upregulation was verified to aggregate MPP(+)-induced neurotoxicity in a PD cell model [205]. However, there is still a controversial issue about whether circRNAs can serve as miRNA sponges because some studies have revealed that most circRNAs do not have the function of sponging miRNAs [211] (Figure 5).…”

“…Therefore, the discovery of minimally invasive biomarkers is of great interest. Circulating cell-free miRNAs exist in the extracellular circulation, including plasma, serum, cerebrospinal fluid, saliva, urine, breast milk, and seminal plasma [ 205 ]. They are stable in severe environmental conditions and resistant to cellular RNase in circular systems owing to their existence in extracellular spaces [ 206 , 207 ].…”

Circulating Exosome Cargoes Contain Functionally Diverse Cancer Biomarkers: From Biogenesis and Function to Purification and Potential Translational Utility

“…MiRNAs control gene expression by binding to imperfect complementary sites within the 3′ untranslated regions of their mRNA targets and orchestrate their degradation and/or post-transcriptional repression [ 286 , 287 ]. MiRNAs are involved in the control of all normal biological processes and their expression deregulation (i.e., increased or decreased expression) has been associated with the initiation and development of cancers [ 288 , 289 , 290 , 291 ]. Mature and functional cellular miRNAs can be detected in the blood and other biological fluids and can generally be found in two forms: either as cell/membrane-free molecules (i.e., free, bound to Argonaute (Argo) or to nucleophosmin proteins, complexed with high density lipoprotein (HDL)) or encapsulated within extracellular vesicles [ 274 , 291 , 292 ].…”