Acute aerobic exercise is associated with a biphasic, temporally ordered shift in serum extracellular vesicle microRNA expression in major depressive disorder

Introduction Acute aerobic exercise (AAE) is known to reduce symptoms of Major Depressive Disorder (MDD), yet the underlying biological mechanisms remain poorly understood. Here, we profiled microRNA (miRNA) expression within the serum extracellular vesicle (EV) enriched fraction (hereafter 'EV-enriched miRNA') of individuals diagnosed with MDD at multiple timepoints: before, during (mid), immediately after, and 75 min following a single 30-min session of moderate aerobic exercise. By characterizing the temporal dynamics of EV-enriched miRNA responses to AAE, our objective was to uncover molecular changes that may mediate exercise-induced molecular adaptations relevant to short- or long-term antidepressant effects of exercise and to identify candidate EV-enriched miRNAs for future mechanistic investigation of MDD. Methods An EV-enriched serum fraction was isolated from a minimum of 28 individuals diagnosed with MDD. MicroRNA profiles were then assessed via RNA deep sequencing and analyzed with using DESeq2. Results We identified time-dependent, significant (false discovery rate [FDR] ≤ 0.05) changes in EV-enriched microRNAs across AAE, with 15 differentially expressed at mid-AAE, 33 immediately post-AAE, and four at 75 min post-AAE. The response was biphasic and directional: miRNAs were predominantly downregulated during and immediately after exercise (13 of 15 down at mid-AAE; all 33 down post-AAE) and exclusively upregulated during recovery (all four up at 75 min post-AAE). hsa-miR-12523p was the only microRNA differentially expressed across all three postexercise timepoints, showing consistent downregulation. Functional enrichment of predicted targets of significantly differentially expressed miRNAs revealed a temporally ordered shift from RNA processing and stability at mid-AAE, to dendrite, synapse, and axon organization immediately post-AAE, to synaptic transmission and neuronal development at 75 min post-AAE. Discussion AAE is associated with time-dependent, directional changes in EV-enriched microRNAs in MDD, whose predicted targets converge on synaptic plasticity pathways implicated in the disorder. Together, this suggests microRNAs may contribute to the beneficial short- and potentially long-term effects of aerobic exercise in individuals with MDD and provides specific targets for future mechanistic investigation.