MoTrPAC: Acute Exercise Stimulates Sex-Specific Hepatic Secretion of Extracellular Vesicles Capable of Enhancing Mitochondrial Respiration in Primary Neurons

Exercise supports healthy aging in the brain leading to adaptations that slow cognitive decline, including increasing neurogenesis in the hippocampus and promoting the maintenance of mitochondrial function. Evidence demonstrates that exercise stimulates the release of factors, exerkines, that modulate systemic benefits. Extracellular vesicles (EVs) facilitate inter-organ crosstalk in response to exercise by disseminating exerkines. The liver, crucial to maintaining systemic metabolic homeostasis, undergoes substantial changes with exercise and is central to exercise induced adaptations that promote metabolic health. Taken together, these findings point to exercise induced liver derived EVs as a critical area of study in potentially mediating the benefit of exercise to brain health. Male and female 6-month old Fisher (F344) rats were randomized to sedentary or acute exercise conditions (30-minute treadmill running at 70-80% VO 2 max). Immediately after exercise, the common hepatic and portal veins were cannulated for blood sampling in anesthetized rats. EVs were isolated via serial ultracentrifugation and underwent global, untargeted proteomic analysis (n=4/5). Rat primary cortical neurons were cultured from isolated embryonic cortices and treated with pooled sedentary or exercised, male or female, common hepatic vein EVs for 4 hours at a concentration of 2.5ug/mL (n=3). Serum from which the EV populations were isolated was used as a control. Basal mitochondrial respiration was measured using a Seahorse XF. In females, we identified 119 significantly differentially expressed proteins (DEPs) in common hepatic vein EVs between exercise and sedentary conditions, 13 of which were only identified with exercise. While in males, we identified 120 DEPs, 7 of which were unique to exercise. In rat primary cortical neurons male derived hepatic EVs promoted increased basal mitochondrial respiration, predominantly driven by exercise (main effect of EVs, p<0.05), while exercise promoted increased basal mitochondrial respiration, largely driven by hepatic EVs, in females (main effect of exercise, p<0.05). Here we demonstrate that a single bout of exercise stimulates the release of hepatic EVs, with unique and sexually dimorphic proteomic profiles, that are capable of influencing mitochondrial respiration in primary neurons. These data suggest that the liver may mediate exercise induced effects on brain mitochondria through EVs. * MoTrPAC-generated data have undergone preliminary analysis by the authors of this work; results presented here do not represent the final consensus analysis by MoTrPAC. U01AG070928 (The Molecular Transducers of Physical Activity Consortium on behalf of the preclinical animal study sites 2 for the MoTrPAC Study Group) and by FWB, RSR, and JPT. This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.