TABLE 3.

Potential role of exerkines encapsulated in small EVs and their relationship with major depressive disorder.

Exerkines in sEVs		Relationship with exercise	Role in major depressive disorder
miRNAs	miR-451a	A single bout of high intensity interval training (cycling at peak power output - 10 × 60s intervals) increases the expression of miR-451a in exosomes D’Souza et al. (2018)	Serum levels of miR-451a are lower in depressed patients (Kuang et al., 2018)
	miR-150-5p	A single bout of high intensity interval training (Cycling at peak power output - 10 × 60s intervals) increases the expression of miR-150-5p in muscles and exosomes D’Souza et al. (2018)	Lower levels of miR-150-5p are linked to higher levels of prenatal discomfort (Foley et al., 2023). Additionally, miR-150-5p knockout in mice, results in an increase in anxiety-like behavior Zhang et al. (2021)
Neutrophins	Brain-derived neurotrophic factor (BDNF)	Aerobic exercise (20 min—3x/week—12 weeks) increases the levels of BDNF in the cargo of circulating extracellular vesicles Barcellos et al. (2020)	MDD patients have lower serum and exosomal levels of BDNF Gelle et al. (2021)
	Vascular endothelial growth factor (VEGF)	VEGF have been identified as an sEV cargo molecule in various peripheral tissues Zhang and Xu (2022). VEGF is increased by acute systemic exercise (1 h exercise bout at 50% of VO2 max) in human skeletal muscle (Gavin et al., 2004)	Individuals who have attempted suicide show reduced levels of VEGF in their cerebrospinal fluid. Additionally, there is a negative correlation between the levels of VEGF and the severity of depression. Isung et al. (2012)
Cytokines	Interleukin (IL)-1β	Aerobic exercise (20 min—3x/wk—12 weeks) increases the levels of IL-1β in the cargo of circulating extracellular vesicles Barcellos et al. (2020)	Chronically elevated levels of IL-1β have been associated with the pathophysiology of MDD (Farooq et al., 2017)
	Interleukin (IL)-10	Exercise training (45 min/d x 7 days - aerobic 70% of VO2 max + resistance) changes skeletal muscle small EV microRNAs that target inflammatory pathways such as IL-10, suggestive of reduced inflammation Su et al. (2022)	Some studies have shown that individuals with depression may have lower levels of IL-10, suggesting that reduced anti-inflammatory activity could be involved in the development of depressive symptoms (Roque et al., 2009). However, there is also evidence suggesting that higher levels of IL-10 could be linked to chronic or recurrent depression. (Roque et al., 2009)