Inflammatory activity of extracellular vesicles induced by physical exercise

It is well-known that physical exercise induces systemic adaptations that improve health benefits. Skeletal muscle (SkM) is an important secretory organ releasing myokines and emerging evidence identifies extracellular vesicles (EVs) as key communicators between SkM and other tissues. First, we explored EV dynamics in response to different exercise programmes. Particularly, acute aerobic exercise (AAE) led to a greater increase in circulating EVs in sedentary individuals compared to trained subjects, revealing an exercise-dependent modulation. Moreover, EV-MyomiRs such as -206, -133b, and -146a increased following AAE in an intensity-dependent manner. These EVs stimulated inflammatory gene expression in THP1 cells, highlighting their role in immunomodulation. In parallel we performed electrical pulse stimulation (EPS), a well-known model for in vitro exercise mimicking chronic low-frequency muscle contraction of C2C12 myotubes. We isolated two EV populations (10k-EVs and 100k-EVs) and found that chronic EPS induces the release of specific CD81⁻/α7-INT⁺ 10k-EV subpopulation. Moreover, qPCR analysis showed that EV mitochondrial DNA content is higher in EPS-derived 10k-EVs compared to no-EPS, suggesting that exercise could drive the upregulation of pro-inflammatory cytokines in murine macrophages. Altogether our findings confirm that EVs play a key role in exercise-related inflammation and the release of EV-MyomiRs is influenced by exercise: more trained individuals show a reduced increase in circulating EV-MyomiRs after exercise. Moreover, the contraction activity elicited by in vitro chronic sessions of EPS can stimulate the secretion of a specific CD81-/α7-INT+ EV subpopulation from C2C12 myotubes which may have a role in regulating physical adaptations to chronic low frequency exercise.