Muscle‐Derived Small Extracellular Vesicles Mediate Exercise‐Induced Cognitive Protection in Chronic Cerebral Hypoperfusion

Abstract Physical exercise protects against cognitive impairment caused by chronic cerebral hypoperfusion (CCH). However, the mechanisms through which exercise sends signals from the periphery to the central nervous system remain incompletely understood. This study demonstrated that exercise promotes the secretion of muscle‐derived small extracellular vesicles (sEVs), which facilitate interorgan communication between the muscle and the brain. Systematic delivery of muscle‐derived sEVs enhances synaptic plasticity and alleviated cognitive impairment in CCH. Notably, miRNA sequencing reveal miR‐17/20a‐5p as key cargos in sEVs involved in the exercise‐induced muscle‐brain crosstalk. Muscle‐derived sEVs are also identified as the primary source of swimming‐induced miR‐17/20a‐5p in circulating sEVs. Mechanistically, miR‐17/20a‐5p binds to the DEP‐domain containing mTOR‐interacting protein (DEPTOR) and activates the mammalian target of rapamycin (mTOR) pathway in the hippocampus. Depletion of miR‐17/20a‐5p from muscle‐derived sEVs impairs the exercise‐induced enhancement of synaptic plasticity and cognitive function. Moreover, overexpression of DEPTOR in the hippocampus attenuates the cognitive benefits of exercise. Conversely, hippocampus‐specific activation of mTOR reverses these effects, highlighting the crucial role of mTOR in mediating the positive effects of exercise. Collectively, these findings identify miR‐17/20a‐5p in muscle‐derived sEVs as the exercise‐induced myokine with potent effects on the brain, emphasizing the therapeutic potential of exercise in managing cognitive impairment.