Exercise-Induced Myonectin Protects Against Cerebral Ischemia-Reperfusion Injury.

BACKGROUND: There exists muscle-brain signaling via myokines. However, not all members of myokines have been thoroughly studied. Here, we identify myonectin, an exercise-induced myokine, as a new regulator of cerebral ischemia-reperfusion (I/R) injury. METHODS: Cerebral ischemia was induced by middle cerebral artery occlusion (MCAO/R) in wild-type mice and skeletal muscle-specific myonectin-knockout mice. Laser speckle contrast imaging (LSCI) and TTC staining were used to assess cerebral injury. HT22 and BV2 cells were utilized to mimic I/R-associated cellular damage using oxygen-glucose deprivation and reoxygenation (OGD/R). Intravenous recombinant myonectin was administered to assess therapeutic effects on I/R injury. Immunohistochemistry, TUNEL, ELISA, and Western blotting assays were performed to detect morphological and molecular changes in cells and tissues. RESULTS: Exercise elevated serum and brain myonectin and reduced infarct size and neuronal damage in wild-type but not myonectin-deficient mice after MCAO/R. Systemic myonectin administration significantly protected against cerebral I/R injury. Mechanically, myonectin exerted neuroprotective effects by suppressing excessive autophagic apoptosis and microglia-mediated neuroinflammation thorough activation of the PI3K/Akt/mTOR pathway. CONCLUSION: Skeletal muscle-derived myonectin protects the brain from I/R injury, contributing to exercise benefits via muscle-brain communication. Myonectin may serve as a promising therapeutic agent against cerebral I/R injury.