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.