Serpina1e mediates the exercise-induced enhancement of hippocampal memory in male mice

Exercise enhances learning and memory, not only through improved cardiometabolic but also through body-brain interactions mediated by secreted factors. Given the prominent role of skeletal muscle during exercise, muscle-derived factors, myokines, are believed to mediate the exercise-induced cognitive enhancements. Here, we demonstrate that intramuscular Serpina1e is upregulated following exercise in male mice. Systemic delivery of recombinant Serpina1e or intramuscular overexpression of Serpina1e reproduces exercise-induced memory enhancements in sedentary male mice. Conversely, muscle-specific depletion of Serpina1e abolishes hippocampal memory enhancement, indicating a requirement of muscle-derived Serpina1e for these cognitive benefits. Mechanistically, elevated plasma Serpina1e stimulates neurogenesis, brain-derived neurotrophic factor (BDNF) expression, and neurite growth in the hippocampus by crossing the blood–cerebrospinal fluid (CSF) and blood–brain barrier. Our findings identify Serpina1e as a key mediator of skeletal muscle-brain interaction that enables the beneficial effects of exercise on cognitive function. Exercise is known to have positive effects on memory. Here the authors show that Serpina1e produced by skeletal muscle is upregulated following exercise in male mice, which may contribute to the effects of exercise on cognitive function.