Exercise-induced Serpina1e as a hippocampal memory enhancer

초록

The exercise-induced enhancement of learning and memory is thought to be regulated not only by improved cardiometabolic and psychosocial health but also by body‒brain interactions mediated by metabolites and proteins derived from peripheral organs. Given the prominent role of skeletal muscle during exercise, muscle-derived factors are believed to mediate the cognitive enhancements induced by exercise. However, the specific myokines that exert beneficial effects on cognitive functions remain to be elucidated. Here, we reveal that a novel myokine, Serpina1e, acts as a molecular mediator that directly supports long-term memory formation in the hippocampus. Using an in vivo myokine-labeling mouse model, proteomic analysis revealed that the Serpina1 family of proteins are the myokines whose levels increased the most in plasma after 4 weeks of chronic aerobic exercise in male mice. Systemic delivery of recombinant Serpina1e or intramuscular overexpression of Serpina1e in sedentary male mice was sufficient to reproduce the enhancement of hippocampus-associated cognitive functions. Conversely, mice with a muscle-specific reduction in Serpina1e did not exhibit exercise-induced hippocampal memory enhancement, indicating a requirement of muscle-derived Serpina1e for exercise-induced cognitive enhancement. Moreover, our data showed that an increase in plasma Serpina1e level led to upregulated neurogenesis, brain-derived neurotrophic factor (BDNF), and neurite growth in the hippocampus, suggesting a positive role of exercise-induced Serpina1e in boosting hippocampal function. Because plasma Serpina1e can cross the blood-cerebrospinal fluid (CSF) and blood-brain barrier to reach the brain, our findings reveal that Serpina1e is a myokine that migrates to the brain and mediates exercise-induced memory enhancement by triggering neurotrophic growth signaling in the hippocampus. This discovery elucidates the molecular mechanisms underlying the beneficial effects of exercise on cognitive function and may have implications for the development of novel therapeutic interventions for alleviating cognitive disorders.