Serpina1e mediates the exercise-induced enhancement of hippocampal memory in male mice.
basic_science · Level V
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- Record sourced from PubMed, PMID 41957371.
- Also identified by DOI 10.1038/s41467-026-71420-0.
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Abstract
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.