Myokine Cathepsin B as a Key Muscle–Brain Axis Regulator Mediates Treadmill-Running-Induced Hippocampal Neurogenesis and Cognitive Improvement in Mice

作者：Xuchang Zhou, Dongxue Wang, Huili Deng, Jianmin Guo, Xier Chen, Zhangyu Lin, Baolong Liu, Ruobing Zhao, Lu Gao, Xuan Yin, Yun Zhang, Yan Chen, Yajing Yang, Qingxian Li, Qing Shen, Jianguang Ji, Guoxin Ni · 发表于：Research · 年份：2026 · DOI：10.34133/research.1233 · 被引用次数：1 · 研究领域：Neurogenesis and neuroplasticity mechanisms、Neurological Disorders and Treatments、Nerve injury and regeneration

This study aimed to explore the impact of treadmill running at different intensities and durations on hippocampal neurogenesis and cognitive function in mice, with a focus on the interorgan communication mechanism mediated by the extracellular vesicle (EV) cargo cathepsin B (CTSB) via the muscle–brain axis. We define the intensity of treadmill running mice based on measurements of maximum oxygen uptake. The findings from treadmill running studies at varying intensities and durations in C57BL/6J mice revealed that treadmill running improved hippocampal neurogenesis and memory in wild-type (WT) mice in an intensity-dependent manner. Omics and UK Biobank cohort analyses identified muscle-derived CTSB as a key exercise-responsive factor, whose expression may be regulated by O-linked N -acetylglucosaminylation. Overexpression of O-linked N -acetylglucosaminyltransferase (OGT) prolonged the half-life of CTSB and inhibited its ubiquitination-mediated degradation, whereas inhibition of OGT accelerated its degradation. Mechanistically, treadmill running may promote the secretion of muscle-derived CTSB into the bloodstream via EVs and its subsequent delivery to the hippocampus through activation of the OGT/CTSB signaling. In WT mice, knockdown of muscular CTSB partially reversed the treadmill-running-induced improvements in hippocampal neurogenesis and memory, while overexpression of muscular OGT further enhanced the release of muscle-derived CTSB. Moreover, in amyloid precursor protei...