TY - JOUR
T1 - Myokine Cathepsin B as a Key Muscle–Brain Axis Regulator Mediates Treadmill-Running-Induced Hippocampal Neurogenesis and Cognitive Improvement in Mice
AU - Zhou, Xuchang
AU - Wang, Dongxue
AU - Deng, Huili
AU - Guo, Jianmin
AU - Chen, Xier
AU - Lin, Zhangyu
AU - Liu, Baolong
AU - Zhao, Ruobing
AU - Gao, Lu
AU - Yin, Xuan
AU - Zhang, Yun
AU - Chen, Yan
AU - Yang, Yajing
AU - Li, Qingxian
AU - Shen, Qu
AU - Ji, Jianguang
AU - Ni, Guoxin
N1 - This work was supported by the Beijing Natural Science Foundation (no. 7222115), Fujian Province’s Natural Science Foundation (no. 2024J08319), Xiamen Health High-quality Development Science and Technology Program (no. 2024GZL-GG07), the start-up grant from the University of Macau (UMDF-TISF/2025/001/FHS), and faculty PI allocated fund (FHS-CC-046-001-2024).
Publisher Copyright:
Copyright © 2026 Xuchang Zhou et al.
PY - 2026/4/23
Y1 - 2026/4/23
N2 - 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 protein/presenilin 1 mice, treadmill running potentially improved cognitive function, reduced amyloid-β deposition, neurofibrillary degeneration, and neuroinflammation by up-regulating muscular CTSB. Knockdown of muscular CTSB attenuated the benefits of treadmill running, while overexpression of CTSB further enhanced the exercise-induced effects. Overall, this study demonstrates that treadmill running may activate the muscular OGT/ CTSB signaling axis, promoting the secretion of the myokine CTSB protein into the circulatory system via EVs and its transport to the brain, thereby improving hippocampal neurogenesis and cognitive function in both WT and amyloid precursor protein/presenilin 1 mice. These findings highlight the role of myokine CTSB as a pivotal modulator in muscle–brain axis communication mechanism, with its stability regulated by O-linked N-acetylglucosaminylation.
AB - 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 protein/presenilin 1 mice, treadmill running potentially improved cognitive function, reduced amyloid-β deposition, neurofibrillary degeneration, and neuroinflammation by up-regulating muscular CTSB. Knockdown of muscular CTSB attenuated the benefits of treadmill running, while overexpression of CTSB further enhanced the exercise-induced effects. Overall, this study demonstrates that treadmill running may activate the muscular OGT/ CTSB signaling axis, promoting the secretion of the myokine CTSB protein into the circulatory system via EVs and its transport to the brain, thereby improving hippocampal neurogenesis and cognitive function in both WT and amyloid precursor protein/presenilin 1 mice. These findings highlight the role of myokine CTSB as a pivotal modulator in muscle–brain axis communication mechanism, with its stability regulated by O-linked N-acetylglucosaminylation.
UR - https://www.scopus.com/pages/publications/105036605481
U2 - 10.34133/research.1233
DO - 10.34133/research.1233
M3 - Journal article
AN - SCOPUS:105036605481
SN - 2096-5168
VL - 9
JO - Research
JF - Research
M1 - 1233
ER -