Running-induced systemic cathepsin B secretion is associated with memory function
Open accessAbstract
Peripheral processes that mediate beneficial effects of exercise on the brain remain sparsely explored. Here, we show that a muscle secretory factor, cathepsin B (CTSB) protein, is important for the cognitive and neurogenic benefits of running. Proteomic analysis revealed elevated levels of CTSB in conditioned medium derived from skeletal muscle cell cultures treated with AMP-kinase agonist AICAR. Consistently, running increased CTSB levels in mouse gastrocnemius muscle and plasma. Furthermore, recombinant CTSB application enhanced expression of brain-derived neurotrophic factor (BDNF) and doublecortin (DCX) in adult hippocampal progenitor cells through a mechanism dependent on the multifunctional protein P11. In vivo, in CTSB knockout (KO) mice, running did not enhance adult hippocampal neurogenesis and spatial memory function. Interestingly, in Rhesus monkeys and humans, treadmill exercise elevated CTSB in plasma. In humans, changes in CTSB levels correlated with fitness and hippocampus-dependent memory function. Our findings suggest CTSB as a mediator of effects of exercise on cognition.
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The myokine cathepsin B might be involved in mediating the exercise-induced improvement in hippocampal neurogenesis, memory, and learning.
“In 2016, Moon et al. show that the myokine cathepsin B (Ctsb) might be involved in mediating the exercise-induced improvement in hippocampal neurogenesis, memory, and learning [236].”
From Neurotrophic Factor BDNF, Physiological Functions and Therapeutic Potential in Depression, Neurodegeneration and Brain Cancer (2020) · cites this paper as [236]
The Discussion (page unavailable) says CTSB may mediate exercise benefits and that running enhanced adult neurogenesis and spatial-memory retention in wild-type but not CTSB-knockout mice. The Results (page unavailable) report no difference between groups in acquisition of the spatial task, so the claimed improvement in learning is not supported. (LLM, conf=0.88)
Experimental — accuracy not yet measuredDuring exercise, peripheral muscle-secreted proteins such as cathepsin B and FNDC5/irisin cross the blood brain barrier to mediate BDNF expression in the hippocampus and subsequent neurogenesis and memory improvement.
“Furthermore, during exercise, proteins and their metabolic derivatives secreted from peripheral muscles, such as cathepsin B and FNDC5/irisin, also cross the blood brain barrier to mediate BDNF expression in the hippocampus and subsequent neurogenesis and memory improvement (Wrann et al., 2013; Moon et al., 2016).”
From Exercise-Mediated Neurogenesis in the Hippocampus via BDNF (2018) · cites this paper as Moon et al., 2016
The Results (Permeability of CTSB across the Blood-Brain-Barrier; no page given) show that intravenously injected cathepsin B reached mouse brain tissue, but do not show muscle-secreted cathepsin B crossing during exercise. The Results on hippocampal progenitor cells report increased BDNF after cathepsin B treatment, while the Introduction links muscle-derived FNDC5/irisin to hippocampal Bdnf expression. The paper also links cathepsin B to running-related neurogenesis and memory, but does not establish the claimed complete pathway for both proteins or show irisin crossing the barrier. (LLM, conf=0.88)
Experimental — accuracy not yet measuredIn humans, chronic exercise increases plasma cathepsin B.
“although chronic exercise does increase plasma levels of cathepsin B145,157.”
From Exerkines in health, resilience and disease (2022) · cites this paper as [157]
In animal models and humans, plasma cathepsin B is positively associated with hippocampus-dependent memory.
“In both animal models and humans, plasma levels of cathepsin B, a lysosomal thiol proteinase produced by muscle, is positively associated with hippocampus-dependent memory145,157.”
From Exerkines in health, resilience and disease (2022) · cites this paper as [157]
The secreted form of lysosomal enzyme cathepsin B (CTSB) is an exercise‐responsive myokine that targets the brain, promotes hippocampal neurogenesis, and therefore enhances cognitive abilities.
“Finally, a recent study using proteomic approaches demonstrates that the secreted form of lysosomal enzyme cathepsin B (CTSB) is also an exercise–responsive myokine that targets the brain, promotes hippocampal neurogenesis, and therefore enhances cognitive abilities 122.”
From Inter‐organ communication: a gatekeeper for metabolic health (2019) · cites this paper as [122]
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BackgroundResultSuzuki, W. A. (2016) · Cell Metabolism · doi:10.1016/j.cmet.2016.07.022 · Cited by 17 · see citing works
Wang, N., Zhu, S., Chen, S., Zou, J., Zeng, P., & Tan, S. (2025) · Reviews in the Neurosciences · doi:10.1515/revneuro-2024-0147 · Cited by 12 · see citing works
Of sound mind and body: Exploring the diet-strength interaction in healthy aging
Askow, A. T., McKenna, C. F., Box, A. G., Khan, N. A., Petruzzello, S. J., De Lisio, M., Phillips, S. M., & Burd, N. A. (2020) · Frontiers in Nutrition · doi:10.3389/fnut.2020.00145 · Cited by 10 · see citing works
- Authors
- Moon, H. Y., Becke, A., Berron, D., Becker, B., Sah, N., Benoni, G., Janke, E., Lubejko, S. T., Greig, N. H., Mattison, J. A., Duzel, E., & van Praag, H.
- Affiliations
- National Institute on Aging (US)
- Otto-von-Guericke-Universität Magdeburg (DE)
- ORCID
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2016-08
- Volume
- 24
- Issue
- 2
- Pages
- 332-340
- ISSN
- 1550-4131 (ISSN-L)
- PMC
- PMC6029441
- OpenAlex
- W2470343227
- Cited by
- 628
- References
- 42
- Citations by year
- 2026: 73 · 2025: 86 · 2024: 68 · 2023: 77 · 2022: 76 · 2021: 52 · 2020: 62 · 2019: 48 · 2018: 40 · 2017: 37 · 2016: 8 · 2013: 1
- FWCI
- 22.63
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- UCL Discovery (University College London) (submittedVersion)
- DZNE Pub (submittedVersion)
- Seoul National University Open Repository (Seoul National University) (submittedVersion)
- Funders
- National Institutes of Health
- National Institute on Aging (Z01AG000328)
- Topics
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nerve injury and regeneration
- Health Sciences › Medicine › Rehabilitation › Exercise and Physiological Responses
- Keywords
- cathepsin B, running, exercise and cognition, hippocampal neurogenesis, brain-derived neurotrophic factor, doublecortin, p11, AICAR, AMP kinase, spatial memory, rhesus monkeys
- MeSH terms
- Doublecortin Domain Proteins, Doublecortin Protein, Adult, Affect, Aging, Animals, Behavior, Animal, Cathepsin B, Cognition, Exercise Test, Female, Hippocampus, Humans, Macaca mulatta, Male, Memory, Mice, Inbred C57BL, Microtubule-Associated Proteins, Motor Activity, Neurons, Neuropeptides, Physical Conditioning, Animal, Running, Reproducibility of Results, Mice, Knockout, Brain-Derived Neurotrophic Factor, Neurogenesis, Young Adult, Sedentary Behavior
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