Myokine Cathepsin B as a Key Muscle-Brain Axis Regulator Mediates Treadmill-Running-Induced Hippocampal Neurogenesis and Cognitive Improvement in Mice.
Level 5 - mechanism / opinion, no new human data
Preclinical animal and in vitro mechanistic experiments combined with observational human cohort analysis
PubMed 42038255 · doi:10.34133/research.1233
What was done
Researchers evaluated the effects of treadmill running at various intensities (defined by maximum oxygen uptake) and durations on hippocampal neurogenesis and cognitive function in wild-type (C57BL/6J) and Alzheimer's disease model (APP/PS1) mice. They integrated omics and UK Biobank cohort analyses to identify exercise-responsive factors. Mechanistic investigations tested the regulation of cathepsin B (CTSB) stability by O-linked N-acetylglucosaminyltransferase (OGT), extracellular vesicle (EV)-mediated CTSB delivery across the muscle-brain axis, and the impact of muscular CTSB and OGT knockdown or overexpression on neurogenesis, neuroinflammation, amyloid-beta deposition, and memory.
What was found
The abstract reports directional findings without specific numerical values or effect sizes. Treadmill running improved hippocampal neurogenesis and memory in wild-type mice in an intensity-dependent manner. Muscle-derived CTSB was identified as a primary exercise-responsive myokine stabilized against ubiquitination-mediated degradation by OGT-dependent O-GlcNAcylation. Treadmill running facilitated CTSB packaging into EVs and transport to the hippocampus. Muscular CTSB knockdown partially attenuated exercise-induced cognitive and neurogenic gains in wild-type mice. In APP/PS1 mice, exercise and CTSB upregulation reduced amyloid-beta accumulation, neurofibrillary degeneration, and neuroinflammation while improving cognitive performance.
Why it matters
This work maps a specific molecular pathway (OGT/CTSB) linking physical exertion in skeletal muscle to extracellular vesicle-mediated neuroprotection and neurogenesis in the brain. Defining these muscle-brain axis mediators provides candidate targets for therapeutic strategies aimed at mitigating cognitive decline and Alzheimer's disease pathology.
Limits
The abstract provides no exact quantitative metrics, sample sizes, or variance estimates. The interventional findings are derived from rodent and cellular models, which may not replicate in human physiology. The human component is limited to correlational cohort and omics analyses rather than interventional exercise trials. Long-term safety, systemic off-target effects of CTSB modulation, and precise EV delivery kinetics in vivo require further evaluation.
Cited by
- context Skeletal muscle acts as an endocrine organ that produces and secretes myokines and signaling molecules, including irisin, cathepsin D, BDNF, and interleukin-6.