Running-Induced Systemic Cathepsin B Secretion Is Associated with Memory Function

• Proteomics of AICAR-treated L6 muscle cells reveals myokine cathepsin B (CTSB)
• Exercise increases CTSB levels in mouse, monkey, and human plasma
• Running does not improve memory or adult neurogenesis in CTSB knockout mice
• CTSB enhances neurotrophin levels in adult hippocampal progenitor cells
• In humans, plasma CTSB levels are positively correlated with fitness and memory

SummaryPeripheral 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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