Figure 4.

Peripheral mechanisms involved in EX-induced BDNF increase. Many organs respond to EX through the release of exerkines. Among them, the liver and the skeletal muscle have received particular attention and several exerkines originating from these organs have the potential to influence brain BDNF expression. (A) In response to EX, the liver secretes exerkines named hepatokines. Studies have reported that β-HB can cross the BBB and function as a signaling molecule promoting hippocampal BDNF expression by HDAC inhibition. In addition, IGF-1 can cross the BBB through IGF-1 receptor binding. Inhibition of IGF-1 signaling through blocking antibodies prevented EX-induced hippocampal BDNF expression. FGF-21 is also secreted by the liver in response to EX, can enter the brain and improve cognition possibly through an increase in brain BDNF expression since intraperitoneal administration of FGF-21 was associated with BDNF upregulation in aged mice. Recent research has unveiled Gpld1 as a newly discovered hepatokine that appears to correlate with cognitive performance in mice undergoing EX. Moreover, overexpression of Gpld1 in the liver has been associated with a significant rise in hippocampal BDNF expression and an enhancement of neurogenesis. Although Gpld1 does not cross the BBB, data suggest that this enzyme may be involved in coagulation as well as in the complement system cascades of molecules downstream of GPI-anchored substrate. (B) Several molecules named myokines are secreted by skeletal muscles in response to EX and have been shown to promote brain BDNF expression. Lactate that is significantly produced and released during EX can cross the BBB via MCT transporters. The pharmacological blockade of MCT in mice submitted to EX abolished hippocampal bdnf gene expression while intraperitoneal administration of lactate elicited a hippocampal BDNF increase comparable to that observed in trained mice. Lactate effect on hippocampal bdnf gene expression is thought to be dependent on the potentiation of NMDA glutamatergic transmission and upregulation of SIRT-1 activity fostering the PGC-1α/FNDC5/BDNF pathway. The myokine CTSB is also released by skeletal muscle during EX though an AMPK-dependent mechanism. In vivo experiments provide evidence that CTSB can cross the BBB and elicit BDNF expression while EX in CTSB KO mice failed to enhance neurogenesis and improve spatial memory. Although the role of skeletal muscle as a source of blood BDNF remains a topic of debate, recent studies using NMES as a model of muscle contraction seem to support this hypothesis. The BBB crossing of circulating BDNF is uncertain but exosomal transport might be involved. Additionally, peripheral delivery of BDNF has been shown to induce neurogenesis and increase hippocampal BDNF levels. During muscle contraction, the increased calcium signaling enhances PGC-1α activation which leads to an increase in FNDC5, a transmembrane protein that is cleaved during EX and released in the bloodstream as irisin. Data reported that irisin could cross or signal at the BBB, potentially via its recently discovered binding to activated integrin αVβ5 receptors. In an AD mice model, peripheral delivery of FNDC5/irisin rescued memory impairment and synaptic plasticity deficits through mechanisms dependent on cerebral BDNF. Conversely, the blockade of peripheral FNDC5/irisin attenuates the effect of EX on LTP and memory tests. PGC-1α activation during EX also stimulates the expression of KAT enzymes within skeletal muscle. This enzyme catalyzes the conversion of KYN, a neurotoxic metabolite that can cross the BBB and lead to depression to KYNA which is unable to cross the BBB. Mice with muscle-specific overexpression of PGC-1α were resilient to stress-induced depression and did not display decreased hippocampal bdnf gene expression while peripheral KYN administration induced depressive behavior in wild-type but not in transgenic animals. This last mechanism illustrates the crosstalk between peripheral organs, as KYN is a metabolite of tryptophan produced in the liver. Created with BioRender.com.