Effects of exercise on cognition, hippocampal neurogenesis, and learning: Muscle–brain crosstalk in health and diseases

Dear Editor-in-Chief
 
Based on recent studies, it is now clear that there is a muscle–brain endocrine loop that can be partly mediated by myokine signaling. There are also other metabolites as mediators which can affect circulating compounds (Rai & Demontis, 2016) and these include noncoding RNAs (Makarova et al., 2014), hormone-associated responses, as well as, muscular enzymes (Pedersen, 2019). Brain-Derived Neurotrophic Factor (BDNF) is considered to be a key role in helping to mediate the impacts of exercise on the hippocampus (Loprinzi & Frith, 2019). Studies conducted on laboratory rats showed an increase in BDNF mRNA and BDNF protein in the hippocampus of these animals when wheel running exercise was performed for 1 to 8 weeks (Adlard, Perreau, & Cotman, 2005; Farmer et al., 2004; Liu & Nusslock, 2018; Neeper, Góauctemez-Pinilla, Choi, & Cotman, 1995; Oliff, Berchtold, Isackson, & Cotman, 1998; Van Hoomissen, Chambliss, Holmes, & Dishman, 2003). In terms of cognitive functions, i.e. memory and learning, BDNF has also been demonstrated to be effective in the improvement of such functions (Vaynman, Ying, & Gomez‐Pinilla, 2004; Vaynman, Ying, & Gómez‐Pinilla, 2004).
Research on humans indicates that their brains can release BDNF while cycling (Rasmussen et al., 2009; Seifert et al., 2010), also in another study in healthy people as well as people with schizophrenia who had been training in aerobic exercise for three months, the level of BDNF increased in their hippocampus by 12% and 16%, respectively (Pajonk et al., 2010). As a growth factor for the hippocampus, BDNF plays a significant role in learning and improving cell survival (Wrann et al., 2013). Interestingly enough, research findings show that BDNF can also be expressed in skeletal muscle tissues during exercise in humans; nonetheless, it is not clear whether muscle-derived BDNF can get into the bloodstream from the muscle to create a direct interaction between muscle and brain (Matthews et al., 2009).
Some fascinating studies indicate that irisin and myokines cathepsin-B might cross the (BBB) blood-brain barrier, and consequently, BDNF levels may increase. In recent a study conducted by Moon et al. (Moon et al., 2016) a novel myokine, cathepsin B (CTSB) was identified. Other work also demonstrated that exercise can increase CTSB systemic level, therefore, BDNF expression will be promoted in the hippocampus and lead to the formation of nerve tissue as well. Running on a treadmill for four months increased CTSB plasma levels, as well as CTSB gene expression in humans, mice, and rhesus monkeys. In addition, it was indicated that CTSB could cross BBB in mice. In studies by Moon et al. (2016) on CTSB knockout mice, it was made clear that mice without CTSB refused to do voluntary exercise regarding hippocampal growth and cognitive development. It is not clear whether myokine CTSB can lead to cognitive function development in humans regarding exercise training or not (Moon et al., 2016; Suzuki, 2016).
The PGC-1α-dependent myokine irisin, which is famous for its browning impacts (Boström et al., 2012), can play a role in the intervention of the brain’s physical activity (Wrann et al., 2013). An excessive expression of irisin in the primary cortical neurons can cause a higher BDNF expression, while FNDC5 knockdown mediated by RNAi can cause a lower BDNF expression. Furthermore, irisin delivery to the mice’s liver by adenoviral vectors will raise the systemic irisin level, consequently resulting in a higher level of BDNF in the hippocampus. Whether doing exercise can increase irisin plasma concentration in humans (Albrecht et al., 2015; Wrann, 2015), and whether irisin is affected by a muscle–brain endocrine loop is a disputable issue.