Roles of myokines in exercise-induced improvement of neuropsychiatric function.

Exercise is a well-known non-pharmacological intervention to improve brain functions, including cognition, memory, and motor coordination. Contraction of skeletal muscles during exercise releases humoral factors that regulate the whole-body metabolism via interaction with other non-muscle organs. Myokines are muscle-derived effectors that regulate body metabolism by autocrine, paracrine, or endocrine action and were reportedly suggested as "exercise factors" that can improve the brain function. However, several aspects remain to be elucidated, namely the specific activities of myokines related to the whole-body metabolism or brain function, the mechanisms of regulation of other organs or cells, the sources of "exercise factors" that regulate brain function, and their mechanisms of interaction with non-muscle organs. In this paper, we present the physiological functions of myokines secreted by exercise, including regulation of the whole-body metabolism by interaction with other organs and adaptation of skeletal muscles to exercise. In addition, we discuss the functions of myokines that possibly contribute to exercise-induced improvement of brain function. Among several myokines, brain-derived neurotrophic factor (BDNF) is the most studied myokine that regulates adult neurogenesis and synaptic plasticity. However, the source of circulating BDNF and its upstream effector, insulin-like growth factor (IGF-1), and irisin and the effect size of peripheral BDNF, irisin, and IGF-1 released after exercise should be further investigated. Recently, cathepsin B has been reported to be secreted from skeletal muscles and upregulate BDNF following exercise, which was associated with improved cognitive function. We reviewed the level of evidence for the effect of myokine on the brain function. Level of evidence for the association of the change in circulating myokine following exercise and improvement of neuropsychiatric function is lower than the level of evidence for the benefit of exercise on the brain. Therefore, more clinical evidences for the association of myokine release after exercise and their effect on the brain function are required. Finally, we discuss the effect size of the action of myokines on cognitive benefits of exercise, in addition to other contributors, such as improvement of the cardiovascular system or the effect of "exercise factors" released from non-muscle organs, particularly in patients with sarcopenia.