Molecular Mechanisms Underlying the Beneficial Effects of Exercise on Brain Function and Neurological Disorders

Abstract

As life expectancy has increased, particularly in developed countries, due to medical advances and increased prosperity, age-related neurological diseases and mental health disorders have become more prevalent health issues, reducing the well-being and quality of life of sufferers and their families. In recent decades, due to reduced work-related levels of physical activity, and key research insights, prescribing adequate exercise has become an innovative strategy to prevent or delay the onset of these pathologies and has been demonstrated to have therapeutic benefits when used as a sole or combination treatment. Recent evidence suggests that the beneficial effects of exercise on the brain are related to several underlying mechanisms related to muscle-brain, liver-brain and gut-brain crosstalk. Therefore, this review aims to summarize the most relevant current knowledge of the impact of exercise on mood disorders and neurodegenerative diseases, and to highlight the established and potential underlying mechanisms involved in exercise-brain communication and their benefits for physiology and brain function.

Keywords: Alzheimer’s disease; BDNF; Parkinson’s disease; brain; exercise; iron; microbiota.

Figure 1

Impact of exercise on mental and brain health.

Figure 2

Main mechanisms by which active skeletal muscle can impact the brain. (1) Cathepsin B transcription is upregulated in brain and skeletal muscle, and its concentration increases in the blood in response to exercise. Cathepsin B is able to cross the BBB and may induce BDNF transcription in hippocampal neurons. (2) During exercise, glycolysis converts glucose into pyruvate to produce ATP. Lactate is produced from this reaction and accumulates in the blood. Lactate can cross the BBB and activate the PGC1α/FNDC5 signalling pathway and promote BDNF expression. (3) Exercise increases the release of irisin into the circulation. Irisin can cross the BBB and/or trigger several signalling pathways (including the cAMP/PKA/CREB) to activate BDNF production. (4) Kynurenine aminotransferases are increased in ‘trained’ skeletal muscles. These enzymes convert Kyn into kynurenic acid (KynA). Consequently, peripheral Kyn-to-KynA conversion is increased and prevents the accumulation of Kyn and its related neurotoxic metabolites (3-hydroxykynurenine or quinolinic acid) in the brain.

Figure 3

Proposed mechanisms by which exercise can impact the gut microbiota–brain axis. Exercise promotes the development of beneficial bacteria species and increase bacterial diversity in the gut. This phenomenon may have several impacts on the gut microbiota–brain axis: (1) activation of the vagus nerve (VN), (2) activation of the HPA axis, (3) modulation of neurotransmitter metabolism (i.e., tryptophane (Tph) and serotonin (Ser), and/or (4) reduction of inflammation by SCFA production.