Physical activity and muscle–brain crosstalk

Neurological and mental illnesses account for a considerable proportion of the global burden of disease. Exercise has many beneficial effects on brain health, contributing to decreased risks of dementia, depression and stress, and it has a role in restoring and maintaining cognitive function and metabolic control. The fact that exercise is sensed by the brain suggests that muscle-induced peripheral factors enable direct crosstalk between muscle and brain function. Muscle secretes myokines that contribute to the regulation of hippocampal function. Evidence is accumulating that the myokine cathepsin B passes through the blood–brain barrier to enhance brain-derived neurotrophic factor production and hence neurogenesis, memory and learning. Exercise increases neuronal gene expression of FNDC5 (which encodes the PGC1α-dependent myokine FNDC5), which can likewise contribute to increased brain-derived neurotrophic factor levels. Serum levels of the prototype myokine, IL-6, increase with exercise and might contribute to the suppression of central mechanisms of feeding. Exercise also increases the PGC1α-dependent muscular expression of kynurenine aminotransferase enzymes, which induces a beneficial shift in the balance between the neurotoxic kynurenine and the neuroprotective kynurenic acid, thereby reducing depression-like symptoms. Myokine signalling, other muscular factors and exercise-induced hepatokines and adipokines are implicated in mediating the exercise-induced beneficial impact on neurogenesis, cognitive function, appetite and metabolism, thus supporting the existence of a muscle–brain endocrine loop. Exercise has many beneficial effects on brain health, but how exercise is sensed by the brain has not been well understood. This Review describes evidence that supports the existence of a muscle–brain endocrine loop, in which muscle-induced peripheral factors enable direct crosstalk between muscle and brain.