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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.

Key points

  • Exercise can indirectly be sensed by the brain via adipose tissue (adiponectin) or the liver (fibroblast growth factor 21 and insulin-like growth factor 1).

  • Myokines mediate muscle–organ crosstalk to the liver, gut, pancreas, adipose tissue, bone, vascular bed, skin and brain.

  • Cathepsin B is an exercise-induced myokine required for exercise-induced improvement in memory and adult neurogenesis.

  • Exercise enhances neuronal gene expression of FNDC5, the protein product of which might stimulate brain-derived neurotrophic factor in the hippocampus.

  • Serum levels of the myokine IL-6 increase with exercise, and this myokine might regulate central mechanisms for food intake.

  • Exercise increases muscular expression of kynurenine aminotransferases, which convert blood levels of neurotoxic kynurenine to the neuroprotective kynurenic acid, thereby reducing depression-like symptoms.

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Fig. 1: Ways in which exercise might beneficially affect neurogenesis, learning, memory, mood and depression-like symptoms.


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The Centre for Physical Activity Research (CFAS) is supported by a grant from TrygFonden. The author also thanks Alzheimer-forskningsfonden for support.

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Nature Reviews Endocrinology thanks M. Grounds, S. Schiaffino and other anonymous reviewer(s) for their contribution to the peer review of this work.

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Correspondence to Bente Klarlund Pedersen.

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Physical activity

Any bodily movement produced by skeletal muscles that requires energy expenditure.

Moderate-to-vigorous physical activity

Any activity with an energy expenditure of ≥3 metabolic equivalents (for example, brisk walking); the WHO minimum recommendations are 150 min of moderate-to-vigorous physical activity each week (or 20 min or 10,000 steps on most days of the week) for adults and 60 min of active playing on most days of the week for children and adolescents.

Aerobic exercise

Exercise involving dynamic movements and large muscle groups that predominantly rely on aerobic metabolism for fuelling muscle contractions; examples include jogging, running, swimming and rowing.

Resistance training

Movement performed against a specific external force that is regularly increased during training; examples include weightlifting and exercises using resistance machines.

Exercise training

A subset of physical activity that is planned, structured and repetitive and has a final or intermediate objective of improving or maintaining physical fitness. The terms ‘exercise’ and ‘exercise training’ are used interchangeably to refer to the cardiovascular adaptations produced by this specific type of physical activity; a single bout of exercise is referred to as ‘acute exercise’.


Cytokines or peptides produced by skeletal muscle cells and subsequently released into the circulation, where they exert autocrine, paracrine or endocrine effects in other cells, tissues or organs.


Browning can be defined as any substantial increase in the expression of uncoupling protein 1 (UCP1) at the mRNA level occurring in what is normally considered as a white adipose tissue depot. The resulting brown adipocytes that express UCP1 and appear in white adipose tissue are referred to as beige, brite, convertible, ectopic, inducible or recruitable.


Derived from the Greek sarx (‘flesh’) and penia (‘loss’), sarcopenia is the age-induced loss of muscle mass and function that typically manifests as reduced gait speed.

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Pedersen, B.K. Physical activity and muscle–brain crosstalk. Nat Rev Endocrinol 15, 383–392 (2019).

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