Sweat Signals: The Muscle Molecule That Carries Exercise’s Mood Boost to the Brain
The health benefits of regular exercise are well established, ranging from improved cardiovascular health and metabolic function to better sleep and blood pressure regulation. Exercise is also recognised as a promising non-pharmacological intervention for alleviating depressive symptoms. However, while its beneficial effects on mental health are widely acknowledged, the molecular mechanisms underlying communication between skeletal muscle and the brain remain incompletely understood.
During physical activity, contracting skeletal muscle releases small signalling proteins known as myokines, which can act locally or travel through the bloodstream to influence distant organs. These molecules are increasingly recognised as important mediators of muscle–brain communication. One such myokine is apelin, a protein whose expression increases in response to exercise and which has established roles in cardiovascular regulation, energy metabolism and muscle function. Emerging evidence also suggests that apelin has neuroprotective and antidepressant properties, including the ability to promote hippocampal neurogenesis and enhance synaptic function. However, the precise mechanisms through which muscle-derived apelin influences brain function and mood have remained unclear.
In a recent study published in Molecular Psychiatry in 2026, Yu and colleagues investigated whether exercise-induced apelin mediates the antidepressant effects of physical activity through the apelin receptor, APJ, in the brain. Using a mouse model of depression, the researchers explored how muscle-derived apelin influences hippocampal neuroplasticity and the molecular pathways involved in these effects.
To establish a model of depression-like behaviour, the researchers exposed mice to chronic unpredictable stress (CUS), a widely used experimental paradigm involving repeated exposure to different stressors. The stressed mice exhibited several depression-like behavioural changes, including reduced sucrose preference, decreased self-grooming and increased immobility in behavioural tests. Importantly, four weeks of voluntary wheel running alleviated these behavioural changes.
The researchers also observed that serum apelin levels were significantly reduced in stressed mice but increased following voluntary running. Higher serum apelin levels were associated with more favourable behavioural outcomes across several tests, suggesting a relationship between circulating apelin and the beneficial effects of exercise. Analysis of different tissues identified the gastrocnemius and tibialis anterior muscles of the hindlimb as important peripheral sources of exercise-induced apelin.
Muscle-derived apelin is essential for the antidepressant effects of exercise
To determine whether apelin released from skeletal muscle was directly responsible for these effects, the researchers generated mice in which apelin expression was selectively disrupted in skeletal muscle. Despite undertaking comparable amounts of voluntary running, these mice did not exhibit the same improvements in depression-like behaviours observed in control animals.
The researchers then investigated whether muscle-derived apelin influenced adult hippocampal neurogenesis, the process through which new neurons are generated in the adult brain. The hippocampus plays an important role in mood regulation, learning and memory, and exercise is known to promote neuroplasticity in this region.
Using Ki-67 as a marker of proliferating cells and doublecortin (DCX) as a marker of immature neurons, the researchers found that voluntary running increased both cell populations in the dentate gyrus of the hippocampus. These exercise-associated increases were absent in mice lacking muscle-derived apelin, indicating that apelin is required for the full neurogenic response to exercise in this model.
The researchers further demonstrated that increasing apelin expression specifically in skeletal muscle reproduced several of the beneficial effects of running. Using adeno-associated viral vectors to overexpress apelin in muscle, they observed increased apelin levels in both the bloodstream and hippocampus, alongside improvements in selected depression-like behavioural measures and increased hippocampal neurogenesis. These findings provide further evidence that muscle-derived apelin acts as a mediator of exercise-induced brain adaptations.
How does apelin influence neuronal function?
Having established the importance of muscle-derived apelin, the researchers investigated how it influences neuronal communication within the hippocampus.
Their findings indicated that apelin enhances excitatory synaptic transmission, particularly through N-methyl-D-aspartate receptors (NMDARs), which are glutamate receptors that play a central role in synaptic plasticity. These receptors are important for strengthening connections between neurons and supporting processes involved in learning, memory and mood regulation.
To investigate the role of the APJ receptor in this process, the researchers selectively reduced APJ expression in glutamatergic neurons in the ventral hippocampus. This intervention attenuated the antidepressant-like effects of voluntary running and prevented the associated increases in hippocampal neurogenesis. These findings suggest that the interaction between apelin and APJ in hippocampal neurons is a key component of the brain's response to exercise.
The apelin–APJ signalling pathway: From muscle contraction to hippocampal plasticity
One of the study's most important contributions was the identification of a molecular pathway linking muscle-derived apelin to changes in neuronal function.
The researchers found that apelin–APJ signalling increased the activity of casein kinase 2 (CK2), an enzyme involved in cellular signalling. CK2 promoted phosphorylation of the GluN2B subunit of the NMDA receptor at a specific site, serine 1480 (S1480), thereby enhancing NMDAR function. This signalling cascade was also associated with increased expression of calpain-2, a calcium-activated protease implicated in synaptic remodelling.
Importantly, inhibiting CK2 attenuated several of the antidepressant-like effects associated with muscle apelin overexpression and exercise. Together, these findings support a model in which exercise stimulates apelin release from skeletal muscle, circulating apelin reaches the brain and activates APJ receptors, and downstream CK2 and calpain-2 signalling contributes to enhanced hippocampal synaptic plasticity and neurogenesis.
What do these findings mean for future depression research?
This study provides important mechanistic evidence that skeletal muscle is more than a tissue responsible for movement: it can also communicate with the brain through signalling molecules released during exercise. By identifying apelin as a mediator of exercise-induced antidepressant-like effects in mice, the researchers have uncovered a potential therapeutic target for future depression research.
Nevertheless, these findings should be interpreted in the context of the experimental model. The study was conducted in male mice, and further research is needed to establish whether the same mechanisms operate in females and humans. The authors note that oestrogen tends to increase apelin/APJ signalling while progesterone suppresses it, and that hormonal cycles affect synaptic plasticity. Women are roughly twice as likely to experience depression and, on average, carry less muscle mass. Whether women produce comparable apelin in response to exercise, and whether that response shifts across the menstrual cycle, pregnancy, postpartum or the menopause transition, is entirely unknown. This matters most in perimenopause, when falling oestrogen coincides with accelerated muscle loss and a recognised rise in depression risk. A muscle–apelin–mood axis could be one biological thread connecting these changes, but until female animals and women are studied, that remains a hypothesis.
Ultimately, the study advances our understanding of the muscle–brain axis and highlights the potential of exercise-responsive myokines as targets for developing novel therapeutic strategies. Further investigation of apelin and its downstream signalling pathways may help clarify how physical activity influences brain health and could, in time, inform new approaches to treating depression.
Reference
Yu J, Cheng T, Guo H, Song Z, Zhong Y, Lee TH, Li J, Formolo DA, Hussain A, Le K, Yao Y, Abel RL, Cheung WH, Lin K, Xu A, Cheng KK, Yau SY. How muscle talks to brain: apelin protein mediates exercise-induced antidepressant effects. Mol Psychiatry. 2026 Oct;31(10):5692-5706. doi: 10.1038/s41380-026-03651-y. Epub 2026 May 14. PMID: 42135522; PMCID: PMC13569424.
