Your calf muscles may be doing more than helping you walk. They could be talking to your brain through a protein that may influence mood and trigger the growth of new neurons

It has long been established that physical exercise influences not only muscles, bones and the cardiovascular system but also sleep, memory and mood. Physical exercise is even related to a decreased chance of depression.

However, there is a recent study that shows how exactly this process might occur.

It was found that there is a protein called apelin, which is responsible for sending a message about physical exercise performed by leg muscles to the brain. This means that the muscles exercised in running could send signals to the brain via blood and thus affect neurons in the hippocampus that control memory and mood.


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This research was conducted by Sonata Suk-Yu Yau at Hong Kong Polytechnic University. It was recently published in the journal Molecular Psychiatry.

Although the research was performed on mice, it does not mean that this process is the one responsible for the antidepressant effect in humans.

However, this is what makes a better understanding of the biological pathway that starts with muscle activity and ends up in some molecular change in the brain that responds to stress.

The signal begins in the lower leg

To investigate the relationship between exercise and mood, researchers first exposed male mice to four weeks of chronic unpredictable stress.

The animals subsequently displayed behaviours commonly used in laboratory studies to model depression-like states. They showed less interest in sugar water, groomed themselves less and gave up more quickly during swimming tests.

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The researchers then gave some of the animals access to running wheels for another four weeks.

The behavioural changes were accompanied by a rise in apelin, both in the bloodstream and in the hippocampus. Researchers traced much of the exercise-related apelin production to two muscles in the lower leg: the gastrocnemius, which forms much of the calf, and the tibialis anterior, which runs along the front of the shin.

That finding shifts attention away from exercise as a vague "feel-good" activity and towards a measurable biological signal.

The researchers were able to follow that signal from contracting muscles into the circulation and eventually to the brain.

Apelin carries the message into the brain

The next question was whether apelin was simply associated with the effects of running or whether it was actually necessary for them.

The researchers used genetic techniques to remove apelin production from the muscles of some mice. Although these animals could still run, the exercise no longer produced the same behavioural improvements or increase in the formation of new neurons.

The opposite experiment produced an equally striking result.

Scientists used a viral vector to increase apelin production in the leg muscles of mice that did not exercise. Those animals showed behavioural changes similar to those seen in exercising mice, along with increased neuronal growth.

The findings pointed to apelin as an important part of the muscle-brain pathway.

According to the study, circulating apelin can cross the blood-brain barrier and interact with APJ receptors on hippocampal neurons. That interaction activates a series of molecular events inside the cells.

The pathway involves casein kinase 2, which modifies NMDA receptors involved in communication between neurons. Further downstream, calpain-2 is implicated in changes to synapses and the growth of new neurons.

Blocking the APJ receptor or casein kinase 2 prevented the exercise-related behavioural effects in the experiments.

Why new neurons matter for mood

Besides the well-known functions related to learning and memory, the hippocampus is also responsible for the brain’s response to stress and for mood regulation.

One of the recent areas of interest has been adult neurogenesis – the formation of new nerve cells in mature brain regions.

Changes in hippocampal neurogenesis in response to physical activity have already been demonstrated; however, the biological mechanism behind the effect is still being investigated.

In the new research, the process has been linked to a particular signal produced in the skeletal muscle.

Exercise resulted in increasing apelin levels in the hippocampus together with neurogenesis-related changes in male mice. In the case where the apelin signalling pathway was blocked, these changes disappeared.

This does not mean that apelin is simply a “switch” turning on/depressing depression. Human depression is a complicated disease that involves genetic factors, brain circuitry, environment, stress, sleep and many other elements.

Moreover, this research is not the proof that taking apelin will help people with depression because the experiments were performed on mice.

However, this study gives an explanation for one of the components of the puzzle linking exercise and the brain.

Could muscle health affect the brain?

The results also bring up the problem of what might happen in case of muscle mass decrease.

The problem of muscle mass decrease and low physical activity becomes more frequent with the increase of the age. Connections have been found between poor muscle condition and depression among the elderly.

One of the reasons can be the fact that skeletal muscle is not only a mechanical tissue, but also a source of different molecules, which can affect other organs. Apelin can be one of these molecules, participating in the exchange between active muscles and the brain.

This issue becomes especially important, since it is possible that the positive effect of exercising is not unidirectional. On the one hand, the brain gives the signal to muscles; on the other hand, active muscles release certain molecules influencing the brain.

The results of the research do not state that there is a method of treating depression with apelin, or how many exercises are needed to get similar results in humans.

In general, the message is quite simple: the next time you feel burning in calf muscles while running or walking fast, its effects might go far beyond the muscles themselves.

FAQ

1. What is apelin?

Apelin is a signalling protein made in different tissues, such as the skeletal muscles. In the new mouse study, it has been shown that exercise of leg muscles caused higher levels of apelin in relation to the hippocampus.

2. How do the calf muscles interact with the brain?

It has been suggested in the study that physical exercise of muscles causes the release of apelin into the blood, which gets to the brain and binds to APJ receptors in the hippocampal neurons, causing a number of molecular reactions.

3. Could exercise improve symptoms of depression?

Exercise has been reported to have positive effects on mood and is included in complex treatments of depression. Nevertheless, this specific study was done on mice and cannot demonstrate that apelin or physical exercise can treat human depression.

4. Is there any proof that apelin can treat depression?

There is no proof because the current study has revealed a possible biological mechanism of interaction between muscle activity and brain alterations, but further human studies should be carried out.