Scientists discover how exercising muscles communicate with the brain to fight depression

Physical exercise helps relieve symptoms of depression, and new evidence points to a specific protein released by muscles as a primary reason why. A recent study published in Molecular Psychiatry suggests that a protein called apelin travels from exercising muscles to the brain to enhance neuron growth and improve mood. This discovery offers a better understanding of how the body and mind interact during physical activity.

Major depressive disorder is a severe mental health condition characterized by persistent low mood and a loss of interest in rewarding activities. Medical professionals often recommend physical exercise as a natural way to alleviate these symptoms. Exercise tends to improve mental health by promoting changes in the hippocampus, a brain region involved in mood regulation and memory.

Older adults experiencing age-related muscle loss, a condition known as sarcopenia, often have an increased risk of mental health conditions. “Sarcopenia is significantly linked to depression and cognitive decline in older adults, prompting interest in muscle-secreted factors that influence hippocampal function,” said Sonata Suk-yu Yau, an associate professor in the Department of Rehabilitation Sciences at the Hong Kong Polytechnic University.

During physical activity, muscles release specific proteins known as myokines into the bloodstream. These proteins act as messengers that travel to different parts of the body, including the brain. One such protein is apelin, which is naturally produced by skeletal muscles and becomes more abundant during physical exertion.

“Since physical exercise counteracts both muscle atrophy and depression, we therefore investigated the exercise-induced factor apelin as a potential mediator of exercise-induced brain health,” Yau said. Prior observations note that older adults with sarcopenia tend to have lower levels of apelin in their blood. Providing apelin supplements has been shown to improve muscle function in these individuals.

To explore this process, the scientists designed a series of experiments using male mice. In the first phase, they exposed groups of six-week-old mice to a mild, unpredictable stress routine for four weeks to induce depression-like behaviors. The researchers then gave some of these stressed mice access to a running wheel for voluntary exercise over another four weeks.

The team measured the animals’ mood using three specific behavioral assessments. The first was a sucrose preference test, which evaluates anhedonia, or the inability to feel pleasure, by seeing if the mice prefer sugar water over plain water. The second evaluation was a splash test, which measured how much time the animals spent grooming themselves, as reduced grooming indicates a depressed state.

The third evaluation was a forced swim test, which measured how long the mice remained immobile while placed in a small tank of water. This acts as a standard way to assess behavioral despair in animal models. The stressed mice that did not exercise showed a low sugar preference, less grooming time, and high immobility.

In contrast, the mice that had access to running wheels displayed improved mood in all three behavioral tests. When the researchers examined the blood and brain tissue of the exercising mice, they found elevated levels of apelin. They also determined that the calf and shin muscles of the hind legs, specifically the gastrocnemius and tibialis anterior muscles, were the primary sources of this protein.

Next, the scientists bred genetically modified mice that lacked the ability to produce apelin specifically in their muscle tissues. These genetically modified mice participated in the same four-week running program as the normal mice. The mice without muscle apelin showed no improvement in their depression-like behaviors after running. They also lacked any increase in the growth of newborn brain cells, a process called adult neurogenesis.

To see if apelin alone could replicate the benefits of exercise, the researchers injected a specialized virus into the leg muscles of stressed mice. This virus was designed to force the muscle cells to produce high amounts of apelin without any physical exercise. The mice with artificially high apelin levels showed the same mood improvements and brain cell growth as the mice that had been running on wheels.

The researchers confirmed that the apelin produced in the muscles successfully crossed the blood-brain barrier to reach the hippocampus. They then examined the precise chemical pathways in the brain to see how apelin exerts its effects. They focused on the apelin receptor, known as APJ, which sits on the surface of specific nerve cells in the hippocampus.

“Apelin increases glutamatergic transmission in the hippocampal neurons through a novel pathway,” Yau explained. Glutamatergic transmission refers to the way nerve cells send signals to one another using glutamate, which is a primary chemical messenger in the nervous system.

Using advanced electrical recording techniques, the scientists found that high apelin levels strengthened these connections between nerve cells. Specifically, apelin enhanced the function of N-methyl-D-aspartate receptors. These receptors are specialized docking sites on brain cells that help manage learning, memory, and mood.

The researchers then used another targeted virus to specifically reduce the number of APJ receptors in the ventral region of the hippocampus. When these genetically altered mice ran on their wheels, they did not experience any mood improvements or brain cell growth.

Finally, the team explored the internal cell machinery that links the APJ receptor to the N-methyl-D-aspartate receptor. They found that an enzyme called Casein Kinase 2 acts as a bridge between the two. The enzyme helps activate the receptor, which then turns on a downstream signaling protein called calpain-2 to build stronger neural connections.

When the researchers gave the mice a specific chemical compound to block Casein Kinase 2, the positive effects of apelin vanished. This indicates that apelin must activate this specific enzyme to improve brain cell function and alleviate depression-like behaviors.

The findings come with a few limitations that warrant future investigation. “While this study was limited to adult male mice, future validation in female, aged, and human cohorts is essential,” Yau noted. “This is particularly important because sex-based differences in muscle mass may influence both exercise response and depression susceptibility.”

Female mice experience different hormonal fluctuations, involving hormones like estrogen and progesterone, which can independently influence brain plasticity and mood. Female bodies also generally have different muscle mass ratios compared to males. This physiological difference might alter how much apelin is produced and secreted into the bloodstream during exercise.

Another limitation involves the specific type of apelin used in the experiments. The apelin protein can be broken down into several different active forms in the body, such as apelin-13 or apelin-36. The authors did not identify which exact version of the apelin protein is the most responsible for the observed brain benefits following physical exercise.

The researchers also point out that memory and learning share the same brain pathways as mood regulation. Because the experiments only tested for depression-like behaviors, it is possible that muscle-derived apelin also improves general cognitive functions. Exploring how apelin affects learning and memory could expand its potential use for treating age-related cognitive decline.

The findings highlight a tangible link between physical fitness and mental health. “Maintaining muscle strength and function is the key to prevent depression, and one of the best ways is with regular exercise training,” Yau said.

She added that the team has specific plans to continue this line of research. “Our next steps are to study the potential ways of increasing muscle strength resulting in increased apelin secretion,” Yau said.

The study, “How muscle talks to brain: apelin protein mediates exercise-induced antidepressant effects,” was authored by Jiasui Yu, Tong Cheng, Huihui Guo, Zhiping Song, Yunxiao Zhong, Thomas Ho-yin Lee, Jiyang Li, Douglas A. Formolo, Akhlaq Hussain, Kai Le, Yuxuan Yao, Richard L. Abel, Wing-Hoi Cheung, Kangguang Lin, Aimin Xu, Kenneth King-Yip Cheng, and Suk-Yu Yau.