Exercise can help reduce symptoms of depression, and new evidence points to a specific protein released by muscles as the main reason. Recent research published in molecular psychiatry It has been suggested that a protein called apelin travels from muscles during exercise to the brain to promote neuron growth and improve mood. This discovery improves our 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 loss of interest in rewarding activities. Medical professionals often recommend exercise as a natural way to reduce these symptoms. Exercise tends to improve mental health by promoting changes in the hippocampus, a brain region involved in mood regulation and memory.
Older people who experience age-related muscle loss, a condition known as sarcopenia, are often at increased risk for mental health conditions. Associate Professor Sonata Sok-Yu Yau of the School of Rehabilitation Sciences at the Hong Kong Polytechnic University said, “Sarcopenia is strongly associated with depression and cognitive decline in the elderly, and there is growing interest in muscle-secreted factors that affect hippocampal function.”
During physical activity, muscles release certain 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. Apelin is naturally produced by skeletal muscle and becomes even more abundant during exercise.
“Because exercise counters both muscle atrophy and depression, we investigated the exercise-induced factor apelin, which may mediate exercise-induced brain health,” Yau said. Previous observations have noted 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 people.
To investigate this process, scientists designed a series of experiments using male mice. In the first stage, groups of 6-week-old mice were exposed to a mild, unpredictable stress routine for four weeks to induce depression-like behavior. The researchers then gave some of the stressed mice a running wheel and allowed them to exercise voluntarily for an additional four weeks.
The research team used three specific behavioral assessments to measure the animals’ moods. The first was a sucrose preference test, which assessed anhedonia, or the inability to feel pleasure, by determining whether the mice preferred sugar water over plain water. The second assessment was the splash test, which measured the amount of time the animals spent grooming, as decreased grooming indicates depression.
The third assessment was a forced swim test, in which mice were placed in a small tank of water and the time they remained motionless was measured. This serves as a standard method to assess despair behavior in animal models. Stressed mice that did not exercise had a lower preference for sugar, spent less time grooming, and were more immobile.
In contrast, mice that used the wheel showed improved mood in all three behavioral tests. When researchers examined the blood and brain tissue of mice during exercise, they found that levels of apelin increased. They also found that the calf and shin muscles of the hindlimbs, particularly the gastrocnemius and tibialis anterior muscles, were the main sources of this protein.
The scientists then bred genetically modified mice that lacked the ability to produce apelin specifically in their muscle tissue. These genetically modified mice participated in the same four-week running program as normal mice. Mice lacking muscle apelin showed no improvement in depression-like behavior after running. They also did not see an increase in the growth of newborn brain cells, a process called adult neurogenesis.
To see if apelin alone could replicate the effects of exercise, the researchers injected a special virus into the leg muscles of stressed mice. This virus is designed to cause muscle cells to produce large amounts of apelin even without exercise. Mice with artificially increased apelin levels showed the same improved mood and brain cell growth as mice that ran on wheels.
The researchers confirmed that apelin produced in the muscles crossed the blood-brain barrier and reached the hippocampus. They then looked at the exact chemical pathways in the brain to see how apelin exerts its effects. They focused on apelin receptors, known as APJs, located on the surface of certain neurons in the hippocampus.
“Apelin increases glutamatergic transmission in hippocampal neurons through a new pathway,” Yau explained. Glutamatergic transmission refers to the way nerve cells send signals to each other using glutamate, the nervous system’s main chemical messenger.
Using advanced electrical recording techniques, scientists discovered that high apelin levels strengthen 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 with learning, memory, and mood management.
The researchers then used a different targeted virus to specifically reduce the number of APJ receptors in the ventral region of the hippocampus. When these genetically modified mice ran on wheels, they didn’t see any improvement in mood or growth in brain cells.
Finally, the team investigated the internal cellular mechanisms that link APJ receptors to N-methyl-D-aspartate receptors. They discovered that an enzyme called casein kinase 2 acts as a bridge between the two. This enzyme helps activate the receptor, which turns on a downstream signaling protein called calpain-2 to build stronger neural connections.
When the researchers gave mice a specific compound that inhibits casein kinase 2, apelin’s positive effects disappeared. This indicates that apelin is required to activate this particular enzyme to improve brain cell function and reduce depression-like behavior.
The findings of this study have several limitations that require future investigation. “Although this study was limited to adult male mice, future validation in female, elderly, and human cohorts is essential,” Professor Yau noted. “This is particularly important because gender differences in muscle mass can influence both exercise responses and susceptibility to depression.”
Female mice experience a variety of hormonal fluctuations involving hormones such as estrogen and progesterone, which can independently influence brain plasticity and mood. Women’s bodies also generally have different muscle mass ratios compared to men’s. This physiological difference can change how much apelin is produced and secreted into the bloodstream during exercise.
Another limitation involves the specific type of apelin used in the experiment. Apelin protein can be broken down in the body into several different active forms, including apelin-13 and apelin-36. The authors did not identify the exact version of the apelin protein most responsible for the brain effects observed after exercise.
Researchers also point out that memory and learning share the same brain pathways as mood regulation. This experiment only tested for depression-like behaviors, so it’s possible that muscle-derived apelin also improves general cognitive function. Exploring how apelin affects learning and memory may expand the possibility of its application in the treatment of age-related cognitive decline.
The findings highlight a concrete link between physical fitness and mental health. “Maintaining muscle strength and function is the key to preventing depression, and one of the best ways is regular exercise training,” Yau said.
He added that the team has concrete plans to continue this line of research. “Our next step is to study potential ways to increase muscle strength that result in increased apelin secretion,” Yau said.
The study, “How muscles interact with the brain: Apelin protein mediates exercise-induced antidepressant effects,” was contributed 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. Written by Abel, Wing-Hoi Cheung, and Kangguang. Lin, Aiming Xu, Kenneth King-Yip Chen, and Sok-Yu Yau.
