APELIN AS A NOVEL MEDIATOR OF ANTIDEPRESSANT EFFECTS OF PHYSICAL EXERCISE

Abstract Physical exercise is known to be the best effective antidepressant for depression; however, its underlying mechanism is still largely unknown. Identifying the molecular mechanisms underlying the antidepressant effect of physical exercise can provide therapeutic targets for treating depression. Apelin, a novel myokine linked to sarcopenia, can elicit antidepressant effects and influence hippocampal neuroplasticity in rodent studies. Physical exercise in humans is effective in preventing both sarcopenia and depression. A recent study has shown that physical exercise counteracts sarcopenia by restoring decrease in apelin levels of aged mice and humans, suggesting the important role of apelin in both sarcopenia and depression. By using a mouse model of depression induced by chronic unpredictable stress (CUS), here we found that stressed mice showed significantly decreased protein expression of apelin and its receptor (APJ) in the hippocampus, whereas 4-weeks voluntary exercise rescued depression-like behaviour in association with increased Apelin/APJ levels and neurogenesis in the hippocampus, and lower limb muscles including gastrocnemius (Gas), and tibialis anterior (TA) of stressed mice. Specific knockout of Apelin in skeletal muscle attenuated the antidepressant effect of voluntary exercise, suggesting the key role of apelin in mediating the antidepressant effect of physical exercise. In contrast, overexpression of apelin in Gas and TA muscles mimicked antidepressant effects of physical exercise in the CUS mouse model. These data suggest that the potential role of apelin mediating the crosstalk of the muscle-brain axis on sarcopenia-associated depression, and provide a novel potential therapeutic target for treating geriatric depression.