Muslce apelin mediates the antidepressant effects of physical exerise by enhancing adult hippocampal neurogenesis: the muscle-brain axis

Abstract

Physical exercise is well recognized for its potent antidepressant effects, but the underlying molecular mechanisms remain largely unclear. Sarcopenia, an ageing condition with muscle atrophy, is highly associated with a higher risk of developing depression in elderly. This study investigates the role of apelin, a novel myokine linked to sarcopenia, in modulating hippocampal neuroplasticity and its contribution to the antidepressant effects of exercise. Using a mouse model of depression induced by chronic unpredictable stress (CUS), it was found a significant reduction in the protein expression of apelin and its receptor (APJ) in the hippocampus. Remarkably, physical exercise in terms of voluntary wheel running for 4 weeks alleviated depression-like behavior, which is correlated with increased apelin and APJ protein expression and enhanced adult neurogenesis in the hippocampus. Running elevated mRNA expression levels of apelin in skeletal muscles, particularly the tibialis anterior (TA) and gastrocnemius (Gas) muscles, suggesting these muscles are primary sources of apelin secretion in response to running. Transgenic mice with skeletal muscle specific knockout of apelin with running did not exhibit antidepressant effects and enhancement in adult hippocampal neurogenesis, highlighting the dispensable role of myokine apelin in mediating the antidepressant effects of running. Furthermore, overexpression of apelin in the TA and Gas muscles via adeno-associated viral infection mimicked beneficial effects of running on reducing depression-like behavior and enhancing hippocampal neurogenesis and synaptic NMDA receptor-mediated neurotransmission. This was accompanied by increased phosphorylation of NMDA receptors. Additionally, knockdown of APJ in glutamatergic neurons of the ventral hippocampus diminished the antidepressant effects of running, highlighting the importance of apelin-APJ-mediated hippocampal plasticity. Since production of apelin is reduced by ageing, it was also found that muscle apelin deficiency in the transgenic mice accelerated age-related muscle atrophy and motor coordination impairment, but showed no effect on cognitive deficits or emotional dysregulation. These findings highlight the critical role of apelin in mediating the antidepressant effects of voluntary running and suggest its potential involvement in the muscle-brain crosstalk axis in depression.
 

Date of Award	19 Feb 2025
Original language	English
Awarding Institution	The Hong Kong Polytechnic University
Supervisor	Suk Yu Yau (Chief supervisor)