时钟基因Rev-erbα在运动诱导线粒体生物合成中的作用及可能机制

Role and Possible Mechanism of Clock Gene Rev-erbαin Exercise-induced Mitochondrial Biogenesis

线粒体生物合成是细胞适应能量需求、维持能量稳态的重要手段,其过程受到生物钟系统的全局调控。作为机体的能量供应站点,线粒体生物合成障碍与各种疾病的发生发展密切相关。时钟基因Rev-erbα能整合昼夜节律与能量代谢,在调节线粒体生物合成过程中起到了重要作用。运动作为一种行之有效的改善健康、促进恢复的非药用方式,不仅能促进线粒体生物合成增强,还与Rev-erbα存在着双向调节,因此考虑Rev-erbα可能是运动诱导线粒体生物合成的中介物质。本文就Rev-erbα在调节线粒体生物合成中的作用、影响Rev-erbα的可能因素、运动与Rev-erbα的相互作用及运动通过Rev-erbα诱导线粒体生物合成的潜在机制进行了梳理和探讨,以期为运动促进线粒体生物合成机制提供理论参考。

The clock gene Rev-erbα,also known as nuclear receptor subfamily 1 group D member 1(Nr1d1),is a crucial regulatory factor in organisms.It exhibits circadian rhythmic expression in metabolically active tissues such as skeletal muscles,heart,liver,and adipose tissue,responding to various environmental stimuli.Rev-erbαplays a significant role in regulating circadian rhythms,metabolic homeostasis,and other physiological processes,earning its designation as an“integrator”of the circadian system and metabolism.Rev-erbαestablishes complex connections with other clock genes through the transcriptional-translational feedback loop(TTFL),which is important for the rhythmic output of biological clock system and for the relative stability of phases and cycles.Mitochondrial biogenesis is a physiological process initiated by cells to maintain energy homeostasis by using existing mitochondria as a template for self-growth and division.As the“energy factory”of organism,disruptions in mitochondrial biogenesis are closely associated with the development of various diseases.Studies have shown that not only the factors involved in mitochondrial biogenesis have circadian oscillations,but also the morphology,dynamics and energy metabolism of mitochondria themselves have cyclic fluctuations throughout the day,suggesting that mitochondrial biogenesis is regulated by the biological clock system,in which the clock gene Rev-erbαplays a key role,it drives mitochondrial biogenesis and synergistically regulates autophagy to normalize a number of physiological processes in the body.Rev-erbαis sensitive to both internal and external environmental changes,and disruptions in circadian rhythms,metabolic diseases,and aging are significant inducers of changes in Rev-erbαexpression,and its concomitant inflammation and oxidative stress may be an intrinsic mechanism for inhibiting mitochondrial biogenesis.Therefore,the enhancement of mitochondrial biogenesis by regulating the Rev-erbαactivity status may be an important way to improve the pathology and promote the health of organism.Exercise,as a commonly accepted non-pharmacological tool,plays an important role in enhancing mitochondrial biogenesis and promoting health.It has been found that there is a close relationship between exercise and Rev-erbα.On the one hand,exercise stimulation directly affects the expression of Rev-erbα,especially high-intensity and long-term regular exercise;on the other hand,Rev-erbαachieves indirect regulation of exercise capacity by mediating processes such as skeletal muscle mitochondrial biogenesis and autophagy,muscle mass maintenance,energy metabolism and skeletal muscle regeneration.Based on the above findings,it is hypothesized that Rev-erbαmay serve as a key bridge between exercise and mitochondrial biogenesis.Exercise enhances the transcriptional response of Rev-erbαin the nucleus,upregulates the expression of Rev-erbαprotein in cytoplasm,activates the AMP-activated proteinkinase(AMPK)/silent information regulator 1(SIRT1)/peroxisome proliferator-activated receptorγcoactivator-1α(PGC-1α)pathway,regulates Ca2+flux and downstream signaling molecules;meanwhile,exercise can upregulate antioxidant gene expression and alleviate oxidative stress through Rev-erbα,which ultimately enhances the function of mitochondria,and promotes mitochondrial biogenesis.In conclusion,the clock gene Rev-erbαemerges as a crucial target for exercise-induced enhancement of mitochondrial biogenesis.In this paper,the biological characteristics of Rev-erbα,the role of Rev-erbαin regulating mitochondrial biogenesis and the factors that may influence it,the interaction between exercise and Rev-erbα,and the potential mechanism of exercise-induced mitochondrial biogenesis via Rev-erbαare sorted out and discussed,which can provide theoretical references to the mechanism of exercise-promoted mitochondrial biogenesis.