About two thousand years ago,Hippocrates observed that“walking is man's best medicine”[1],a notion increasingly validated in modern society.The benefits of physical activity in preventing chronic diseases and in...About two thousand years ago,Hippocrates observed that“walking is man's best medicine”[1],a notion increasingly validated in modern society.The benefits of physical activity in preventing chronic diseases and in improving longevity have been extensively studied[2].展开更多
Adult hippocampal neurogenesis(AHN)is affected by multiple factors,such as enriched environment,exercise,ageing,and neurodegenerative disorders.Neurodegenerative disorders can impair AHN,leading to progressive neurona...Adult hippocampal neurogenesis(AHN)is affected by multiple factors,such as enriched environment,exercise,ageing,and neurodegenerative disorders.Neurodegenerative disorders can impair AHN,leading to progressive neuronal loss and cognitive decline.Compelling evidence suggests that individuals engaged in regular exercise exhibit higher production of proteins that are essential for AHN and memory.Interestingly,specific molecules that mediate the effects of exercise have shown effectiveness in promoting AHN and cognition in different transgenic animal models.Despite these advancements,the precise mechanisms by which exercise mimetics induce AHN remain partially understood.Recently,some novel exercise molecules have been tested and the underlying mechanisms have been proposed,involving intercommunications between multiple organs such as muscle-brain crosstalk,liver-brain crosstalk,and gut-brain crosstalk.In this review,we will discuss the current evidence regarding the effects and potential mechanisms of exercise mimetics on AHN and cognition in various neurological disorders.Opportunities,challenges,and future directions in this research field are also discussed.展开更多
Efficient signal transduction that mediates mitochondrial turnover is a strong determinant of metabolic health in skeletal muscle.Of these pathways,our focus was aimed towards the enhancement of antioxidant capacity,m...Efficient signal transduction that mediates mitochondrial turnover is a strong determinant of metabolic health in skeletal muscle.Of these pathways,our focus was aimed towards the enhancement of antioxidant capacity,mitophagy,and mitochondrial biogenesis.While physical activity is an excellent inducer of mitochondrial turnover,its ability to ubiquitously activate and enhance mitochondrial turnover prevents definitive differentiation of the contribution made by each pathway.Therefore,we employed three agents,Sulforaphane(SFN),Urolithin A(UroA),and ZLN005(ZLN),which are activators of important biological markers involved in antioxidant signaling,mitophagy,and biogenesis,respectively.We investigated the time-dependent changes in proteins related to each mechanism in C2C12 myotubes.SFN treatment resulted in increased nuclear localization of the transcription factor Nuclear factor(erythroid-derived 2)-like 2(Nrf-2)after 4 hour(h),with subsequent 2-fold increases in the antioxidant enzymes Nicotinamide Quinone Oxidoreductase 1(NQO1)and Heme-Oxygenase-1(HO-1)by 24 h and 48 h.Mitochondrial respiration and ATP production were significantly increased by both 24 h and 48 h.UroA showed a 2-fold increase in AMP-activated Protein Kinase(AMPK)after 4 h,which led to a modest 30%increase in whole cell mitophagy markers p62 and LC3,after 48 h.This was accompanied by a reduction in cellular Reactive Oxygen Species(ROS),detected with the CellROX Green reagent.Mitophagy flux measurements showed mitophagy activation as both LC3-II and p62 flux increased with UroA at 24-h and 48-h time points,respectively.Finally,AMPK activation was observed by 4 h,in addition to a 2-fold increase in Mitochondrial Transcription Factor A(TFAM)promoter activity by 24 h of ZLN treatment following transient transfection of a TFAM promoter-luciferase construct.Mitochondrial respiration and ATP production were enhanced by 24 h.Our results suggest that early time points of treatment increase upstream pathway activity,whereas later time points represent the increased phenotypic expression of related downstream markers.Our findings suggest that the spatiotemporal progression of these mechanisms following drug treatment is another important factor to consider when examining subcellular changes towards mitochondrial turnover in muscle.展开更多
基金supported by grants from the National Natural Science Foundation of China(Nos.92057207,92357303,92254308,32271223,and 32021003)the National Key Research and Development Program of China(No.2024YFA1306102).
文摘About two thousand years ago,Hippocrates observed that“walking is man's best medicine”[1],a notion increasingly validated in modern society.The benefits of physical activity in preventing chronic diseases and in improving longevity have been extensively studied[2].
文摘Adult hippocampal neurogenesis(AHN)is affected by multiple factors,such as enriched environment,exercise,ageing,and neurodegenerative disorders.Neurodegenerative disorders can impair AHN,leading to progressive neuronal loss and cognitive decline.Compelling evidence suggests that individuals engaged in regular exercise exhibit higher production of proteins that are essential for AHN and memory.Interestingly,specific molecules that mediate the effects of exercise have shown effectiveness in promoting AHN and cognition in different transgenic animal models.Despite these advancements,the precise mechanisms by which exercise mimetics induce AHN remain partially understood.Recently,some novel exercise molecules have been tested and the underlying mechanisms have been proposed,involving intercommunications between multiple organs such as muscle-brain crosstalk,liver-brain crosstalk,and gut-brain crosstalk.In this review,we will discuss the current evidence regarding the effects and potential mechanisms of exercise mimetics on AHN and cognition in various neurological disorders.Opportunities,challenges,and future directions in this research field are also discussed.
基金supported by a grant from the Natural Science and Engineering Council(NSERC).
文摘Efficient signal transduction that mediates mitochondrial turnover is a strong determinant of metabolic health in skeletal muscle.Of these pathways,our focus was aimed towards the enhancement of antioxidant capacity,mitophagy,and mitochondrial biogenesis.While physical activity is an excellent inducer of mitochondrial turnover,its ability to ubiquitously activate and enhance mitochondrial turnover prevents definitive differentiation of the contribution made by each pathway.Therefore,we employed three agents,Sulforaphane(SFN),Urolithin A(UroA),and ZLN005(ZLN),which are activators of important biological markers involved in antioxidant signaling,mitophagy,and biogenesis,respectively.We investigated the time-dependent changes in proteins related to each mechanism in C2C12 myotubes.SFN treatment resulted in increased nuclear localization of the transcription factor Nuclear factor(erythroid-derived 2)-like 2(Nrf-2)after 4 hour(h),with subsequent 2-fold increases in the antioxidant enzymes Nicotinamide Quinone Oxidoreductase 1(NQO1)and Heme-Oxygenase-1(HO-1)by 24 h and 48 h.Mitochondrial respiration and ATP production were significantly increased by both 24 h and 48 h.UroA showed a 2-fold increase in AMP-activated Protein Kinase(AMPK)after 4 h,which led to a modest 30%increase in whole cell mitophagy markers p62 and LC3,after 48 h.This was accompanied by a reduction in cellular Reactive Oxygen Species(ROS),detected with the CellROX Green reagent.Mitophagy flux measurements showed mitophagy activation as both LC3-II and p62 flux increased with UroA at 24-h and 48-h time points,respectively.Finally,AMPK activation was observed by 4 h,in addition to a 2-fold increase in Mitochondrial Transcription Factor A(TFAM)promoter activity by 24 h of ZLN treatment following transient transfection of a TFAM promoter-luciferase construct.Mitochondrial respiration and ATP production were enhanced by 24 h.Our results suggest that early time points of treatment increase upstream pathway activity,whereas later time points represent the increased phenotypic expression of related downstream markers.Our findings suggest that the spatiotemporal progression of these mechanisms following drug treatment is another important factor to consider when examining subcellular changes towards mitochondrial turnover in muscle.
