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
Mitochondria are vital organelles that provide energy for muscle function.When these organelles become dysfunctional,they produce less energy as well as excessive levels of reactive oxygen species which can trigger mu...Mitochondria are vital organelles that provide energy for muscle function.When these organelles become dysfunctional,they produce less energy as well as excessive levels of reactive oxygen species which can trigger muscle atrophy,weakness and loss of endurance.In this review,molecular evidence is provided to show that exercise serves as a useful therapeutic countermeasure to overcome mitochondrial dysfunction,even when key regulators of organelle biogenesis are absent.These findings illustrate the complexity and compensatory nature of exercise-induced molecular signaling to transcription,as well as to post-transcriptional events within the mitochondrial synthesis and degradation(i.e.turnover)pathways.Beginning with the first bout of contractile activity,exercise exerts a medicinal effect to improve mitochondrial health and whole muscle function.展开更多
This special issue highlights comprehensive reviews and researches on topics in fundamentally important areas of skeletal muscle physiology.1–6 The most important adaptive response of skeletal muscle to exercise,part...This special issue highlights comprehensive reviews and researches on topics in fundamentally important areas of skeletal muscle physiology.1–6 The most important adaptive response of skeletal muscle to exercise,particularly resistant exercise,is increased protein synthesis,which is critical for promoting muscle hypertrophy and/or preventing atrophy.This process plays an essential role in promoting and maintaining skeletal muscle contractile and metabolic functions.展开更多
Skeletal muscle health and function are essential determinants of metabolic health,physical performance,and overall quality of life.The quality of skeletal muscle is heavily dependent on the complex mitochondrial reti...Skeletal muscle health and function are essential determinants of metabolic health,physical performance,and overall quality of life.The quality of skeletal muscle is heavily dependent on the complex mitochondrial reticulum that contributes toward its unique adaptability.It is now recognized that mitochondrial perturbations can activate various innate immune pathways,such as the nucleotide-binding oligomerization domain(NOD)-like receptor protein 3(NLRP3)inflammasome complex by propagating inflammatory signaling in response to damage-associated molecular patterns(DAMPs).The NLRP3 inflammasome is a multimeric protein complex and is a prominent regulator of innate immunity and cell death by mediating the activation of caspase-1,pro-inflammatory cytokines interleukin-1βand interleukin-18 and pro-pyroptotic protein gasdermin-D.While several studies have begun to demonstrate the relationship between various mitochondrial DAMPs(mtDAMPs)and NLRP3 inflammasome activation,the influence of various metabolic states on the production of these DAMPs and subsequent inflammatory profile remains poorly understood.This narrative review aimed to address this by highlighting the effects of skeletal muscle use and disuse on mitochondrial quality mechanisms including mitochondrial biogenesis,fusion,fission and mitophagy.Secondly,this review summarized the impact of alterations in mitochondrial quality control mechanisms following muscle denervation,aging,and exercise training in relation to NLRP3 inflammasome activation.By consolidating the current body of literature,this work aimed to further the understanding of innate immune signaling within skeletal muscle,which can highlight areas for future research and therapeutic strategies to regulate NLRP3 inflammasome activation during divergent metabolic conditions.展开更多
Mitochondria are essential energy-providing organelles that are required in the maintenance of healthy skeletal muscle.As such,the removal of damaged mitochondria,through mitophagy,is necessary to maintain mitochondri...Mitochondria are essential energy-providing organelles that are required in the maintenance of healthy skeletal muscle.As such,the removal of damaged mitochondria,through mitophagy,is necessary to maintain mitochondrial quality.In aging muscle,mitochondrial content and function are often found to be reduced compared to young individuals.This occurs despite the fact that measures of mitophagy are elevated,suggesting that mitophagy is insufficiently high to remove all of the dysfunctional organelles in aging muscle.Recent evidence has shown that acute exercise promotes mitophagic signaling,leading to organelle degradation.This exercise-induced signaling is attenuated in aging muscle,suggesting that aging muscle loses its capacity for mitochondrial turnover in response to exercise.This contributes to the reduction in muscle health in elderly individuals.Chronic exercise training improves mitochondrial content and function,even in aging muscle,leading to reduced mitophagy signaling.Thus,exercise training should be prescribed for both young and elderly populations to pro-mote the maintenance of a healthy mitochondrial pool,through the stimulation of both organelle biogenesis and mitophagy.展开更多
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.
基金The work was funded by Natural Sciences and Engineering Research Council(NSERC)and Canadian Institutes of Health Research(CIHR)grants to D.A.H.A.N.O.is the recipient of an NSERC CGS-D.D.A.H.is the recipient of a Canada Research Chair in Cell Physiology.
文摘Mitochondria are vital organelles that provide energy for muscle function.When these organelles become dysfunctional,they produce less energy as well as excessive levels of reactive oxygen species which can trigger muscle atrophy,weakness and loss of endurance.In this review,molecular evidence is provided to show that exercise serves as a useful therapeutic countermeasure to overcome mitochondrial dysfunction,even when key regulators of organelle biogenesis are absent.These findings illustrate the complexity and compensatory nature of exercise-induced molecular signaling to transcription,as well as to post-transcriptional events within the mitochondrial synthesis and degradation(i.e.turnover)pathways.Beginning with the first bout of contractile activity,exercise exerts a medicinal effect to improve mitochondrial health and whole muscle function.
文摘This special issue highlights comprehensive reviews and researches on topics in fundamentally important areas of skeletal muscle physiology.1–6 The most important adaptive response of skeletal muscle to exercise,particularly resistant exercise,is increased protein synthesis,which is critical for promoting muscle hypertrophy and/or preventing atrophy.This process plays an essential role in promoting and maintaining skeletal muscle contractile and metabolic functions.
文摘Skeletal muscle health and function are essential determinants of metabolic health,physical performance,and overall quality of life.The quality of skeletal muscle is heavily dependent on the complex mitochondrial reticulum that contributes toward its unique adaptability.It is now recognized that mitochondrial perturbations can activate various innate immune pathways,such as the nucleotide-binding oligomerization domain(NOD)-like receptor protein 3(NLRP3)inflammasome complex by propagating inflammatory signaling in response to damage-associated molecular patterns(DAMPs).The NLRP3 inflammasome is a multimeric protein complex and is a prominent regulator of innate immunity and cell death by mediating the activation of caspase-1,pro-inflammatory cytokines interleukin-1βand interleukin-18 and pro-pyroptotic protein gasdermin-D.While several studies have begun to demonstrate the relationship between various mitochondrial DAMPs(mtDAMPs)and NLRP3 inflammasome activation,the influence of various metabolic states on the production of these DAMPs and subsequent inflammatory profile remains poorly understood.This narrative review aimed to address this by highlighting the effects of skeletal muscle use and disuse on mitochondrial quality mechanisms including mitochondrial biogenesis,fusion,fission and mitophagy.Secondly,this review summarized the impact of alterations in mitochondrial quality control mechanisms following muscle denervation,aging,and exercise training in relation to NLRP3 inflammasome activation.By consolidating the current body of literature,this work aimed to further the understanding of innate immune signaling within skeletal muscle,which can highlight areas for future research and therapeutic strategies to regulate NLRP3 inflammasome activation during divergent metabolic conditions.
文摘Mitochondria are essential energy-providing organelles that are required in the maintenance of healthy skeletal muscle.As such,the removal of damaged mitochondria,through mitophagy,is necessary to maintain mitochondrial quality.In aging muscle,mitochondrial content and function are often found to be reduced compared to young individuals.This occurs despite the fact that measures of mitophagy are elevated,suggesting that mitophagy is insufficiently high to remove all of the dysfunctional organelles in aging muscle.Recent evidence has shown that acute exercise promotes mitophagic signaling,leading to organelle degradation.This exercise-induced signaling is attenuated in aging muscle,suggesting that aging muscle loses its capacity for mitochondrial turnover in response to exercise.This contributes to the reduction in muscle health in elderly individuals.Chronic exercise training improves mitochondrial content and function,even in aging muscle,leading to reduced mitophagy signaling.Thus,exercise training should be prescribed for both young and elderly populations to pro-mote the maintenance of a healthy mitochondrial pool,through the stimulation of both organelle biogenesis and mitophagy.
