Cancer cachexia(CC)is a devastating syndrome characterized by weight loss,reduced fat mass and muscle mass that affects approximately 80%of cancer patients and is responsible for 22%-30%of cancer-associated deaths.Und...Cancer cachexia(CC)is a devastating syndrome characterized by weight loss,reduced fat mass and muscle mass that affects approximately 80%of cancer patients and is responsible for 22%-30%of cancer-associated deaths.Understanding underlying mechanisms for the development of CC are crucial to advance therapies to treat CC and improve cancer outcomes.CC is a multi-organ syndrome that results in extensive skeletal muscle and adipose tissue wasting;however,CC can impair other organs such as the liver,heart,brain,and bone as well.A considerable amount of CC research focuses on changes that occur within the muscle,but cancer-related impairments in other organ systems are understudied.Furthermore,metabolic changes in organ systems other than muscle may contribute to CC.Therefore,the purpose of this review is to address degenerative mechanisms which occur during CC from a whole-body perspective.Outlining the information known about metabolic changes that occur in response to cancer is necessary to develop and enhance therapies to treat CC.As much of the current evidences in CC are from pre-clinical models we should note the majority of the data reviewed here are from preclinical models.展开更多
Non-alcoholic fatty liver disease(NAFLD)has recently become a public health concern concurrent with the obesity crisis.Previous work has shown aberrant mitochondrial content/quality and autophagy in models of NAFLD,wh...Non-alcoholic fatty liver disease(NAFLD)has recently become a public health concern concurrent with the obesity crisis.Previous work has shown aberrant mitochondrial content/quality and autophagy in models of NAFLD,whereas exercise is known to improve these derangements.The purpose of this study was to examine the effect of different weight-loss modalities on hepatic mitochondrial content,autophagy and mitophagy in NAFLD.Forty-eight male C57BL/6J mice were divided into 1 of 4 groups:low fat diet(LFD,10%fat,18 weeks),high fat diet(HFD,60%fat diet,18 weeks),weight-loss by diet(D,60%fat diet for 10 weeks then 10%fat diet for 8 weeks)or weight-loss by diet and physical activity(D/PA,60%fat diet for 10 weeks,then 10%fat diet plus a running wheel for 8 weeks).Immunoblot data were analyzed by one-way analysis of variance(ANOVA)with significance denoted at p<0.05.COX-IV protein contents were approximately 50%less in HFD compared to LFD.D/PA had 50%more BNIP3 compared to HFD.PINK1 content was 40%higher in D and D/PA compared to LFD.PPARKIN/PARKIN levels were 40%lower in HFD,D,and D/PA compared to LFD.Whereas p-UbSer65 was 3-fold higher in HFD.LC3II/I ratio was 50%greater in HFD and D/PA,yet p62 protein content was 2.5 fold higher in HFD.High-fat diet causes disruptions in markers of mitochondrial quality control.Physical activity combined with diet were able to ameliorate these derangements and seemingly improve hepatic mitochondrial quality above control values.展开更多
Exercise mitigates obesity-associated pathologies;however,there is controversy regarding optimal exercise interventions.Autophagy,is known to decrease during obesity and is an important moderator for exercise adaptati...Exercise mitigates obesity-associated pathologies;however,there is controversy regarding optimal exercise interventions.Autophagy,is known to decrease during obesity and is an important moderator for exercise adaptations.Purpose:To investigate individual and combined effects of different exercise interventions and autophagy inhibition on exercise adaptations during obesity.Methods:C57BL/6J mice initiated 45%high fat diet at 8 weeks of age.After 6 weeks of diet,animals were divided into moderate(MOD)or high intensity interval training interventions(HIIT),animals were further divided into autophagy inhibition or vehicle conditions(n=10/group).Animals exercised and autophagy was inhibited 3X/week by NSC185058 injections,thereby blocking autophagosome formation.Interventions continued for 4 weeks.Results:High fat diet impaired glucose handling~17%;exercise interventions normalized glucoregulation to prehigh fat diet levels,without differences between any interventions.High fat diet induced~25%decrease in aerobic capacity,which returned to baseline after exercise interventions,with no differences between any interventions.No effects of autophagy inhibition were noted.Conclusions:HIIT and MOD training confer similar health-related adaptations.展开更多
Diet-induced obesity has previously been shown to occur with the concomitant rise in the expression of proin-flammatory cytokines and increases in collagen deposition.While it has been known that the regenerative proc...Diet-induced obesity has previously been shown to occur with the concomitant rise in the expression of proin-flammatory cytokines and increases in collagen deposition.While it has been known that the regenerative process of skeletal muscle is altered in obese mice following an acute muscle injury,we sought to examine differences in the expression of various markers of extracellular matrix remodeling and repair.Our laboratory has previously reported an impaired inflammatory and protein synthetic signaling in these mice that may contribute negatively to the muscle regenerative process.To expand upon this previous investigation,tissues from these animals un-derwent further analysis to determine the extent of changes to the regenerative response within the extracellular matrix,including transcriptional changes in CollagenⅠ,CollagenⅢ,and Fibronectin.Here,we show that the expression of CollagenⅢ:Ⅰis significantly increased at 3-days post-injury in obese injured animals compared to lean injured animals(p=0.0338),and by 28-days the obese injured animals exhibit a significantly lower CollagenⅢ:Ⅰthan their lean injured counterparts(p=0.0035).We demonstrate an impaired response to an acute muscle injury in obese mice when compared with lean counterparts.However,further studies are required to elucidate translational consequences of these changes,as well as to determine any causative mechanisms that may be driving this effect.展开更多
Introduction At the 2018 Annual Meeting of the American College of Sports Medicine,presentations were given by Drs.Nicholas P.Greene,James A.Carson,and James D.Fluckey,at a symposium titled“Emerging Mechanisms for Ex...Introduction At the 2018 Annual Meeting of the American College of Sports Medicine,presentations were given by Drs.Nicholas P.Greene,James A.Carson,and James D.Fluckey,at a symposium titled“Emerging Mechanisms for Exercise Effects on Muscle Wasting and Anabolic Resistance”.Inspired by the presentations at this symposium,the following reviews have been crafted to examine the current understanding of muscle diseases characterized by muscle wasting and anabolic resistance,particularly their identification,development,progression,and mitigation.展开更多
基金Authors would like to thank the dedicated faculty,staff and students at both the Exercise Science Research Center at the University of Arkansas and the Aging and Metabolism Research Program at the Oklahoma Medical Research Foundation for their consistent support of this research.Work presented here was funded by National Institutes of Health under Award Number R15AR069913 and R01AR075794 from the National Institute of Arthritis and Musculoskeletal and Skin Diseases and the National Institute of General Medical SciencesAuthor Jacob L.Brown is supported by National Institute of Aging at the National Institutes of Health 5T32AG052363-02.
文摘Cancer cachexia(CC)is a devastating syndrome characterized by weight loss,reduced fat mass and muscle mass that affects approximately 80%of cancer patients and is responsible for 22%-30%of cancer-associated deaths.Understanding underlying mechanisms for the development of CC are crucial to advance therapies to treat CC and improve cancer outcomes.CC is a multi-organ syndrome that results in extensive skeletal muscle and adipose tissue wasting;however,CC can impair other organs such as the liver,heart,brain,and bone as well.A considerable amount of CC research focuses on changes that occur within the muscle,but cancer-related impairments in other organ systems are understudied.Furthermore,metabolic changes in organ systems other than muscle may contribute to CC.Therefore,the purpose of this review is to address degenerative mechanisms which occur during CC from a whole-body perspective.Outlining the information known about metabolic changes that occur in response to cancer is necessary to develop and enhance therapies to treat CC.As much of the current evidences in CC are from pre-clinical models we should note the majority of the data reviewed here are from preclinical models.
文摘Non-alcoholic fatty liver disease(NAFLD)has recently become a public health concern concurrent with the obesity crisis.Previous work has shown aberrant mitochondrial content/quality and autophagy in models of NAFLD,whereas exercise is known to improve these derangements.The purpose of this study was to examine the effect of different weight-loss modalities on hepatic mitochondrial content,autophagy and mitophagy in NAFLD.Forty-eight male C57BL/6J mice were divided into 1 of 4 groups:low fat diet(LFD,10%fat,18 weeks),high fat diet(HFD,60%fat diet,18 weeks),weight-loss by diet(D,60%fat diet for 10 weeks then 10%fat diet for 8 weeks)or weight-loss by diet and physical activity(D/PA,60%fat diet for 10 weeks,then 10%fat diet plus a running wheel for 8 weeks).Immunoblot data were analyzed by one-way analysis of variance(ANOVA)with significance denoted at p<0.05.COX-IV protein contents were approximately 50%less in HFD compared to LFD.D/PA had 50%more BNIP3 compared to HFD.PINK1 content was 40%higher in D and D/PA compared to LFD.PPARKIN/PARKIN levels were 40%lower in HFD,D,and D/PA compared to LFD.Whereas p-UbSer65 was 3-fold higher in HFD.LC3II/I ratio was 50%greater in HFD and D/PA,yet p62 protein content was 2.5 fold higher in HFD.High-fat diet causes disruptions in markers of mitochondrial quality control.Physical activity combined with diet were able to ameliorate these derangements and seemingly improve hepatic mitochondrial quality above control values.
文摘Exercise mitigates obesity-associated pathologies;however,there is controversy regarding optimal exercise interventions.Autophagy,is known to decrease during obesity and is an important moderator for exercise adaptations.Purpose:To investigate individual and combined effects of different exercise interventions and autophagy inhibition on exercise adaptations during obesity.Methods:C57BL/6J mice initiated 45%high fat diet at 8 weeks of age.After 6 weeks of diet,animals were divided into moderate(MOD)or high intensity interval training interventions(HIIT),animals were further divided into autophagy inhibition or vehicle conditions(n=10/group).Animals exercised and autophagy was inhibited 3X/week by NSC185058 injections,thereby blocking autophagosome formation.Interventions continued for 4 weeks.Results:High fat diet impaired glucose handling~17%;exercise interventions normalized glucoregulation to prehigh fat diet levels,without differences between any interventions.High fat diet induced~25%decrease in aerobic capacity,which returned to baseline after exercise interventions,with no differences between any interventions.No effects of autophagy inhibition were noted.Conclusions:HIIT and MOD training confer similar health-related adaptations.
文摘Diet-induced obesity has previously been shown to occur with the concomitant rise in the expression of proin-flammatory cytokines and increases in collagen deposition.While it has been known that the regenerative process of skeletal muscle is altered in obese mice following an acute muscle injury,we sought to examine differences in the expression of various markers of extracellular matrix remodeling and repair.Our laboratory has previously reported an impaired inflammatory and protein synthetic signaling in these mice that may contribute negatively to the muscle regenerative process.To expand upon this previous investigation,tissues from these animals un-derwent further analysis to determine the extent of changes to the regenerative response within the extracellular matrix,including transcriptional changes in CollagenⅠ,CollagenⅢ,and Fibronectin.Here,we show that the expression of CollagenⅢ:Ⅰis significantly increased at 3-days post-injury in obese injured animals compared to lean injured animals(p=0.0338),and by 28-days the obese injured animals exhibit a significantly lower CollagenⅢ:Ⅰthan their lean injured counterparts(p=0.0035).We demonstrate an impaired response to an acute muscle injury in obese mice when compared with lean counterparts.However,further studies are required to elucidate translational consequences of these changes,as well as to determine any causative mechanisms that may be driving this effect.
基金Work presented here was funded by National Institutes of Health under Award Number R01AR075794 from the National Institute of Arthritis and Musculoskeletal and Skin Diseases.
文摘Introduction At the 2018 Annual Meeting of the American College of Sports Medicine,presentations were given by Drs.Nicholas P.Greene,James A.Carson,and James D.Fluckey,at a symposium titled“Emerging Mechanisms for Exercise Effects on Muscle Wasting and Anabolic Resistance”.Inspired by the presentations at this symposium,the following reviews have been crafted to examine the current understanding of muscle diseases characterized by muscle wasting and anabolic resistance,particularly their identification,development,progression,and mitigation.
