Background:Mild traumatic brain injury(mTBI)is a common neurological trauma that can lead to cognitive impairment.The sirtuin-1(SIRT-1)/peroxisome proliferator-activated receptor gamma coactivator-1α(PGC-1α)pathway ...Background:Mild traumatic brain injury(mTBI)is a common neurological trauma that can lead to cognitive impairment.The sirtuin-1(SIRT-1)/peroxisome proliferator-activated receptor gamma coactivator-1α(PGC-1α)pathway has been reported to have neuroprotective effects in rats with craniocerebral injury.We evaluated potential mechanisms underlying electroacupuncture-mediated recovery of cognitive function after mTBI,focusing on the SIRT-1/PGC-1α/mitochondrial pathway.Methods:We included forty 6-week-old male Sprague-Dawley rats in this study.Rats were randomly divided into four groups:controlled cortical impactor(CCI,n=10),sham operation(sham,n=10),electroacupuncture-treated CCI(CCI+EA,n=10),and electroacupuncture-treated sham(sham+EA,n=10)group.Randomization was performed by assigning a random number to each rat and using a random number table.The mTBI rat model was established using a controllable cortical impactor.Electroacupuncture therapy was performed on the back of rats,by inserting acupuncture needles to the specific acupoints and setting appropriate parameters for treatment.We evaluated spatial learning and memory functions with the Morris water maze test.We performed quantitative real-time polymerase chain reaction(qRT-PCR),western blotting,adenosine triphosphate(ATP)determination,and mitochondrial respiratory chain complex I(MRCC I)determination on rat hippocampal tissue.We analyzed SIRT-1/PGC-1α expression levels and the results of mitochondrial function assays,and compared differences between groups using bilateral Student’s t-tests.Results:Compared with the sham group,SIRT-1/PGC-1α expression was downregulated in the hippocampus of CCI group(P<0.01).Although this expression was upregulated following electroacupuncture,it did not reach the levels observed in the sham group(P<0.05).Compared with the sham group,MRCC I and ATP levels in the CCI group were significantly reduced,and increased after electroacupuncture(P<0.01).In the Morris water maze,electroacupuncture reduced the incubation period of rats and increased average speed and number of crossing platforms(P<0.05).Conclusion:Electroacupuncture may improve cognitive function in the mTBI rat model by regulating the SIRT-1/PGC-1α/mitochondrial pathway.展开更多
The onset and mechanisms underlying neurodegenerative diseases remain uncertain. The main features of neurodegenerative diseases have been related with cellular and molecular events like neuronal loss, mitochondrial d...The onset and mechanisms underlying neurodegenerative diseases remain uncertain. The main features of neurodegenerative diseases have been related with cellular and molecular events like neuronal loss, mitochondrial dysfunction and aberrant accumulation of misfolded proteins or peptides in specific areas of the brain. The most prevalent neurodegenerative diseases belonging to age-related pathologies are Alzheimer's disease, Huntington's disease, Parkinson's disease and amyotrophic lateral sclerosis. Interestingly, mitochondrial dysfunction has been observed to occur during the early onset of several neuropathological events associated to neurodegenerative diseases. The master regulator of mitochondrial quality control and energetic metabolism is the transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator 1-alpha(PGC-1α). Additionally, it has been observed that PGC-1α appears to be a key factor in maintaining neuronal survival and synaptic transmission. In fact, PGC-1α downregulation in different brain areas(hippocampus, substantia nigra, cortex, striatum and spinal cord) that occurs in function of neurological damage including oxidative stress, neuronal loss, and motor disorders has been seen in several animal and cellular models of neurodegenerative diseases. Current evidence indicates that PGC-1α upregulation may serve as a potent therapeutic approach against development and progression of neuronal damage. Remarkably, increasing evidence shows that PGC-1α deficient mice have neurodegenerative diseases-like features, as well as neurological abnormalities. Finally, we discuss recent studies showing novel specific PGC-1α isoforms in the central nervous system that appear to exert a key role in the age of onset of neurodegenerative diseases and have a neuroprotective function in the central nervous system, thus opening a new molecular strategy for treatment of neurodegenerative diseases. The purpose of this review is to provide an up-to-date overview of the PGC-1α role in the physiopathology of neurodegenerative diseases, as well as establish the importance of PGC-1α function in synaptic transmission and neuronal survival.展开更多
Purpose: The purpose of the present study was to evaluate whole-muscle content of several proteins involved in the regulation of skeletal muscle mitochondrial protein content and anaerobic capacity following 4 weeks o...Purpose: The purpose of the present study was to evaluate whole-muscle content of several proteins involved in the regulation of skeletal muscle mitochondrial protein content and anaerobic capacity following 4 weeks of extremely low-volume high-intensity interval training (HIT). Methods: Young, healthy, recreationally active adult males (n = 8) trained 4 times a week for 4 weeks on a cycle ergometer. Each session involved 4 min of total exercise comprised of eight 20 s intervals at ~170% of peak aerobic power separated by 10 s rest. Muscle biopsies were taken prior to (pre) and ~72 hrs post-training (post). Par- ticipants completed an incremental peak oxygen up- take (VO2peak) test and a Wingate test pre-, mid-, and post-training. Results: VO2peak was elevated (p p < 0.05) and post-training (pre: 40.5 ± 3.8 ml·kg-1·min-1, mid: 43.4 ± 2.5 ml·kg-1·min-1, post-: 47.2 ± 2.9 ml·kg-1·min-1). Wingate mean power also increased with training (pre-: 701.0 ± 73.0 W, mid-: 745.5 ± 73.3 W, post-: 786.8 ± 80.0 W). While maximal citrate synthase activity was unchanged, protein expression of the mitochondrial protein cytochrome c oxidase (COX) subunit I (+27%;p p p = 0.08) increased. Increases (p α (+19%), and nuclear PGC-1α (+46%) were also observed after 4 weeks of HIT. No changes were observed in the whole-muscle contents of PDHe1a, PDK4, SIRT1, mTOR, S6K1, MCT1, or PFK protein. Conclusions: These results demonstrate that several mitochondrial protein (but not citrate synthase activity), PGC-1α protein content, and exercise capacity can be improved in only 4 min of total training time per day, 4 days per wk using HIT cycle training.展开更多
Although it is widely accepted that human induced pluripotent stem cell-derived cardiomyocytes(hiPSC-CMs)are readily available,robustly reproducible,and physiologically appropriate human cells for clinical application...Although it is widely accepted that human induced pluripotent stem cell-derived cardiomyocytes(hiPSC-CMs)are readily available,robustly reproducible,and physiologically appropriate human cells for clinical applications and research in the cardiovascular field,hiPSC-CMs cultured in vitro retain an immature metabolic phenotype that limits their application,and little is known about the underlying molecular mechanism controlling mitochondrial metabolic maturation during human induced pluripotent stem cells(hiPSCs)differentiation into cardiomyocytes.In this study,we found that peroxisome proliferator-activated receptor g coactivator-1α(PGC-1α)played an important role in inducing mitochondrial biogenesis and establishing oxidative phosphorylation(OXPHOS)during the cardiac differentiation of hiPSCs.Knocking down PGC-1α by siRNA impaired mitochondrial respiration,while upregulating PGC-1α by ZLN005 promoted mitochondrial biosynthesis and function by regulating the expression of downstream genes involved in mitochondrial dynamics and oxidative metabolism in hiPSCCMs.Furthermore,we found that estrogen-related receptor a(ERRa)was required for the induction of PGC-1α stimulatory effects in hiPSC-CMs.These findings provide key insights into the molecular control of mitochondrial metabolism during cardiac differentiation and may be used to generate more metabolically mature cardiomyocytes for application.展开更多
Cisplatin(CDDP)-induced ototoxicity is one of the common adverse effects of cisplatin chemotherapy.Thus far,effective approaches for attenuating hearing loss are unavailable in clinical practice.Mitochondrial biogenes...Cisplatin(CDDP)-induced ototoxicity is one of the common adverse effects of cisplatin chemotherapy.Thus far,effective approaches for attenuating hearing loss are unavailable in clinical practice.Mitochondrial biogenesis acts as a master element of mitochondrial health and is necessary for mitochondrial quality control.The current study examined whether mitochondrial biogenesis is involved in CDDP-induced ototoxicity.Herein,we showed that CDDP damaged mitochondrial function and caused death of House Ear Institute-Organ of Corti 1(HEI-OC1)cells by impairing mitochondrial biogenesis.Moreover,overexpression of peroxisome proliferatoractivated receptor-g coactivator-1a,a key factor in mitochondrial biogenesis,promoted mitochondrial biogenesis in HEI-OC1 cells and protected them against CDDP-induced cytotoxicity.These findings suggest that mitochondrial biogenesis is involved in the pathology of CDDP cytotoxicity of HEI-OC1 cells,and activation of peroxisome proliferator-activated receptor-g coactivator-1a can be considered a potential therapeutic strategy to attenuate CDDP-mediated ototoxicity.展开更多
Activated G-protein-coupled receptor 39(GPR39)has been shown to attenuate inflammation by interacting with sirtuin 1(SIRT1)and peroxisome proliferator-activated receptor-γcoactivator 1α(PGC-1α).However,whether GPR3...Activated G-protein-coupled receptor 39(GPR39)has been shown to attenuate inflammation by interacting with sirtuin 1(SIRT1)and peroxisome proliferator-activated receptor-γcoactivator 1α(PGC-1α).However,whether GPR39 attenuates neuropathic pain remains unclear.In this study,we established a Sprague-Dawley rat model of spared nerve injury-induced neuropathic pain and found that GPR39 expression was significantly decreased in neurons and microglia in the spinal dorsal horn compared with sham-operated rats.Intrathecal injection of TC-G 1008,a specific agonist of GPR39,significantly alleviated mechanical allodynia in the rats with spared nerve injury,improved spinal cord mitochondrial biogenesis,and alleviated neuroinflammation.These changes were abolished by GPR39 small interfering RNA(siRNA),Ex-527(SIRT1 inhibitor),and PGC-1αsiRNA.Taken together,these findings show that GPR39 activation ameliorates mechanical allodynia by activating the SIRT1/PGC-1αpathway in rats with spared nerve injury.展开更多
基金funded by a scientic research fund from Beijing Jishuitan Hospital(No.ZR-202107).
文摘Background:Mild traumatic brain injury(mTBI)is a common neurological trauma that can lead to cognitive impairment.The sirtuin-1(SIRT-1)/peroxisome proliferator-activated receptor gamma coactivator-1α(PGC-1α)pathway has been reported to have neuroprotective effects in rats with craniocerebral injury.We evaluated potential mechanisms underlying electroacupuncture-mediated recovery of cognitive function after mTBI,focusing on the SIRT-1/PGC-1α/mitochondrial pathway.Methods:We included forty 6-week-old male Sprague-Dawley rats in this study.Rats were randomly divided into four groups:controlled cortical impactor(CCI,n=10),sham operation(sham,n=10),electroacupuncture-treated CCI(CCI+EA,n=10),and electroacupuncture-treated sham(sham+EA,n=10)group.Randomization was performed by assigning a random number to each rat and using a random number table.The mTBI rat model was established using a controllable cortical impactor.Electroacupuncture therapy was performed on the back of rats,by inserting acupuncture needles to the specific acupoints and setting appropriate parameters for treatment.We evaluated spatial learning and memory functions with the Morris water maze test.We performed quantitative real-time polymerase chain reaction(qRT-PCR),western blotting,adenosine triphosphate(ATP)determination,and mitochondrial respiratory chain complex I(MRCC I)determination on rat hippocampal tissue.We analyzed SIRT-1/PGC-1α expression levels and the results of mitochondrial function assays,and compared differences between groups using bilateral Student’s t-tests.Results:Compared with the sham group,SIRT-1/PGC-1α expression was downregulated in the hippocampus of CCI group(P<0.01).Although this expression was upregulated following electroacupuncture,it did not reach the levels observed in the sham group(P<0.05).Compared with the sham group,MRCC I and ATP levels in the CCI group were significantly reduced,and increased after electroacupuncture(P<0.01).In the Morris water maze,electroacupuncture reduced the incubation period of rats and increased average speed and number of crossing platforms(P<0.05).Conclusion:Electroacupuncture may improve cognitive function in the mTBI rat model by regulating the SIRT-1/PGC-1α/mitochondrial pathway.
基金supported by Fondecyt 1200908(to JF)the Conicyt 21141247(to JDP)。
文摘The onset and mechanisms underlying neurodegenerative diseases remain uncertain. The main features of neurodegenerative diseases have been related with cellular and molecular events like neuronal loss, mitochondrial dysfunction and aberrant accumulation of misfolded proteins or peptides in specific areas of the brain. The most prevalent neurodegenerative diseases belonging to age-related pathologies are Alzheimer's disease, Huntington's disease, Parkinson's disease and amyotrophic lateral sclerosis. Interestingly, mitochondrial dysfunction has been observed to occur during the early onset of several neuropathological events associated to neurodegenerative diseases. The master regulator of mitochondrial quality control and energetic metabolism is the transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator 1-alpha(PGC-1α). Additionally, it has been observed that PGC-1α appears to be a key factor in maintaining neuronal survival and synaptic transmission. In fact, PGC-1α downregulation in different brain areas(hippocampus, substantia nigra, cortex, striatum and spinal cord) that occurs in function of neurological damage including oxidative stress, neuronal loss, and motor disorders has been seen in several animal and cellular models of neurodegenerative diseases. Current evidence indicates that PGC-1α upregulation may serve as a potent therapeutic approach against development and progression of neuronal damage. Remarkably, increasing evidence shows that PGC-1α deficient mice have neurodegenerative diseases-like features, as well as neurological abnormalities. Finally, we discuss recent studies showing novel specific PGC-1α isoforms in the central nervous system that appear to exert a key role in the age of onset of neurodegenerative diseases and have a neuroprotective function in the central nervous system, thus opening a new molecular strategy for treatment of neurodegenerative diseases. The purpose of this review is to provide an up-to-date overview of the PGC-1α role in the physiopathology of neurodegenerative diseases, as well as establish the importance of PGC-1α function in synaptic transmission and neuronal survival.
文摘Purpose: The purpose of the present study was to evaluate whole-muscle content of several proteins involved in the regulation of skeletal muscle mitochondrial protein content and anaerobic capacity following 4 weeks of extremely low-volume high-intensity interval training (HIT). Methods: Young, healthy, recreationally active adult males (n = 8) trained 4 times a week for 4 weeks on a cycle ergometer. Each session involved 4 min of total exercise comprised of eight 20 s intervals at ~170% of peak aerobic power separated by 10 s rest. Muscle biopsies were taken prior to (pre) and ~72 hrs post-training (post). Par- ticipants completed an incremental peak oxygen up- take (VO2peak) test and a Wingate test pre-, mid-, and post-training. Results: VO2peak was elevated (p p < 0.05) and post-training (pre: 40.5 ± 3.8 ml·kg-1·min-1, mid: 43.4 ± 2.5 ml·kg-1·min-1, post-: 47.2 ± 2.9 ml·kg-1·min-1). Wingate mean power also increased with training (pre-: 701.0 ± 73.0 W, mid-: 745.5 ± 73.3 W, post-: 786.8 ± 80.0 W). While maximal citrate synthase activity was unchanged, protein expression of the mitochondrial protein cytochrome c oxidase (COX) subunit I (+27%;p p p = 0.08) increased. Increases (p α (+19%), and nuclear PGC-1α (+46%) were also observed after 4 weeks of HIT. No changes were observed in the whole-muscle contents of PDHe1a, PDK4, SIRT1, mTOR, S6K1, MCT1, or PFK protein. Conclusions: These results demonstrate that several mitochondrial protein (but not citrate synthase activity), PGC-1α protein content, and exercise capacity can be improved in only 4 min of total training time per day, 4 days per wk using HIT cycle training.
基金This work was supported by the National Natural Science Foundation of China[grant numbers 81670270,81970244,81700250].
文摘Although it is widely accepted that human induced pluripotent stem cell-derived cardiomyocytes(hiPSC-CMs)are readily available,robustly reproducible,and physiologically appropriate human cells for clinical applications and research in the cardiovascular field,hiPSC-CMs cultured in vitro retain an immature metabolic phenotype that limits their application,and little is known about the underlying molecular mechanism controlling mitochondrial metabolic maturation during human induced pluripotent stem cells(hiPSCs)differentiation into cardiomyocytes.In this study,we found that peroxisome proliferator-activated receptor g coactivator-1α(PGC-1α)played an important role in inducing mitochondrial biogenesis and establishing oxidative phosphorylation(OXPHOS)during the cardiac differentiation of hiPSCs.Knocking down PGC-1α by siRNA impaired mitochondrial respiration,while upregulating PGC-1α by ZLN005 promoted mitochondrial biosynthesis and function by regulating the expression of downstream genes involved in mitochondrial dynamics and oxidative metabolism in hiPSCCMs.Furthermore,we found that estrogen-related receptor a(ERRa)was required for the induction of PGC-1α stimulatory effects in hiPSC-CMs.These findings provide key insights into the molecular control of mitochondrial metabolism during cardiac differentiation and may be used to generate more metabolically mature cardiomyocytes for application.
基金supported by the Project funded by China Postdoctoral Science Foundation(No.2018M640863 to JP)the National Natural Science Foundation of China(No.81771018,81570935,81570916,and 81873699 to HX and YZ)+1 种基金the Guangdong Natural Science Foundation of China(No.2015A030313084 and 2017A030313585 to HX)Yixian Research Launch Project of China(No.YXQH201807 to HX).
文摘Cisplatin(CDDP)-induced ototoxicity is one of the common adverse effects of cisplatin chemotherapy.Thus far,effective approaches for attenuating hearing loss are unavailable in clinical practice.Mitochondrial biogenesis acts as a master element of mitochondrial health and is necessary for mitochondrial quality control.The current study examined whether mitochondrial biogenesis is involved in CDDP-induced ototoxicity.Herein,we showed that CDDP damaged mitochondrial function and caused death of House Ear Institute-Organ of Corti 1(HEI-OC1)cells by impairing mitochondrial biogenesis.Moreover,overexpression of peroxisome proliferatoractivated receptor-g coactivator-1a,a key factor in mitochondrial biogenesis,promoted mitochondrial biogenesis in HEI-OC1 cells and protected them against CDDP-induced cytotoxicity.These findings suggest that mitochondrial biogenesis is involved in the pathology of CDDP cytotoxicity of HEI-OC1 cells,and activation of peroxisome proliferator-activated receptor-g coactivator-1a can be considered a potential therapeutic strategy to attenuate CDDP-mediated ototoxicity.
基金supported by the National Notural Science Foundation of China,Nos.82071556 and 82271291 (both to WM)
文摘Activated G-protein-coupled receptor 39(GPR39)has been shown to attenuate inflammation by interacting with sirtuin 1(SIRT1)and peroxisome proliferator-activated receptor-γcoactivator 1α(PGC-1α).However,whether GPR39 attenuates neuropathic pain remains unclear.In this study,we established a Sprague-Dawley rat model of spared nerve injury-induced neuropathic pain and found that GPR39 expression was significantly decreased in neurons and microglia in the spinal dorsal horn compared with sham-operated rats.Intrathecal injection of TC-G 1008,a specific agonist of GPR39,significantly alleviated mechanical allodynia in the rats with spared nerve injury,improved spinal cord mitochondrial biogenesis,and alleviated neuroinflammation.These changes were abolished by GPR39 small interfering RNA(siRNA),Ex-527(SIRT1 inhibitor),and PGC-1αsiRNA.Taken together,these findings show that GPR39 activation ameliorates mechanical allodynia by activating the SIRT1/PGC-1αpathway in rats with spared nerve injury.