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David A. Hood - One of the best experts on this subject based on the ideXlab platform.
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sirtuin 1 mediated effects of exercise and resveratrol on Mitochondrial Biogenesis
Journal of Biological Chemistry, 2013Co-Authors: Keir J Menzies, David A. Hood, Kaustabh Singh, Ayesha SaleemAbstract:The purpose of this study was to evaluate the role of sirtuin 1 (SirT1) in exercise- and resveratrol (RSV)-induced skeletal muscle Mitochondrial Biogenesis. Using muscle-specific SirT1-deficient (KO) mice and a cell culture model of differentiated myotubes, we compared the treatment of resveratrol, an activator of SirT1, with that of exercise in inducing Mitochondrial Biogenesis. These experiments demonstrated that SirT1 plays a modest role in maintaining basal Mitochondrial content and a larger role in preserving Mitochondrial function. Furthermore, voluntary exercise and RSV treatment induced Mitochondrial Biogenesis in a SirT1-independent manner. However, when RSV and exercise were combined, a SirT1-dependent synergistic effect was evident, leading to enhanced translocation of PGC-1α and SirT1 to the nucleus and stimulation of Mitochondrial Biogenesis. Thus, the magnitude of the effect of RSV on muscle Mitochondrial Biogenesis is reliant on SirT1, as well as the cellular environment, such as that produced by repeated bouts of exercise.
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How is Mitochondrial Biogenesis affected in Mitochondrial disease?
Medicine and Science in Sports and Exercise, 2005Co-Authors: Béatrice Chabi, Peter J. Adhihetty, Vladimir Ljubicic, David A. HoodAbstract:Mitochondrial Biogenesis occurs when the tissue energy demand is chronically increased to stress the ATP producing capacity of the preexisting mitochondria. In muscle, endurance training is a metabolic stress that is capable of inducing Mitochondrial Biogenesis, the consequence of which is improved performance during exercise. Expansion of the Mitochondrial volume requires the coordinated response of the nuclear and Mitochondrial genomes. During acute exercise, the initial signaling events are the perturbations in ATP turnover and calcium (Ca2+) concentrations caused by the contractile process. These alterations activate signal transduction pathways which target transcription factors involved in gene expression. Nuclear gene products are then posttranslationally imported into mitochondria. One of these, Tfam, is important for the regulation of Mitochondrial DNA (mtDNA) gene expression. In muscle, a broad range of Mitochondrial-specific diseases due to mutations in nuclear DNA or mtDNA exist, termed Mitochondrial myopathies. These mutations result in dysfunctional Mitochondrial assembly which ultimately leads to reduced ATP production. Mitochondrial myopathy patients exhibit a variety of compensatory responses which attempt to reconcile this energy deficiency, but the extent and the type of compensatory adaptations are disease-specific. Understanding the role of exercise in mediating these compensatory responses leading to Mitochondrial Biogenesis could help us in prescribing exercise designed to improve Mitochondrial function in patients with Mitochondrial myopathies. In addition, numerous other diseases (e.g., neurological disorders, cancer, diabetes, and cardiomyopathies), as well as the aging process, have etiologies or consequences attributed, in part, to Mitochondrial dysfunction. Thus, insight gained by investigating the steps involved in exercise-induced Mitochondrial Biogenesis may help us to understand the underlying basis of these other disease states.
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Regulation of Mitochondrial Biogenesis in Muscle by Endurance Exercise
Sports Medicine, 2003Co-Authors: Isabella Irrcher, Vladimir Ljubicic, Peter J. Adhihetty, Anna-maria Joseph, David A. HoodAbstract:Behavioural and hereditary conditions are known to decrease Mitochondrial volume and function within skeletal muscle. This reduces endurance performance, and is manifest both at high- and low-intensity levels of exertion. A programme of regular endurance exercise, undertaken over a number of weeks, produces significant adaptations within skeletal muscle such that noticeable improvements in oxidative capacity are evident, and the related decline in endurance performance can be attenuated. Notwithstanding the important implications that this has for the highly trained endurance athlete, an improvement in Mitochondrial volume and function through regular physical activity also endows the previously sedentary and/or aging population with an improved quality of life, and a greater functional independence. An understanding of the molecular and cellular mechanisms that govern the increases in Mitochondrial volume with repeated bouts of exercise can provide insights into possible therapeutic interventions to care for those with Mitochondrially-based diseases, and those unable to withstand regular physical activity. This review focuses on the recent developments in the molecular aspects of Mitochondrial Biogenesis in chronically exercising muscle. Specifically, we discuss the initial signalling events triggered by muscle contraction, the activation of transcription factors involved in both nuclear and Mitochondrial DNA transcription, as well as the post-translational import mechanisms required for Mitochondrial Biogenesis. We consider the importance and relevance of chronic physical activity in the induction of Mitochondrial Biogenesis, with particular emphasis on how an endurance training programme could positively affect the age-related decline in Mitochondrial content and delay the progression of age- and physical inactivity-related diseases.
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invited review contractile activity induced Mitochondrial Biogenesis in skeletal muscle
Journal of Applied Physiology, 2001Co-Authors: David A. HoodAbstract:Chronic contractile activity produces Mitochondrial Biogenesis in muscle. This adaptation results in a significant shift in adenine nucleotide metabolism, with attendant improvements in fatigue res...
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Mitochondrial Biogenesis in Striated Muscle
Canadian Journal of Applied Physiology-revue Canadienne De Physiologie Appliquee, 1994Co-Authors: David A. Hood, Atila Balaban, Michael K. Connor, Elaine E. Craig, Mary L. Nishio, Mojgan Rezvani, Mark TakahashiAbstract:Mitochondrial Biogenesis (synthesis) has been observed to occur in skeletal muscle in response to chronic use. It also occurs in cardiac muscle during growth and hypertrophy, and it may be impaired during the aging process. This review summarizes the literature on the processes of Mitochondrial Biogenesis at the biochemical and molecular levels, with particular reference to striated muscles. Mitochondrial Biogenesis involves the expression of nuclear and Mitochondrial genes and the coordination of these two genomes, the synthesis of proteins and phospholipids and their import into the organelle, and the incorporation of these lipids and proteins into their appropriate locations within the matrix, inner or outer membranes. The emphasis is on the regulation of these events, with information derived in part from other cellular systems. Although descriptions of Mitochondrial content changes in heart and skeletal muscle during altered physiological states are plentiful, much work is needed at the molecular lev...
John O Holloszy - One of the best experts on this subject based on the ideXlab platform.
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effects of resveratrol and sirt1 on pgc 1α activity and Mitochondrial Biogenesis a reevaluation
PLOS Biology, 2013Co-Authors: Kazuhiko Higashida, John O Holloszy, Sanghyun Kim, Su Ryun Jung, Meiko Asaka, Dongho HanAbstract:It has been reported that feeding mice resveratrol activates AMPK and SIRT1 in skeletal muscle leading to deacetylation and activation of PGC-1α, increased Mitochondrial Biogenesis, and improved running endurance. This study was done to further evaluate the effects of resveratrol, SIRT1, and PGC-1α deacetylation on Mitochondrial Biogenesis in muscle. Feeding rats or mice a diet containing 4 g resveratrol/kg diet had no effect on Mitochondrial protein levels in muscle. High concentrations of resveratrol lowered ATP concentration and activated AMPK in C2C12 myotubes, resulting in an increase in Mitochondrial proteins. Knockdown of SIRT1, or suppression of SIRT1 activity with a dominant-negative (DN) SIRT1 construct, increased PGC-1α acetylation, PGC-1α coactivator activity, and Mitochondrial proteins in C2C12 cells. Expression of a DN SIRT1 in rat triceps muscle also induced an increase in Mitochondrial proteins. Overexpression of SIRT1 decreased PGC-1α acetylation, PGC-1α coactivator activity, and Mitochondrial proteins in C2C12 myotubes. Overexpression of SIRT1 also resulted in a decrease in Mitochondrial proteins in rat triceps muscle. We conclude that, contrary to some previous reports, the mechanism by which SIRT1 regulates Mitochondrial Biogenesis is by inhibiting PGC-1α coactivator activity, resulting in a decrease in mitochondria. We also conclude that feeding rodents resveratrol has no effect on Mitochondrial Biogenesis in muscle.
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exercise induced Mitochondrial Biogenesis begins before the increase in muscle pgc 1α expression
Journal of Biological Chemistry, 2007Co-Authors: David C Wright, Terry E Jones, Pablo M Garciaroves, Paige C Geiger, John O HolloszyAbstract:Exercise results in rapid increases in expression of the transcription coactivator peroxisome proliferator-activated receptor coactivator-1 (PGC-1) and in Mitochondrial Biogenesis in skeletal muscle. PGC-1 regulates and coordinates Mitochondrial Biogenesis, and overexpression of PGC-1 in muscle cells results in increases in Mitochondrial content. In this context, it has been proposed that the increase in PGC-1 protein expression mediates the exercise-induced increase in Mitochondrial Biogenesis. However, we found that Mitochondrial proteins with a short half-life increase as rapidly as, or more rapidly than, PGC-1 protein. This finding led us to hypothesize that activation, rather than increased expression, of PGC-1 mediates the initial phase of the exercise-induced increase in mitochondria. In this study, we found that most of the PGC-1 in resting skeletal muscle is in the cytosol. Exercise resulted in activation of p38 MAPK and movement of PGC-1 into the nucleus. In support of our hypothesis, binding of the transcription factor nuclear respiratory factor 1 (NRF-1) to the cytochrome c promoter and NRF-2 to the cytochrome oxidase subunit 4 promoter increased in response to exercise prior to an increase in PGC-1 protein. Furthermore, exercise-induced increases in the mRNAs of cytochrome c, -aminolevulinate synthase, and citrate synthase also occurred before an increase in PGC-1 protein. Thus, it appears that activation of PGC-1 may mediate the initial phase of the exercise-induced adaptive increase in muscle mitochondria, whereas the subsequent increase in PGC-1 protein sustains and enhances the increase in Mitochondrial Biogenesis.
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exercise induced Mitochondrial Biogenesis begins before the increase in muscle pgc 1α expression
Journal of Biological Chemistry, 2007Co-Authors: David C Wright, Terry E Jones, Dongho Han, Pablo M Garciaroves, Paige C Geiger, John O HolloszyAbstract:Exercise results in rapid increases in expression of the transcription coactivator peroxisome proliferator-activated receptor coactivator-1 (PGC-1) and in Mitochondrial Biogenesis in skeletal muscle. PGC-1 regulates and coordinates Mitochondrial Biogenesis, and overexpression of PGC-1 in muscle cells results in increases in Mitochondrial content. In this context, it has been proposed that the increase in PGC-1 protein expression mediates the exercise-induced increase in Mitochondrial Biogenesis. However, we found that Mitochondrial proteins with a short half-life increase as rapidly as, or more rapidly than, PGC-1 protein. This finding led us to hypothesize that activation, rather than increased expression, of PGC-1 mediates the initial phase of the exercise-induced increase in mitochondria. In this study, we found that most of the PGC-1 in resting skeletal muscle is in the cytosol. Exercise resulted in activation of p38 MAPK and movement of PGC-1 into the nucleus. In support of our hypothesis, binding of the transcription factor nuclear respiratory factor 1 (NRF-1) to the cytochrome c promoter and NRF-2 to the cytochrome oxidase subunit 4 promoter increased in response to exercise prior to an increase in PGC-1 protein. Furthermore, exercise-induced increases in the mRNAs of cytochrome c, -aminolevulinate synthase, and citrate synthase also occurred before an increase in PGC-1 protein. Thus, it appears that activation of PGC-1 may mediate the initial phase of the exercise-induced adaptive increase in muscle mitochondria, whereas the subsequent increase in PGC-1 protein sustains and enhances the increase in Mitochondrial Biogenesis.
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raising ca2 in l6 myotubes mimics effects of exercise on Mitochondrial Biogenesis in muscle
The FASEB Journal, 2003Co-Authors: Edward O Ojuka, Terry E Jones, Dongho Han, May Chen, John O HolloszyAbstract:Skeletal muscle adapts to endurance exercise with an increase in mitochondria. Muscle contractions generate numerous potential signals. To determine which of these stimulates Mitochondrial Biogenesis, we are using L6 myotubes. Using this model we have found that raising cytosolic Ca2+ induces an increase in mitochondria. In this study, we tested the hypothesis that raising cytosolic Ca2+ in L6 myotubes induces increased expression of PGC-1, NRF-1, NRF-2, and mtTFA, factors that have been implicated in Mitochondrial Biogenesis and in the adaptation of muscle to exercise. Raising cytosolic Ca2+ by exposing L6 myotubes to caffeine for 5 h induced significant increases in PGC-1 and mtTFA protein expression and in NRF-1 and NRF-2 binding to DNA. These adaptations were prevented by dantrolene, which blocks Ca2+ release from the SR. Exposure of L6 myotubes to caffeine for 5 h per day for 5 days induced significant increases in Mitochondrial marker enzyme proteins. Our results show that the adaptive response of L6 myotubes to an increase in cytosolic Ca2+ mimics the stimulation of Mitochondrial Biogenesis by exercise. They support the hypothesis that an increase in cytosolic Ca2+ is one of the signals that mediate increased Mitochondrial Biogenesis in muscle.
Dongho Han - One of the best experts on this subject based on the ideXlab platform.
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effects of resveratrol and sirt1 on pgc 1α activity and Mitochondrial Biogenesis a reevaluation
PLOS Biology, 2013Co-Authors: Kazuhiko Higashida, John O Holloszy, Sanghyun Kim, Su Ryun Jung, Meiko Asaka, Dongho HanAbstract:It has been reported that feeding mice resveratrol activates AMPK and SIRT1 in skeletal muscle leading to deacetylation and activation of PGC-1α, increased Mitochondrial Biogenesis, and improved running endurance. This study was done to further evaluate the effects of resveratrol, SIRT1, and PGC-1α deacetylation on Mitochondrial Biogenesis in muscle. Feeding rats or mice a diet containing 4 g resveratrol/kg diet had no effect on Mitochondrial protein levels in muscle. High concentrations of resveratrol lowered ATP concentration and activated AMPK in C2C12 myotubes, resulting in an increase in Mitochondrial proteins. Knockdown of SIRT1, or suppression of SIRT1 activity with a dominant-negative (DN) SIRT1 construct, increased PGC-1α acetylation, PGC-1α coactivator activity, and Mitochondrial proteins in C2C12 cells. Expression of a DN SIRT1 in rat triceps muscle also induced an increase in Mitochondrial proteins. Overexpression of SIRT1 decreased PGC-1α acetylation, PGC-1α coactivator activity, and Mitochondrial proteins in C2C12 myotubes. Overexpression of SIRT1 also resulted in a decrease in Mitochondrial proteins in rat triceps muscle. We conclude that, contrary to some previous reports, the mechanism by which SIRT1 regulates Mitochondrial Biogenesis is by inhibiting PGC-1α coactivator activity, resulting in a decrease in mitochondria. We also conclude that feeding rodents resveratrol has no effect on Mitochondrial Biogenesis in muscle.
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exercise induced Mitochondrial Biogenesis begins before the increase in muscle pgc 1α expression
Journal of Biological Chemistry, 2007Co-Authors: David C Wright, Terry E Jones, Dongho Han, Pablo M Garciaroves, Paige C Geiger, John O HolloszyAbstract:Exercise results in rapid increases in expression of the transcription coactivator peroxisome proliferator-activated receptor coactivator-1 (PGC-1) and in Mitochondrial Biogenesis in skeletal muscle. PGC-1 regulates and coordinates Mitochondrial Biogenesis, and overexpression of PGC-1 in muscle cells results in increases in Mitochondrial content. In this context, it has been proposed that the increase in PGC-1 protein expression mediates the exercise-induced increase in Mitochondrial Biogenesis. However, we found that Mitochondrial proteins with a short half-life increase as rapidly as, or more rapidly than, PGC-1 protein. This finding led us to hypothesize that activation, rather than increased expression, of PGC-1 mediates the initial phase of the exercise-induced increase in mitochondria. In this study, we found that most of the PGC-1 in resting skeletal muscle is in the cytosol. Exercise resulted in activation of p38 MAPK and movement of PGC-1 into the nucleus. In support of our hypothesis, binding of the transcription factor nuclear respiratory factor 1 (NRF-1) to the cytochrome c promoter and NRF-2 to the cytochrome oxidase subunit 4 promoter increased in response to exercise prior to an increase in PGC-1 protein. Furthermore, exercise-induced increases in the mRNAs of cytochrome c, -aminolevulinate synthase, and citrate synthase also occurred before an increase in PGC-1 protein. Thus, it appears that activation of PGC-1 may mediate the initial phase of the exercise-induced adaptive increase in muscle mitochondria, whereas the subsequent increase in PGC-1 protein sustains and enhances the increase in Mitochondrial Biogenesis.
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raising ca2 in l6 myotubes mimics effects of exercise on Mitochondrial Biogenesis in muscle
The FASEB Journal, 2003Co-Authors: Edward O Ojuka, Terry E Jones, Dongho Han, May Chen, John O HolloszyAbstract:Skeletal muscle adapts to endurance exercise with an increase in mitochondria. Muscle contractions generate numerous potential signals. To determine which of these stimulates Mitochondrial Biogenesis, we are using L6 myotubes. Using this model we have found that raising cytosolic Ca2+ induces an increase in mitochondria. In this study, we tested the hypothesis that raising cytosolic Ca2+ in L6 myotubes induces increased expression of PGC-1, NRF-1, NRF-2, and mtTFA, factors that have been implicated in Mitochondrial Biogenesis and in the adaptation of muscle to exercise. Raising cytosolic Ca2+ by exposing L6 myotubes to caffeine for 5 h induced significant increases in PGC-1 and mtTFA protein expression and in NRF-1 and NRF-2 binding to DNA. These adaptations were prevented by dantrolene, which blocks Ca2+ release from the SR. Exposure of L6 myotubes to caffeine for 5 h per day for 5 days induced significant increases in Mitochondrial marker enzyme proteins. Our results show that the adaptive response of L6 myotubes to an increase in cytosolic Ca2+ mimics the stimulation of Mitochondrial Biogenesis by exercise. They support the hypothesis that an increase in cytosolic Ca2+ is one of the signals that mediate increased Mitochondrial Biogenesis in muscle.
Vladimir Veksler - One of the best experts on this subject based on the ideXlab platform.
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transcriptional control of Mitochondrial Biogenesis the central role of pgc 1alpha
Cardiovascular Research, 2008Co-Authors: Anne Garnier, Renee Venturaclapier, Vladimir VekslerAbstract:Although the concept of energy starvation in the failing heart was proposed decades ago, still very little is known about the origin of energetic failure. Recent advances in molecular biology have started to elucidate the transcriptional events governing Mitochondrial Biogenesis. In particular, a great step was taken with the discovery that peroxisome proliferator-activated receptor gamma co-activator (PGC-1α) is the master regulator of Mitochondrial Biogenesis. The molecular mechanisms underlying the downregulation of PGC-1α and the consequent decrease in Mitochondrial function in heart failure are, however, still poorly understood. Indeed, the main pathways involved in Mitochondrial Biogenesis are thought to be up- rather than down-regulated in pathological hypertrophy and heart failure. The current review summarizes recent advances in this field and is restricted to the heart when cardiac data are available.
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Transcriptional control of Mitochondrial Biogenesis. The central role of PGC-1alpha.
Cardiovascular Research, 2008Co-Authors: Renée Ventura-clapier, Anne Garnier, Vladimir VekslerAbstract:Although the concept of energy starvation in the failing heart was proposed decades ago, still very little is known about the origin of energetic failure. Recent advances in molecular biology have started to elucidate the transcriptional events governing Mitochondrial Biogenesis. In particular a great step forwards was taken with the discovery that peroxisome proliferator-activated receptor gamma co-activator (PGC-1alpha) is the master regulator of Mitochondrial Biogenesis. The molecular mechanisms underlying the downregulation of PGC-1α and the consequent decrease in Mitochondrial function in heart failure are, however, still poorly understood. Indeed, the main pathways involved in Mitochondrial Biogenesis are thought to be up- rather than down-regulated in pathological hypertrophy and heart failure. The current review summarizes recent advances in this field and is restricted to the heart when cardiac data is available.
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Mitochondrial Biogenesis in fast skeletal muscle of CK deficient mice
Biochimica et Biophysica Acta (BBA) - Reviews on Bioenergetics, 2008Co-Authors: Anika Vaarmann, Renée Ventura-clapier, Vladimir Veksler, Dominique Fortin, Iman Momken, Anne GarnierAbstract:Creatine kinase (CK) is a phosphotransfer kinase that catalyzes the reversible transfer of a phosphate moiety between ADP and creatine and that is highly expressed in skeletal muscle. In fast glycolytic skeletal muscle, deletion of the cytosolic M isoform of CK in mice (M-CK-/-) leads to a massive increase in the oxidative capacity and of Mitochondrial volume. This study was aimed at investigating the transcriptional pathways leading to Mitochondrial Biogenesis in response to CK deficiency. Wild type and M-CK-/- mice of eleven months of age were used for this study. Gastrocnemius muscles of M-CK-/- mice exhibited a dramatic increase in citrate synthase (+120%) and cytochrome oxidase (COX, +250%) activity, and in Mitochondrial DNA (+60%), showing a clear activation of Mitochondrial Biogenesis. Similarly, mRNA expression of the COXI (mitochondria-encoded) and COXIV (nuclear-encoded) subunits were increased by +103 and +94 % respectively. This was accompanied by an increase in the expression of the nuclear respiratory factor (NRF2Α and the Mitochondrial transcription factor (mtTFA). Expression of the co-activator PGC-1Α, a master gene in Mitochondrial Biogenesis was not significantly increased while that of PGC-1Β and PRC, two members of the same family, was moderately increased (+45% and +55% respectively). While the expression of the modulatory calcineurin-interacting protein 1 (MCIP1) was dramatically decreased (minus 68%) suggesting inactivation of the calcineurin pathway, the metabolic sensor AMPK was activated (+86%) in M-CK-/- mice. These results evidence that Mitochondrial Biogenesis in response to a metabolic challenge exhibits a unique pattern of regulation, involving activation of the AMPK pathway.
Rick G. Schnellmann - One of the best experts on this subject based on the ideXlab platform.
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Mitochondrial Biogenesis as a pharmacological target a new approach to acute and chronic diseases
Annual Review of Pharmacology and Toxicology, 2016Co-Authors: Ryan M Whitaker, Craig C Beeson, Daniel Corum, Rick G. SchnellmannAbstract:Mitochondrial dysfunction is a key pathophysiological component of many acute and chronic diseases. Maintenance of Mitochondrial homeostasis through the balance of Mitochondrial turnover, fission and fusion, and generation of new mitochondria via Mitochondrial Biogenesis is critical for tissue health. Pharmacological activation of Mitochondrial Biogenesis can enhance oxidative metabolism and tissue bioenergetics, and improve organ function in conditions characterized by Mitochondrial dysfunction. However, owing to the complexity of Mitochondrial assembly and maintenance, identification of specific activators of Mitochondrial Biogenesis has been difficult. This review provides an overview of the role of Mitochondrial dysfunction in acute and chronic diseases, details the current state of therapeutics for the stimulation of Mitochondrial Biogenesis and their effects on disease outcomes, describes new screening methodologies to identify novel stimulators and noncanonical pathways of Mitochondrial Biogenesis,...
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srt1720 induces Mitochondrial Biogenesis and rescues Mitochondrial function after oxidant injury in renal proximal tubule cells
Journal of Pharmacology and Experimental Therapeutics, 2010Co-Authors: Jason A Funk, Sina Odejinmi, Rick G. SchnellmannAbstract:Mitochondrial Biogenesis occurs under basal conditions and is an adaptive response initiated by cells to maintain energetic demands and metabolic homeostasis after injuries targeting Mitochondrial function. Identifying pharmacological agents that stimulate Mitochondrial Biogenesis is a critical step in the development of new therapeutics for the treatment of these injuries and to test the hypothesis that these agents will expedite recovery of cell and organ function after acute organ injuries. In this study, we examined the effects of N-[2-[3-(piperazin-1-ylmethyl)imidazo[2,1-b][1,3]thiazol-6-yl]phenyl]quinoxaline-2-carboxamide (SRT1720) on Mitochondrial Biogenesis and function in primary cultures of renal proximal tubule cells (RPTCs). We also tested the ability of this compound to restore Mitochondrial functions after oxidant-induced RPTC injury. SRT1720 (3–10 μM) induced Mitochondrial Biogenesis in RPTCs within 24 h as determined by elevations in Mitochondrial DNA copy number, increased expression of the Mitochondrial proteins NADH dehydrogenase 1β subcomplex subunit 8 (NDUFB8) and ATP synthase β, and elevated Mitochondrial respiration rates and ATP levels. Induction of Mitochondrial Biogenesis depended on mammalian sirtuin 1 (SIRT1) deacetylase activity, correlated with deacetylated nuclear peroxisome proliferator-activated receptor coactivator (PGC)-1α, and occurred in the absence of AMP-dependent kinase (AMPK) activation. Finally, SRT1720 treatment accelerated recovery of Mitochondrial functions after acute oxidant injury. This study demonstrates that SRT1720 can induce Mitochondrial Biogenesis through SIRT1 activity and deacetylated PGC-1α, but not AMPK, in RPTCs within 24 h after oxidant injury. The results support further study of Mitochondrial Biogenesis as a repair process and a pharmacological target in acute organ injuries and disorders plagued by Mitochondrial impairment.
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isoflavones promote Mitochondrial Biogenesis
Journal of Pharmacology and Experimental Therapeutics, 2008Co-Authors: Kyle A. Rasbach, Rick G. SchnellmannAbstract:Mitochondrial damage is often both the cause and outcome of cell injury resulting from a variety of toxic insults, hypoxia, or trauma. Increasing Mitochondrial Biogenesis after renal proximal tubular cell (RPTC) injury accelerated the recovery of Mitochondrial and cellular functions (Biochem Biophys Res Commun 355:734-739, 2007). However, few pharmacological agents are known to increase Mitochondrial Biogenesis. We report that daidzein, genistein, biochanin A, formononetin, 3-(2',4'-dichlorophenyl)-7-hydroxy-4H-chromen-4-one (DCHC), 7-hydroxy-4H-chromen-4-one (7-C), 4'7-dimethoxyisoflavone (4',7-D), and 5,7,4'-trimethoxyisoflavone (5,7,4'-T) increased peroxisome proliferator-activated receptor gamma coactivator (PGC)-1alpha expression and resulted in Mitochondrial Biogenesis as indicated by increased expression of ATP synthase beta and ND6, and 1.5-fold increases in respiration and ATP in RPTC. Inhibition of estrogen receptors with ICI182780 (fulvestrant) had no effect on daidzein-induced Mitochondrial Biogenesis. The isoflavone derivatives showed differential effects on the activation and expression of sirtuin (SIRT)1, a deacetylase and activator of PGC-1alpha. Daidzein and formononetin induced the expression of SIRT1 in RPTC and the activation of recombinant SIRT1, whereas DCHC and 7-C only induced the activation of recombinant SIRT1. In contrast, genistein, biochanin A, 4',7-D, and 5,7,4'-T only increased SIRT1 expression in RPTC. We have identified a series of substituted isoflavones that produce Mitochondrial Biogenesis through PGC1alpha and increased SIRT1 activity and/or expression, independently of the estrogen receptor. Furthermore, different structural components are responsible for the activities of isoflavones: the hydroxyl group at position 7 is required SIRT1 activation, a hydroxyl group at position 5 blocks SIRT1 activation, and the loss of the phenyl ring at position 3 or the 4'-hydroxy or -methoxy substituent blocks increased SIRT1 expression.
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Isoflavones Promote Mitochondrial Biogenesis
Journal of Pharmacology and Experimental Therapeutics, 2008Co-Authors: Kyle A. Rasbach, Rick G. SchnellmannAbstract:Mitochondrial damage is often both the cause and outcome of cell injury resulting from a variety of toxic insults, hypoxia, or trauma. Increasing Mitochondrial Biogenesis after renal proximal tubular cell (RPTC) injury accelerated the recovery of Mitochondrial and cellular functions ( Biochem Biophys Res Commun 355: 734–739, 2007). However, few pharmacological agents are known to increase Mitochondrial Biogenesis. We report that daidzein, genistein, biochanin A, formononetin, 3-(2′,4′-dichlorophenyl)-7-hydroxy-4 H -chromen-4-one (DCHC), 7-hydroxy-4 H -chromen-4-one (7-C), 4′7-dimethoxyisoflavone (4′,7-D), and 5,7,4′-trimethoxyisoflavone (5,7,4′-T) increased peroxisome proliferator-activated receptor γ coactivator (PGC)-1α expression and resulted in Mitochondrial Biogenesis as indicated by increased expression of ATP synthase β and ND6, and 1.5-fold increases in respiration and ATP in RPTC. Inhibition of estrogen receptors with ICI182780 (fulvestrant) had no effect on daidzein-induced Mitochondrial Biogenesis. The isoflavone derivatives showed differential effects on the activation and expression of sirtuin (SIRT)1, a deacetylase and activator of PGC-1α. Daidzein and formononetin induced the expression of SIRT1 in RPTC and the activation of recombinant SIRT1, whereas DCHC and 7-C only induced the activation of recombinant SIRT1. In contrast, genistein, biochanin A, 4′,7-D, and 5,7,4′-T only increased SIRT1 expression in RPTC. We have identified a series of substituted isoflavones that produce Mitochondrial Biogenesis through PGC1α and increased SIRT1 activity and/or expression, independently of the estrogen receptor. Furthermore, different structural components are responsible for the activities of isoflavones: the hydroxyl group at position 7 is required SIRT1 activation, a hydroxyl group at position 5 blocks SIRT1 activation, and the loss of the phenyl ring at position 3 or the 4′-hydroxy or -methoxy substituent blocks increased SIRT1 expression.