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Sample records for exercise-induced mitochondrial biogenesis

  1. Potential role of lipin-1 in exercise-induced mitochondrial biogenesis.

    PubMed

    Higashida, Kazuhiko; Higuchi, Mitsuru; Terada, Shin

    2008-09-26

    Endurance exercise induces mitochondrial biogenesis in skeletal muscle. It has been shown that lipin-1 acts as a transcriptional coactivator in liver, and stimulates gene expression of mitochondrial enzymes. We hypothesized that lipin-1 might be involved in exercise-induced mitochondrial biogenesis in skeletal muscle. The present investigation first demonstrated that lipin-1 mRNA in rat triceps muscle was increased by approximately 2-fold after an acute bout of endurance swimming exercise. Second, ectopic expression of lipin-1 in L6 myotube increased carnitine palmitoyltransferase-1 and delta-aminolevulinate synthase gene expression. Finally, lipin-1 mRNA expression in rat triceps muscle was significantly elevated at 6h after subcutaneous injections of 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) or clenbuterol, which are 5'-AMP-activated protein kinase (AMPK) and beta2-adrenergic receptor (beta2-AR) activators, respectively. These results may suggest that enhanced expression of lipin-1 is involved in exercise-induced mitochondrial enzyme adaptations, possibly through AMPK- and beta2-AR-related mechanisms.

  2. Utilizing small nutrient compounds as enhancers of exercise-induced mitochondrial biogenesis

    PubMed Central

    Craig, Daniel M.; Ashcroft, Stephen P.; Belew, Micah Y.; Stocks, Ben; Currell, Kevin; Baar, Keith; Philp, Andrew

    2015-01-01

    Endurance exercise, when performed regularly as part of a training program, leads to increases in whole-body and skeletal muscle-specific oxidative capacity. At the cellular level, this adaptive response is manifested by an increased number of oxidative fibers (Type I and IIA myosin heavy chain), an increase in capillarity and an increase in mitochondrial biogenesis. The increase in mitochondrial biogenesis (increased volume and functional capacity) is fundamentally important as it leads to greater rates of oxidative phosphorylation and an improved capacity to utilize fatty acids during sub-maximal exercise. Given the importance of mitochondrial biogenesis for skeletal muscle performance, considerable attention has been given to understanding the molecular cues stimulated by endurance exercise that culminate in this adaptive response. In turn, this research has led to the identification of pharmaceutical compounds and small nutritional bioactive ingredients that appear able to amplify exercise-responsive signaling pathways in skeletal muscle. The aim of this review is to discuss these purported exercise mimetics and bioactive ingredients in the context of mitochondrial biogenesis in skeletal muscle. We will examine proposed modes of action, discuss evidence of application in skeletal muscle in vivo and finally comment on the feasibility of such approaches to support endurance-training applications in humans. PMID:26578969

  3. Mitochondrial biogenesis and turnover.

    PubMed

    Diaz, Francisca; Moraes, Carlos T

    2008-07-01

    Mitochondrial biogenesis is a complex process involving the coordinated expression of mitochondrial and nuclear genes, the import of the products of the latter into the organelle and turnover. The mechanisms associated with these events have been intensively studied in the last 20 years and our understanding of their details is much improved. Mitochondrial biogenesis requires the participation of calcium signaling that activates a series of calcium-dependent protein kinases that in turn activate transcription factors and coactivators such as PGC-1alpha that regulates the expression of genes coding for mitochondrial components. In addition, mitochondrial biogenesis involves the balance of mitochondrial fission-fusion. Mitochondrial malfunction or defects in any of the many pathways involved in mitochondrial biogenesis can lead to degenerative diseases and possibly play an important part in aging.

  4. Mitochondrial biogenesis: pharmacological approaches.

    PubMed

    Valero, Teresa

    2014-01-01

    Organelle biogenesis is concomitant to organelle inheritance during cell division. It is necessary that organelles double their size and divide to give rise to two identical daughter cells. Mitochondrial biogenesis occurs by growth and division of pre-existing organelles and is temporally coordinated with cell cycle events [1]. However, mitochondrial biogenesis is not only produced in association with cell division. It can be produced in response to an oxidative stimulus, to an increase in the energy requirements of the cells, to exercise training, to electrical stimulation, to hormones, during development, in certain mitochondrial diseases, etc. [2]. Mitochondrial biogenesis is therefore defined as the process via which cells increase their individual mitochondrial mass [3]. Recent discoveries have raised attention to mitochondrial biogenesis as a potential target to treat diseases which up to date do not have an efficient cure. Mitochondria, as the major ROS producer and the major antioxidant producer exert a crucial role within the cell mediating processes such as apoptosis, detoxification, Ca2+ buffering, etc. This pivotal role makes mitochondria a potential target to treat a great variety of diseases. Mitochondrial biogenesis can be pharmacologically manipulated. This issue tries to cover a number of approaches to treat several diseases through triggering mitochondrial biogenesis. It contains recent discoveries in this novel field, focusing on advanced mitochondrial therapies to chronic and degenerative diseases, mitochondrial diseases, lifespan extension, mitohormesis, intracellular signaling, new pharmacological targets and natural therapies. It contributes to the field by covering and gathering the scarcely reported pharmacological approaches in the novel and promising field of mitochondrial biogenesis. There are several diseases that have a mitochondrial origin such as chronic progressive external ophthalmoplegia (CPEO) and the Kearns- Sayre syndrome (KSS

  5. Mitochondrial biogenesis in kidney disease.

    PubMed

    Weinberg, Joel M

    2011-03-01

    The transcriptional regulation of mitochondrial biogenesis by normal metabolic adaptation or injury has been clarified over the past decade. Mitochondrial biogenesis and its attendant processes enhance metabolic pathways such as fatty acid oxidation and increase antioxidant defense mechanisms that ameliorate injury from aging, tissue hypoxia, and glucose or fatty acid overload, all of which contribute to the pathogenesis of acute and chronic kidney disease. There has been considerable interest in peroxisome proliferator-activated receptors (PPAR) in the kidney, which affect multiple processes in addition to mitochondrial biogenesis. As yet there is relatively little information focused specifically on mitochondrial biogenesis and its regulation by PPARγ coactivators and their modulators such as SIRT1. The available data indicate that these pathways will be fruitful areas for study in the modification of renal disease.

  6. Mitochondrial biogenesis in cardiac pathophysiology.

    PubMed

    Rimbaud, Stéphanie; Garnier, Anne; Ventura-Clapier, Renée

    2009-01-01

    Cardiac performance depends on a fine balance between the work the heart has to perform to satisfy the needs of the body and the energy that it is able to produce. Thus, energy production by oxidative metabolism, the main energy source of the cardiac muscle, has to be strictly regulated to adapt to cardiac work. Mitochondrial biogenesis is the mechanism responsible for mitochondrial component synthesis and assembly. This process controls mitochondrial content and thus correlates with energy production that, in turn, sustains cardiac contractility. Mitochondrial biogenesis should be finely controlled to match cardiac growth and cardiac work. When the heart is subjected to an increase in work in response to physiological and pathological challenges, it adapts by increasing its mass and expressing a new genetic program. In response to physiological stimuli such as endurance training, mitochondrial biogenesis seems to follow a program involving increased cardiac mass. But in the context of pathological hypertrophy, the modifications of this mechanism remain unclear. What appears clear is that mitochondrial biogenesis is altered in heart failure, and the imbalance between cardiac work demand and energy production represents a major factor in the development of heart failure.

  7. Mitochondrial biogenesis in plants during seed germination.

    PubMed

    Law, Simon R; Narsai, Reena; Whelan, James

    2014-11-01

    Mitochondria occupy a central role in the eukaryotic cell. In addition to being major sources of cellular energy, mitochondria are also involved in a diverse range of functions including signalling, the synthesis of many essential organic compounds and a role in programmed cell death. The active proliferation and differentiation of mitochondria is termed mitochondrial biogenesis and necessitates the coordinated communication of mitochondrial status within an integrated cellular network. Two models of mitochondrial biogenesis have been defined previously, the growth and division model and the maturation model. The former describes the growth and division of pre-existing mature organelles through a form of binary fission, while the latter describes the propagation of mitochondria from structurally and biochemically simple promitochondrial structures that upon appropriate stimuli, mature into fully functional mitochondria. In the last decade, a number of studies have utilised seed germination in plants as a platform for the examination of the processes occurring during mitochondrial biogenesis. These studies have revealed many new aspects of the tightly regulated procession of events that define mitochondrial biogenesis during this period of rapid development. A model for mitochondrial biogenesis that supports the maturation of mitochondria from promitochondrial structures has emerged, where mitochondrial signalling plays a crucial role in the early steps of seed germination.

  8. Mitochondrial Biogenesis and Function in Arabidopsis†

    PubMed Central

    Millar, A. Harvey; Small, Ian D.; Day, David A.; Whelan, James

    2008-01-01

    Mitochondria represent the powerhouse of cells through their synthesis of ATP. However, understanding the role of mitochondria in the growth and development of plants will rely on a much deeper appreciation of the complexity of this organelle. Arabidopsis research has provided clear identification of mitochondrial components, allowed wide-scale analysis of gene expression, and has aided reverse genetic manipulation to test the impact of mitochondrial component loss on plant function. Forward genetics in Arabidopsis has identified mitochondrial involvement in mutations with notable impacts on plant metabolism, growth and development. Here we consider the evidence for components involved in mitochondria biogenesis, metabolism and signalling to the nucleus. PMID:22303236

  9. Mitochondrial nutrients stimulate performance and mitochondrial biogenesis in exhaustively exercised rats.

    PubMed

    Sun, M; Qian, F; Shen, W; Tian, C; Hao, J; Sun, L; Liu, J

    2012-12-01

    The aim of this study was to investigate the effects of a combination of nutrients on physical performance, oxidative stress and mitochondrial biogenesis in rats subjected to exhaustive exercise. Rats were divided into sedentary control (SC), exhaustive exercise (EC) and exhaustive exercise with nutrient supplementation (EN). The nutrients include (mg/kg/day): R-α-lipoic acid 50, acetyl-L-carnitine 100, biotin 0.1, nicotinamide 15, riboflavin 6, pyridoxine 6, creatine 50, CoQ10 5, resveratrol 5 and taurine 100. Examination of running distances over the 4-week period revealed that EN rats ran significantly longer throughout the entire duration of the exhaustive exercise period compared with the EC rats. Nutrient supplementation significantly inhibited the increase in activities of alanine transaminase, lactate dehydrogenase and creatine kinase, reversed increases in malondialdehyde, inhibited decreases in glutathione S-transferase and total antioxidant capacity in plasma, and suppressed the elevation of reactive oxygen species and apoptosis in splenic lymphocytes. Nutrient supplementation increased the protein expression of mitochondrial complexes I, II and III, mtDNA number and transcription factors involved in mitochondrial biogenesis and fusion in skeletal muscle. These findings suggest that mitochondrial nutrient supplementation can reduce exhaustive exercise-induced oxidative damage and mitochondrial dysfunction, thus leading to enhancement of physical performance and of fatigue recovery.

  10. Hyperglycemia decreases mitochondrial function: The regulatory role of mitochondrial biogenesis

    SciTech Connect

    Palmeira, Carlos M. Rolo, Anabela P.; Berthiaume, Jessica; Bjork, James A.; Wallace, Kendall B.

    2007-12-01

    Increased generation of reactive oxygen species (ROS) is implicated in 'glucose toxicity' in diabetes. However, little is known about the action of glucose on the expression of transcription factors in hepatocytes, especially those involved in mitochondrial DNA (mtDNA) replication and transcription. Since mitochondrial functional capacity is dynamically regulated, we hypothesized that stressful conditions of hyperglycemia induce adaptations in the transcriptional control of cellular energy metabolism, including inhibition of mitochondrial biogenesis and oxidative metabolism. Cell viability, mitochondrial respiration, ROS generation and oxidized proteins were determined in HepG2 cells cultured in the presence of either 5.5 mM (control) or 30 mM glucose (high glucose) for 48 h, 96 h and 7 days. Additionally, mtDNA abundance, plasminogen activator inhibitor-1 (PAI-1), mitochondrial transcription factor A (TFAM) and nuclear respiratory factor-1 (NRF-1) transcripts were evaluated by real time PCR. High glucose induced a progressive increase in ROS generation and accumulation of oxidized proteins, with no changes in cell viability. Increased expression of PAI-1 was observed as early as 96 h of exposure to high glucose. After 7 days in hyperglycemia, HepG2 cells exhibited inhibited uncoupled respiration and decreased MitoTracker Red fluorescence associated with a 25% decrease in mtDNA and 16% decrease in TFAM transcripts. These results indicate that glucose may regulate mtDNA copy number by modulating the transcriptional activity of TFAM in response to hyperglycemia-induced ROS production. The decrease of mtDNA content and inhibition of mitochondrial function may be pathogenic hallmarks in the altered metabolic status associated with diabetes.

  11. Targeting mitochondrial biogenesis to overcome drug resistance to MAPK inhibitors

    PubMed Central

    Zhang, Gao; Frederick, Dennie T.; Wu, Lawrence; Wei, Zhi; Krepler, Clemens; Srinivasan, Satish; Chae, Young Chan; Xu, Xiaowei; Choi, Harry; Dimwamwa, Elaida; Shannan, Batool; Basu, Devraj; Zhang, Dongmei; Guha, Manti; Xiao, Min; Randell, Sergio; Sproesser, Katrin; Xu, Wei; Liu, Jephrey; Karakousis, Giorgos C.; Schuchter, Lynn M.; Gangadhar, Tara C.; Amaravadi, Ravi K.; Gu, Mengnan; Xu, Caiyue; Ghosh, Abheek; Xu, Weiting; Tian, Tian; Zhang, Jie; Zha, Shijie; Brafford, Patricia; Weeraratna, Ashani; Davies, Michael A.; Wargo, Jennifer A.; Avadhani, Narayan G.; Lu, Yiling; Mills, Gordon B.; Altieri, Dario C.; Flaherty, Keith T.

    2016-01-01

    Targeting multiple components of the MAPK pathway can prolong the survival of patients with BRAFV600E melanoma. This approach is not curative, as some BRAF-mutated melanoma cells are intrinsically resistant to MAPK inhibitors (MAPKi). At the systemic level, our knowledge of how signaling pathways underlie drug resistance needs to be further expanded. Here, we have shown that intrinsically resistant BRAF-mutated melanoma cells with a low basal level of mitochondrial biogenesis depend on this process to survive MAPKi. Intrinsically resistant cells exploited an integrated stress response, exhibited an increase in mitochondrial DNA content, and required oxidative phosphorylation to meet their bioenergetic needs. We determined that intrinsically resistant cells rely on the genes encoding TFAM, which controls mitochondrial genome replication and transcription, and TRAP1, which regulates mitochondrial protein folding. Therefore, we targeted mitochondrial biogenesis with a mitochondrium-targeted, small-molecule HSP90 inhibitor (Gamitrinib), which eradicated intrinsically resistant cells and augmented the efficacy of MAPKi by inducing mitochondrial dysfunction and inhibiting tumor bioenergetics. A subset of tumor biopsies from patients with disease progression despite MAPKi treatment showed increased mitochondrial biogenesis and tumor bioenergetics. A subset of acquired drug-resistant melanoma cell lines was sensitive to Gamitrinib. Our study establishes mitochondrial biogenesis, coupled with aberrant tumor bioenergetics, as a potential therapy escape mechanism and paves the way for a rationale-based combinatorial strategy to improve the efficacy of MAPKi. PMID:27043285

  12. Diabetes regulates mitochondrial biogenesis and fission in neurons

    PubMed Central

    Edwards, J.L.; Quattrini, A.; Lentz, S.I.; Figueroa-Romero, C.; Cerri, F.; Backus, C.; Hong, Y.; Feldman, E.L.

    2014-01-01

    Aims Normal mitochondrial (Mt) activity is a critical component of neuronal metabolism and function. Disruption of Mt activity by altered Mt fission and fusion is the root cause of both neurodegenerative disorders and Charcot-Marie-Tooth Type 2A inherited neuropathy. The current study addressed the role of Mt fission in the pathogenesis of diabetic neuropathy (DN). Methods Mt biogenesis and fission were assayed in both in vivo and in vitro models of DN. Gene, protein, mitochondrial DNA and ultrastructural analyses were used to assess Mt biogenesis and fission. Results Our data reveal increased Mt biogenesis in dorsal root ganglion (DRG) neurons from diabetic compared to non-diabetic mice. An essential step in Mt biogenesis is Mt fission, regulated by the Mt fission protein Drp1. Evaluation of in vivo diabetic neurons indicated small, fragmented Mt, suggesting increased fission. In vitro studies reveal short-term hyperglycemic exposure increased expression of Drp1. The influence of hyperglycemia-mediated Mt fission on cellular viability was evaluated by knockdown of Drp1. Knockdown of Drp1 resulted in decreased susceptibility to hyperglycemic damage. Conclusions We propose that: 1) Mt undergo biogenesis in response to hyperglycemia, but the increased biogenesis is insufficient to accommodate the metabolic load; 2) hyperglycemia causes an excess of Mt fission, creating small, damaged mitochondria; and 3) reduction of aberrant Mt fission increases neuronal survival and indicates an important role for the fission-fusion equilibrium in the pathogenesis of DN. PMID:19847394

  13. Echinochrome A Increases Mitochondrial Mass and Function by Modulating Mitochondrial Biogenesis Regulatory Genes

    PubMed Central

    Jeong, Seung Hun; Kim, Hyoung Kyu; Song, In-Sung; Noh, Su Jin; Marquez, Jubert; Ko, Kyung Soo; Rhee, Byoung Doo; Kim, Nari; Mishchenko, Natalia P.; Fedoreyev, Sergey A.; Stonik, Valentin A.; Han, Jin

    2014-01-01

    Echinochrome A (Ech A) is a natural pigment from sea urchins that has been reported to have antioxidant properties and a cardio protective effect against ischemia reperfusion injury. In this study, we ascertained whether Ech A enhances the mitochondrial biogenesis and oxidative phosphorylation in rat cardio myoblast H9c2 cells. To study the effects of Ech A on mitochondrial biogenesis, we measured mitochondrial mass, level of oxidative phosphorylation, and mitochondrial biogenesis regulatory gene expression. Ech A treatment did not induce cytotoxicity. However, Ech A treatment enhanced oxygen consumption rate and mitochondrial ATP level. Likewise, Ech A treatment increased mitochondrial contents in H9c2 cells. Furthermore, Ech A treatment up-regulated biogenesis of regulatory transcription genes, including proliferator-activated receptor gamma co-activator (PGC)-1α, estrogen-related receptor (ERR)-α, peroxisome proliferator-activator receptor (PPAR)-γ, and nuclear respiratory factor (NRF)-1 and such mitochondrial transcription regulatory genes as mitochondrial transcriptional factor A (TFAM), mitochondrial transcription factor B2 (TFB2M), mitochondrial DNA direct polymerase (POLMRT), single strand binding protein (SSBP) and Tu translation elongation factor (TUFM). In conclusion, these data suggest that Ech A is a potentiated marine drug which enhances mitochondrial biogenesis. PMID:25196935

  14. The mitochondrial acyl carrier protein (ACP) coordinates mitochondrial fatty acid synthesis with iron sulfur cluster biogenesis

    PubMed Central

    Van Vranken, Jonathan G; Jeong, Mi-Young; Wei, Peng; Chen, Yu-Chan; Gygi, Steven P; Winge, Dennis R; Rutter, Jared

    2016-01-01

    Mitochondrial fatty acid synthesis (FASII) and iron sulfur cluster (FeS) biogenesis are both vital biosynthetic processes within mitochondria. In this study, we demonstrate that the mitochondrial acyl carrier protein (ACP), which has a well-known role in FASII, plays an unexpected and evolutionarily conserved role in FeS biogenesis. ACP is a stable and essential subunit of the eukaryotic FeS biogenesis complex. In the absence of ACP, the complex is destabilized resulting in a profound depletion of FeS throughout the cell. This role of ACP depends upon its covalently bound 4’-phosphopantetheine (4-PP)-conjugated acyl chain to support maximal cysteine desulfurase activity. Thus, it is likely that ACP is not simply an obligate subunit but also exploits the 4-PP-conjugated acyl chain to coordinate mitochondrial fatty acid and FeS biogenesis. DOI: http://dx.doi.org/10.7554/eLife.17828.001 PMID:27540631

  15. Staphylococcus aureus Sepsis Induces Early Renal Mitochondrial DNA Repair and Mitochondrial Biogenesis in Mice

    PubMed Central

    Bartz, Raquel R.; Fu, Ping; Suliman, Hagir B.; Crowley, Stephen D.; MacGarvey, Nancy Chou; Welty-Wolf, Karen; Piantadosi, Claude A.

    2014-01-01

    Acute kidney injury (AKI) contributes to the high morbidity and mortality of multi-system organ failure in sepsis. However, recovery of renal function after sepsis-induced AKI suggests active repair of energy-producing pathways. Here, we tested the hypothesis in mice that Staphyloccocus aureus sepsis damages mitochondrial DNA (mtDNA) in the kidney and activates mtDNA repair and mitochondrial biogenesis. Sepsis was induced in wild-type C57Bl/6J and Cox-8 Gfp-tagged mitochondrial-reporter mice via intraperitoneal fibrin clots embedded with S. aureus. Kidneys from surviving mice were harvested at time zero (control), 24, or 48 hours after infection and evaluated for renal inflammation, oxidative stress markers, mtDNA content, and mitochondrial biogenesis markers, and OGG1 and UDG mitochondrial DNA repair enzymes. We examined the kidneys of the mitochondrial reporter mice for changes in staining density and distribution. S. aureus sepsis induced sharp amplification of renal Tnf, Il-10, and Ngal mRNAs with decreased renal mtDNA content and increased tubular and glomerular cell death and accumulation of protein carbonyls and 8-OHdG. Subsequently, mtDNA repair and mitochondrial biogenesis was evidenced by elevated OGG1 levels and significant increases in NRF-1, NRF-2, and mtTFA expression. Overall, renal mitochondrial mass, tracked by citrate synthase mRNA and protein, increased in parallel with changes in mitochondrial GFP-fluorescence especially in proximal tubules in the renal cortex and medulla. Sub-lethal S. aureus sepsis thus induces widespread renal mitochondrial damage that triggers the induction of the renal mtDNA repair protein, OGG1, and mitochondrial biogenesis as a conspicuous resolution mechanism after systemic bacterial infection. PMID:24988481

  16. Mitochondrial cytochrome c biogenesis: no longer an enigma.

    PubMed

    Babbitt, Shalon E; Sutherland, Molly C; San Francisco, Brian; Mendez, Deanna L; Kranz, Robert G

    2015-08-01

    Cytochromes c (cyt c) and c1 are heme proteins that are essential for aerobic respiration. Release of cyt c from mitochondria is an important signal in apoptosis initiation. Biogenesis of c-type cytochromes involves covalent attachment of heme to two cysteines (at a conserved CXXCH sequence) in the apocytochrome. Heme attachment is catalyzed in most mitochondria by holocytochrome c synthase (HCCS), which is also necessary for the import of apocytochrome c (apocyt c). Thus, HCCS affects cellular levels of cyt c, impacting mitochondrial physiology and cell death. Here, we review the mechanisms of HCCS function and the roles of heme and residues in the CXXCH motif. Additionally, we consider concepts emerging within the two prokaryotic cytochrome c biogenesis pathways.

  17. Mitochondrial cytochrome c biogenesis: no longer an enigma

    PubMed Central

    Babbitt, Shalon E.; Sutherland, Molly C.; Francisco, Brian San; Mendez, Deanna L.; Kranz, Robert G.

    2015-01-01

    Cytochromes c and c1are heme proteins that are essential for aerobic respiration. Release of cytochrome c from mitochondria is an important signal in apoptosis initiation. Biogenesis of c-type cytochromes involves covalent attachment of heme to two cysteines (at a conserved CXXCH sequence) in the apocytochrome. Heme attachment is catalyzed in most mitochondria by holocytochrome c synthase (HCCS), which is also necessary for import of apocytochrome c. Thus, HCCS affects cellular levels of cytochrome c, impacting mitochondrial physiology and cell death. Here, we review the mechanisms of HCCS function and the roles played by heme and residues in the CXXCH motif. Additionally, we consider concepts emerging within the two prokaryotic cytochrome c biogenesis pathways. PMID:26073510

  18. Impaired Muscle Mitochondrial Biogenesis and Myogenesis in Spinal Muscular Atrophy

    PubMed Central

    Ripolone, Michela; Ronchi, Dario; Violano, Raffaella; Vallejo, Dionis; Fagiolari, Gigliola; Barca, Emanuele; Lucchini, Valeria; Colombo, Irene; Villa, Luisa; Berardinelli, Angela; Balottin, Umberto; Morandi, Lucia; Mora, Marina; Bordoni, Andreina; Fortunato, Francesco; Corti, Stefania; Parisi, Daniela; Toscano, Antonio; Sciacco, Monica; DiMauro, Salvatore; Comi, Giacomo P.; Moggio, Maurizio

    2016-01-01

    , implying depression of the entire mitochondrial biogenesis. Results of Western blot analysis confirmed the reduced levels of the respiratory chain subunits that included mitochondrially encoded COX1 (47.5%; P = .004), COX2 (32.4%; P < .001), COX4 (26.6%; P < .001), and succinate dehydrogenase complex subunit A (65.8%; P = .03) as well as the structural outer membrane mitochondrial porin (33.1%; P < .001). Conversely, the levels of expression of 3 myogenic regulatory factors—muscle-specificmyogenic factor 5, myoblast determination 1, and myogenin—were higher in muscles from patients with SMA compared with muscles from age-matched controls (P < .05). CONCLUSIONS AND RELEVANCE Our results strongly support the conclusion that an altered regulation of myogenesis and a downregulated mitochondrial biogenesis contribute to pathologic change in the muscle of patients with SMA. Therapeutic strategies should aim at counteracting these changes. PMID:25844556

  19. Lipophilic antioxidants prevent lipopolysaccharide-induced mitochondrial dysfunction through mitochondrial biogenesis improvement.

    PubMed

    Bullón, Pedro; Román-Malo, Lourdes; Marín-Aguilar, Fabiola; Alvarez-Suarez, José Miguel; Giampieri, Francesca; Battino, Maurizio; Cordero, Mario D

    2015-01-01

    Oxidative stress is implicated in several infectious diseases. In this regard, lipopolysaccharide (LPS), an endotoxic component, induces mitochondrial dysfunction and oxidative stress in several pathological events such as periodontal disease or sepsis. In our experiments, LPS-treated fibroblasts provoked increased oxidative stress, mitochondrial dysfunction, reduced oxygen consumption and mitochondrial biogenesis. After comparing coenzyme Q10 (CoQ10) and N-acetylcysteine (NAC), we observed a more significant protection of CoQ10 than of NAC, which was comparable with other lipophilic and hydrophilic antioxidants such as vitamin E or BHA respectively. CoQ10 improved mitochondrial biogenesis by activating PGC-1α and TFAM. This lipophilic antioxidant protection was observed in mice after LPS injection. These results show that mitochondria-targeted lipophilic antioxidants could be a possible specific therapeutic strategy in pharmacology in the treatment of infectious diseases and their complications.

  20. Cardiac mitochondrial biogenesis in endotoxemia is not accompanied by mitochondrial function recovery.

    PubMed

    Vanasco, Virginia; Saez, Trinidad; Magnani, Natalia D; Pereyra, Leonardo; Marchini, Timoteo; Corach, Alejandra; Vaccaro, María Inés; Corach, Daniel; Evelson, Pablo; Alvarez, Silvia

    2014-12-01

    Mitochondrial biogenesis emerges as a compensatory mechanism involved in the recovery process in endotoxemia and sepsis. The aim of this work was to analyze the time course of the cardiac mitochondrial biogenesis process occurring during endotoxemia, with emphasis on the quantitative analysis of mitochondrial function. Female Sprague-Dawley rats (45 days old) were ip injected with LPS (10 mg/kg). Measurements were performed at 0-24 h after LPS administration. PGC-1α and mtTFA expression for biogenesis and p62 and LC3 expression for autophagy were analyzed by Western blot; mitochondrial DNA levels by qPCR, and mitochondrial morphology by transmission electron microscopy. Mitochondrial function was evaluated as oxygen consumption and respiratory chain complex activity. PGC-1α and mtTFA expression significantly increased in every time point analyzed, and mitochondrial mass was increased by 20% (P<0.05) at 24 h. p62 expression was significantly decreased in a time-dependent manner. LC3-II expression was significantly increased at all time points analyzed. Ultrastructurally, mitochondria displayed several abnormalities (internal vesicles, cristae disruption, and swelling) at 6 and 18 h. Structures compatible with fusion/fission processes were observed at 24 h. A significant decrease in state 3 respiration was observed in every time point analyzed (LPS 6h: 20%, P<0.05). Mitochondrial complex I activity was found decreased by 30% in LPS-treated animals at 6 and 24h. Complex II and complex IV showed decreased activity only at 24 h. The present results show that partial restoration of cardiac mitochondrial architecture is not accompanied by improvement of mitochondrial function in acute endotoxemia. The key implication of our study is that cardiac failure due to bioenergetic dysfunction will be overcome by therapeutic interventions aimed to restore cardiac mitochondrial function.

  1. Mitochondrial biogenesis in the pulmonary vasculature during inhalation lung injury and fibrosis

    EPA Science Inventory

    Cell survival and injury repair is facilitated by mitochondrial biogenesis; however, the role of this process in lung repair is unknown. We evaluated mitochondrial biogenesis in the mouse lung in two injuries that cause acute inflammation and in two that cause chronic inflammatio...

  2. Sirtuin 1 (SIRT1) Deacetylase Activity Is Not Required for Mitochondrial Biogenesis or Peroxisome Proliferator-activated Receptor-γ Coactivator-1α (PGC-1α) Deacetylation following Endurance Exercise*

    PubMed Central

    Philp, Andrew; Chen, Ai; Lan, Debin; Meyer, Gretchen A.; Murphy, Anne N.; Knapp, Amy E.; Olfert, I. Mark; McCurdy, Carrie E.; Marcotte, George R.; Hogan, Michael C.; Baar, Keith; Schenk, Simon

    2011-01-01

    The protein deacetylase, sirtuin 1 (SIRT1), is a proposed master regulator of exercise-induced mitochondrial biogenesis in skeletal muscle, primarily via its ability to deacetylate and activate peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α). To investigate regulation of mitochondrial biogenesis by SIRT1 in vivo, we generated mice lacking SIRT1 deacetylase activity in skeletal muscle (mKO). We hypothesized that deacetylation of PGC-1α and mitochondrial biogenesis in sedentary mice and after endurance exercise would be impaired in mKO mice. Skeletal muscle contractile characteristics were determined in extensor digitorum longus muscle ex vivo. Mitochondrial biogenesis was assessed after 20 days of voluntary wheel running by measuring electron transport chain protein content, enzyme activity, and mitochondrial DNA expression. PGC-1α expression, nuclear localization, acetylation, and interacting protein association were determined following an acute bout of treadmill exercise (AEX) using co-immunoprecipitation and immunoblotting. Contrary to our hypothesis, skeletal muscle endurance, electron transport chain activity, and voluntary wheel running-induced mitochondrial biogenesis were not impaired in mKO versus wild-type (WT) mice. Moreover, PGC-1α expression, nuclear translocation, activity, and deacetylation after AEX were similar in mKO versus WT mice. Alternatively, we made the novel observation that deacetylation of PGC-1α after AEX occurs in parallel with reduced nuclear abundance of the acetyltransferase, general control of amino-acid synthesis 5 (GCN5), as well as reduced association between GCN5 and nuclear PGC-1α. These findings demonstrate that SIRT1 deacetylase activity is not required for exercise-induced deacetylation of PGC-1α or mitochondrial biogenesis in skeletal muscle and suggest that changes in GCN5 acetyltransferase activity may be an important regulator of PGC-1α activity after exercise. PMID:21757760

  3. Coordination of mitophagy and mitochondrial biogenesis during ageing in C. elegans.

    PubMed

    Palikaras, Konstantinos; Lionaki, Eirini; Tavernarakis, Nektarios

    2015-05-28

    Impaired mitochondrial maintenance in disparate cell types is a shared hallmark of many human pathologies and ageing. How mitochondrial biogenesis coordinates with the removal of damaged or superfluous mitochondria to maintain cellular homeostasis is not well understood. Here we show that mitophagy, a selective type of autophagy targeting mitochondria for degradation, interfaces with mitochondrial biogenesis to regulate mitochondrial content and longevity in Caenorhabditis elegans. We find that DCT-1 is a key mediator of mitophagy and longevity assurance under conditions of stress in C. elegans. Impairment of mitophagy compromises stress resistance and triggers mitochondrial retrograde signalling through the SKN-1 transcription factor that regulates both mitochondrial biogenesis genes and mitophagy by enhancing DCT-1 expression. Our findings reveal a homeostatic feedback loop that integrates metabolic signals to coordinate the biogenesis and turnover of mitochondria. Uncoupling of these two processes during ageing contributes to overproliferation of damaged mitochondria and decline of cellular function.

  4. Regulation of Mitoflash Biogenesis and Signaling by Mitochondrial Dynamics

    PubMed Central

    Li, Wenwen; Sun, Tao; Liu, Beibei; Wu, Di; Qi, Wenfeng; Wang, Xianhua; Ma, Qi; Cheng, Heping

    2016-01-01

    Mitochondria are highly dynamic organelles undergoing constant network reorganization and exhibiting stochastic signaling events in the form of mitochondrial flashes (mitoflashes). Here we investigate whether and how mitochondrial network dynamics regulate mitoflash biogenesis and signaling. We found that mitoflash frequency was largely invariant when network fragmentized or redistributed in the absence of mitofusin (Mfn) 1, Mfn2, or Kif5b. However, Opa1 deficiency decreased spontaneous mitoflash frequency due to superimposing changes in respiratory function, whereas mitoflash response to non-metabolic stimulation was unchanged despite network fragmentation. In Drp1- or Mff-deficient cells whose mitochondria hyperfused into a single whole-cell reticulum, the frequency of mitoflashes of regular amplitude and duration was again unaltered, although brief and low-amplitude “miniflashes” emerged because of improved detection ability. As the network reorganized, however, the signal mass of mitoflash signaling was dynamically regulated in accordance with the degree of network connectivity. These findings demonstrate a novel functional role of mitochondrial network dynamics and uncover a magnitude- rather than frequency-modulatory mechanism in the regulation of mitoflash signaling. In addition, our data support a stochastic trigger model for the ignition of mitoflashes. PMID:27623243

  5. Acute Exercise-Induced Mitochondrial Stress Triggers an Inflammatory Response in the Myocardium via NLRP3 Inflammasome Activation with Mitophagy.

    PubMed

    Li, Haiying; Miao, Weiguo; Ma, Jingfen; Xv, Zhen; Bo, Hai; Li, Jianyu; Zhang, Yong; Ji, Li Li

    2016-01-01

    Increasing evidence has indicated that acute strenuous exercise can induce a range of adverse reactions including oxidative stress and tissue inflammation. However, little is currently known regarding the mechanisms that underlie the regulation of the inflammatory response in the myocardium during acute heavy exercise. This study evaluated the mitochondrial function, NLRP3 inflammasome activation, and mitochondrial autophagy-related proteins to investigate the regulation and mechanism of mitochondrial stress regarding the inflammatory response of the rat myocardium during acute heavy exercise. The results indicated that the mitochondrial function of the myocardium was adaptively regulated to meet the challenge of stress during acute exercise. The exercise-induced mitochondrial stress also enhanced ROS generation and triggered an inflammatory reaction via the NLRP3 inflammasome activation. Moreover, the mitochondrial autophagy-related proteins including Beclin1, LC3, and Bnip3 were all significantly upregulated during acute exercise, which suggests that mitophagy was stimulated in response to the oxidative stress and inflammatory response in the myocardium. Taken together, our data suggest that, during acute exercise, mitochondrial stress triggers the rat myocardial inflammatory response via NLRP3 inflammasome activation and activates mitophagy to minimize myocardial injury.

  6. β2-Adrenoceptor agonists in the regulation of mitochondrial biogenesis.

    PubMed

    Peterson, Yuri K; Cameron, Robert B; Wills, Lauren P; Trager, Richard E; Lindsey, Chris C; Beeson, Craig C; Schnellmann, Rick G

    2013-10-01

    The stimulation of mitochondrial biogenesis (MB) via cell surface G-protein coupled receptors is a promising strategy for cell repair and regeneration. Here we report the specificity and chemical rationale of a panel of β2-adrenoceptor agonists with regards to MB. Using primary cultures of renal cells, a diverse panel of β2-adrenoceptor agonists elicited three distinct phenotypes: full MB, partial MB, and non-MB. Full MB compounds had efficacy in the low nanomolar range and represent two chemical scaffolds containing three distinct chemical clusters. Interestingly, the MB phenotype did not correlate with reported receptor affinity or chemical similarity. Chemical clusters were then subjected to pharmacophore modeling creating two models with unique and distinct features, consisting of five conserved amongst full MB compounds were identified. The two discrete pharmacophore models were coalesced into a consensus pharmacophore with four unique features elucidating the spatial and chemical characteristics required to stimulate MB.

  7. Mitochondrial iron-sulfur protein biogenesis and human disease.

    PubMed

    Stehling, Oliver; Wilbrecht, Claudia; Lill, Roland

    2014-05-01

    Work during the past 14 years has shown that mitochondria are the primary site for the biosynthesis of iron-sulfur (Fe/S) clusters. In fact, it is this process that renders mitochondria essential for viability of virtually all eukaryotes, because they participate in the synthesis of the Fe/S clusters of key nuclear and cytosolic proteins such as DNA polymerases, DNA helicases, and ABCE1 (Rli1), an ATPase involved in protein synthesis. As a consequence, mitochondrial function is crucial for nuclear DNA synthesis and repair, ribosomal protein synthesis, and numerous other extra-mitochondrial pathways including nucleotide metabolism and cellular iron regulation. Within mitochondria, the synthesis of Fe/S clusters and their insertion into apoproteins is assisted by 17 proteins forming the ISC (iron-sulfur cluster) assembly machinery. Biogenesis of mitochondrial Fe/S proteins can be dissected into three main steps: First, a Fe/S cluster is generated de novo on a scaffold protein. Second, the Fe/S cluster is dislocated from the scaffold and transiently bound to transfer proteins. Third, the latter components, together with specific ISC targeting factors insert the Fe/S cluster into client apoproteins. Disturbances of the first two steps impair the maturation of extra-mitochondrial Fe/S proteins and affect cellular and systemic iron homeostasis. In line with the essential function of mitochondria, genetic mutations in a number of ISC genes lead to severe neurological, hematological and metabolic diseases, often with a fatal outcome in early childhood. In this review we briefly summarize our current functional knowledge on the ISC assembly machinery, and we present a comprehensive overview of the various Fe/S protein assembly diseases.

  8. Repositioning of antibiotic levofloxacin as a mitochondrial biogenesis inhibitor to target breast cancer.

    PubMed

    Yu, Min; Li, Ruishu; Zhang, Juan

    2016-03-18

    Targeting mitochondrial biogenesis has become a potential therapeutic strategy in cancer due to their unique metabolic dependencies. In this study, we show that levofloxacin, a FDA-approved antibiotic, is an attractive candidate for breast cancer treatment. This is achieved by the inhibition of proliferation and induction of apoptosis in a panel of breast cancer cell lines while sparing normal breast cells. It also acts synergistically with conventional chemo drug in two independent in vivo breast xenograft mouse models. Importantly, levofloxacin inhibits mitochondrial biogenesis as shown by the decreased level of mitochondrial respiration, membrane potential and ATP. In addition, the anti-proliferative and pro-apoptotic effects of levofloxacin are reversed by acetyl-L-Carnitine (ALCAR, a mitochondrial fuel), confirming that levofloxacin's action in breast cancer cells is through inhibition of mitochondrial biogenesis. A consequence of mitochondrial biogenesis inhibition by levofloxacin in breast cancer cells is the deactivation of PI3K/Akt/mTOR and MAPK/ERK pathways. We further demonstrate that breast cancer cells have increased mitochondrial biogenesis than normal breast cells, and this explains their different sensitivity to levofloxacin. Our work suggest that levofloxacin is a useful addition to breast cancer treatment. Our work also establish the essential role of mitochondrial biogenesis on the activation of PI3K/Akt/mTOR and MAPK/ERK pathways in breast cancer cells.

  9. The β2-adrenoceptor agonist formoterol stimulates mitochondrial biogenesis.

    PubMed

    Wills, Lauren P; Trager, Richard E; Beeson, Gyda C; Lindsey, Christopher C; Peterson, Yuri K; Beeson, Craig C; Schnellmann, Rick G

    2012-07-01

    Mitochondrial dysfunction is a common mediator of disease and organ injury. Although recent studies show that inducing mitochondrial biogenesis (MB) stimulates cell repair and regeneration, only a limited number of chemicals are known to induce MB. To examine the impact of the β-adrenoceptor (β-AR) signaling pathway on MB, primary renal proximal tubule cells (RPTC) and adult feline cardiomyocytes were exposed for 24 h to multiple β-AR agonists: isoproterenol (nonselective β-AR agonist), (±)-(R*,R*)-[4-[2-[[2-(3-chlorophenyl)-2-hydroxyethyl]amino]propyl]phenoxy] acetic acid sodium hydrate (BRL 37344) (selective β(3)-AR agonist), and formoterol (selective β(2)-AR agonist). The Seahorse Biosciences (North Billerica, MA) extracellular flux analyzer was used to quantify carbonylcyanide p-trifluoromethoxyphenylhydrazone (FCCP)-uncoupled oxygen consumption rate (OCR), a marker of maximal electron transport chain activity. Isoproterenol and BRL 37244 did not alter mitochondrial respiration at any of the concentrations examined. Formoterol exposure resulted in increases in both FCCP-uncoupled OCR and mitochondrial DNA (mtDNA) copy number. The effect of formoterol on OCR in RPTC was inhibited by the β-AR antagonist propranolol and the β(2)-AR inverse agonist 3-(isopropylamino)-1-[(7-methyl-4-indanyl)oxy]butan-2-ol hydrochloride (ICI-118,551). Mice exposed to formoterol for 24 or 72 h exhibited increases in kidney and heart mtDNA copy number, peroxisome proliferator-activated receptor γ coactivator 1α, and multiple genes involved in the mitochondrial electron transport chain (F0 subunit 6 of transmembrane F-type ATP synthase, NADH dehydrogenase subunit 1, NADH dehydrogenase subunit 6, and NADH dehydrogenase [ubiquinone] 1β subcomplex subunit 8). Cheminformatic modeling, virtual chemical library screening, and experimental validation identified nisoxetine from the Sigma Library of Pharmacologically Active Compounds and two compounds from the ChemBridge DIVERSet

  10. Optimizing intramuscular adaptations to aerobic exercise: effects of carbohydrate restriction and protein supplementation on mitochondrial biogenesis.

    PubMed

    Margolis, Lee M; Pasiakos, Stefan M

    2013-11-01

    Mitochondrial biogenesis is a critical metabolic adaptation to aerobic exercise training that results in enhanced mitochondrial size, content, number, and activity. Recent evidence has shown that dietary manipulation can further enhance mitochondrial adaptations to aerobic exercise training, which may delay skeletal muscle fatigue and enhance exercise performance. Specifically, studies have demonstrated that combining carbohydrate restriction (endogenous and exogenous) with a single bout of aerobic exercise potentiates the beneficial effects of exercise on markers of mitochondrial biogenesis. Additionally, studies have demonstrated that high-quality protein supplementation enhances anabolic skeletal muscle intracellular signaling and mitochondrial protein synthesis following a single bout of aerobic exercise. Mitochondrial biogenesis is stimulated by complex intracellular signaling pathways that appear to be primarily regulated by 5'AMP-activated protein kinase and p38 mitogen-activated protein kinase mediated through proliferator-activated γ receptor co-activator 1 α activation, resulting in increased mitochondrial DNA expression and enhanced skeletal muscle oxidative capacity. However, the mechanisms by which concomitant carbohydrate restriction and dietary protein supplementation modulates mitochondrial adaptations to aerobic exercise training remains unclear. This review summarizes intracellular regulation of mitochondrial biogenesis and the effects of carbohydrate restriction and protein supplementation on mitochondrial adaptations to aerobic exercise.

  11. Mitochondrial biogenesis and fission in axons in cell culture and animal models of diabetic neuropathy.

    PubMed

    Vincent, Andrea M; Edwards, James L; McLean, Lisa L; Hong, Yu; Cerri, Federica; Lopez, Ignazio; Quattrini, Angelo; Feldman, Eva L

    2010-10-01

    Mitochondrial-mediated oxidative stress in response to high glucose is proposed as a primary cause of dorsal root ganglia (DRG) neuron injury in the pathogenesis of diabetic neuropathy. In the present study, we report a greater number of mitochondria in both myelinated and unmyelinated dorsal root axons in a well-established model of murine diabetic neuropathy. No similar changes were seen in younger diabetic animals without neuropathy or in the ventral motor roots of any diabetic animals. These findings led us to examine mitochondrial biogenesis and fission in response to hyperglycemia in the neurites of cultured DRG neurons. We demonstrate overall mitochondrial biogenesis via increases in mitochondrial transcription factors and increases in mitochondrial DNA in both DRG neurons and axons. However, this process occurs over a longer time period than a rapidly observed increase in the number of mitochondria in DRG neurites that appears to result, at least in part, from mitochondrial fission. We conclude that during acute hyperglycemia, mitochondrial fission is a prominent response, and excessive mitochondrial fission may result in dysregulation of energy production, activation of caspase 3, and subsequent DRG neuron injury. During more prolonged hyperglycemia, there is evidence of compensatory mitochondrial biogenesis in axons. Our data suggest that an imbalance between mitochondrial biogenesis and fission may play a role in the pathogenesis of diabetic neuropathy.

  12. Effects of resveratrol and SIRT1 on PGC-1α activity and mitochondrial biogenesis: a reevaluation.

    PubMed

    Higashida, Kazuhiko; Kim, Sang Hyun; Jung, Su Ryun; Asaka, Meiko; Holloszy, John O; Han, Dong-Ho

    2013-07-01

    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.

  13. Sirtuin 1-mediated effects of exercise and resveratrol on mitochondrial biogenesis.

    PubMed

    Menzies, Keir J; Singh, Kaustabh; Saleem, Ayesha; Hood, David A

    2013-03-08

    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.

  14. The fusogenic lipid phosphatidic acid promotes the biogenesis of mitochondrial outer membrane protein Ugo1

    PubMed Central

    Keller, Michael; Taskin, Asli A.; Horvath, Susanne E.; Guan, Xue Li; Prinz, Claudia; Opalińska, Magdalena; Zorzin, Carina; van der Laan, Martin; Wenk, Markus R.; Schubert, Rolf; Wiedemann, Nils; Holzer, Martin

    2015-01-01

    Import and assembly of mitochondrial proteins depend on a complex interplay of proteinaceous translocation machineries. The role of lipids in this process has been studied only marginally and so far no direct role for a specific lipid in mitochondrial protein biogenesis has been shown. Here we analyzed a potential role of phosphatidic acid (PA) in biogenesis of mitochondrial proteins in Saccharomyces cerevisiae. In vivo remodeling of the mitochondrial lipid composition by lithocholic acid treatment or by ablation of the lipid transport protein Ups1, both leading to an increase of mitochondrial PA levels, specifically stimulated the biogenesis of the outer membrane protein Ugo1, a component of the mitochondrial fusion machinery. We reconstituted the import and assembly pathway of Ugo1 in protein-free liposomes, mimicking the outer membrane phospholipid composition, and found a direct dependency of Ugo1 biogenesis on PA. Thus, PA represents the first lipid that is directly involved in the biogenesis pathway of a mitochondrial membrane protein. PMID:26347140

  15. Acute and chronic mitochondrial respiratory chain deficiency differentially regulate lysosomal biogenesis

    PubMed Central

    Fernández-Mosquera, Lorena; Diogo, Cátia V.; Yambire, King Faisal; Santos, Gabriela L.; Luna Sánchez, Marta; Bénit, Paule; Rustin, Pierre; Lopez, Luis Carlos; Milosevic, Ira; Raimundo, Nuno

    2017-01-01

    Mitochondria are key cellular signaling platforms, affecting fundamental processes such as cell proliferation, differentiation and death. However, it remains unclear how mitochondrial signaling affects other organelles, particularly lysosomes. Here, we demonstrate that mitochondrial respiratory chain (RC) impairments elicit a stress signaling pathway that regulates lysosomal biogenesis via the microphtalmia transcription factor family. Interestingly, the effect of mitochondrial stress over lysosomal biogenesis depends on the timeframe of the stress elicited: while RC inhibition with rotenone or uncoupling with CCCP initially triggers lysosomal biogenesis, the effect peaks after few hours and returns to baseline. Long-term RC inhibition by long-term treatment with rotenone, or patient mutations in fibroblasts and in a mouse model result in repression of lysosomal biogenesis. The induction of lysosomal biogenesis by short-term mitochondrial stress is dependent on TFEB and MITF, requires AMPK signaling and is independent of calcineurin signaling. These results reveal an integrated view of how mitochondrial signaling affects lysosomes, which is essential to fully comprehend the consequences of mitochondrial malfunction, particularly in the context of mitochondrial diseases. PMID:28345620

  16. Strenuous exercise induces mitochondrial damage in skeletal muscle of old mice

    SciTech Connect

    Lee, Sangho; Kim, Minjung; Lim, Wonchung; Kim, Taeyoung; Kang, Chounghun

    2015-05-29

    Strenuous exercise is known to cause excessive ROS generation and inflammation. However, the mechanisms responsible for the regulation of mitochondrial integrity in the senescent muscle during high-intensity exercise (HE) are not well studied. Here, we show that HE suppresses up-regulation of mitochondrial function despite increase in mitochondrial copy number, following excessive ROS production, proinflammatory cytokines and NFκB activation. Moreover, HE in the old group resulted in the decreasing of both fusion (Mfn2) and fission (Drp1) proteins that may contribute to alteration of mitochondrial morphology. This study suggests that strenuous exercise does not reverse age-related mitochondrial damage and dysfunction by the increased ROS and inflammation. - Highlights: • Effect of exercise on mitochondrial function of aged skeletal muscles was studied. • Strenuous exercise triggered excessive ROS production and inflammatory cytokines. • Strenuous exercise suppressed mitochondrial function in senescent muscle.

  17. Mitophagy and mitochondrial biogenesis in atrial tissue of patients undergoing heart surgery with cardiopulmonary bypass

    PubMed Central

    Andres, Allen M.; Tucker, Kyle C.; Thomas, Amandine; Taylor, David J.R.; Jahania, Salik M.; Dabir, Reza; Pourpirali, Somayeh; Brown, Jamelle A.; Westbrook, David G.; Ballinger, Scott W.; Mentzer, Robert M.

    2017-01-01

    Mitophagy occurs during ischemia/reperfusion (I/R) and limits oxidative stress and injury. Mitochondrial turnover was assessed in patients undergoing cardiac surgery involving cardiopulmonary bypass (CPB). Paired biopsies of right atrial appendage before initiation and after weaning from CPB were processed for protein analysis, mitochondrial DNA/nuclear DNA ratio (mtDNA:nucDNA ratio), mtDNA damage, mRNA, and polysome profiling. Mitophagy in the post-CPB samples was evidenced by decreased levels of mitophagy adapters NDP52 and optineurin in whole tissue lysate, decreased Opa1 long form, and translocation of Parkin to the mitochondrial fraction. PCR analysis of mtDNA comparing amplification of short vs. long segments of mtDNA revealed increased damage following cardiac surgery. Surprisingly, a marked increase in several mitochondria-specific protein markers and mtDNA:nucDNA ratio was observed, consistent with increased mitochondrial biogenesis. mRNA analysis suggested that mitochondrial biogenesis was traniscription independent and likely driven by increased translation of existing mRNAs. These findings demonstrate in humans that both mitophagy and mitochondrial biogenesis occur during cardiac surgery involving CPB. We suggest that mitophagy is balanced by mitochondrial biogenesis during I/R stress experienced during surgery. Mitigating mtDNA damage and elucidating mechanisms regulating mitochondrial turnover will lead to interventions to improve outcome after I/R in the setting of heart disease. PMID:28239650

  18. Curcumin Attenuates Gentamicin-Induced Kidney Mitochondrial Alterations: Possible Role of a Mitochondrial Biogenesis Mechanism.

    PubMed

    Negrette-Guzmán, Mario; García-Niño, Wylly Ramsés; Tapia, Edilia; Zazueta, Cecilia; Huerta-Yepez, Sara; León-Contreras, Juan Carlos; Hernández-Pando, Rogelio; Aparicio-Trejo, Omar Emiliano; Madero, Magdalena; Pedraza-Chaverri, José

    2015-01-01

    It has been shown that curcumin (CUR), a polyphenol derived from Curcuma longa, exerts a protective effect against gentamicin- (GM-) induced nephrotoxicity in rats, associated with a preservation of the antioxidant status. Although mitochondrial dysfunction is a hallmark in the GM-induced renal injury, the role of CUR in mitochondrial protection has not been studied. In this work, LLC-PK1 cells were preincubated 24 h with CUR and then coincubated 48 h with CUR and 8 mM GM. Treatment with CUR attenuated GM-induced drop in cell viability and led to an increase in nuclear factor (erythroid-2)-related factor 2 (Nrf2) nuclear accumulation and peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) cell expression attenuating GM-induced losses in these proteins. In vivo, Wistar rats were injected subcutaneously with GM (75 mg/Kg/12 h) during 7 days to develop kidney mitochondrial alterations. CUR (400 mg/Kg/day) was administered orally 5 days before and during the GM exposure. The GM-induced mitochondrial alterations in ultrastructure and bioenergetics as well as decrease in activities of respiratory complexes I and IV and induction of calcium-dependent permeability transition were mostly attenuated by CUR. Protection of CUR against GM-induced nephrotoxicity could be in part mediated by maintenance of mitochondrial functions and biogenesis with some participation of the nuclear factor Nrf2.

  19. Curcumin Attenuates Gentamicin-Induced Kidney Mitochondrial Alterations: Possible Role of a Mitochondrial Biogenesis Mechanism

    PubMed Central

    Negrette-Guzmán, Mario; García-Niño, Wylly Ramsés; Tapia, Edilia; Zazueta, Cecilia; Huerta-Yepez, Sara; León-Contreras, Juan Carlos; Hernández-Pando, Rogelio; Aparicio-Trejo, Omar Emiliano; Madero, Magdalena; Pedraza-Chaverri, José

    2015-01-01

    It has been shown that curcumin (CUR), a polyphenol derived from Curcuma longa, exerts a protective effect against gentamicin- (GM-) induced nephrotoxicity in rats, associated with a preservation of the antioxidant status. Although mitochondrial dysfunction is a hallmark in the GM-induced renal injury, the role of CUR in mitochondrial protection has not been studied. In this work, LLC-PK1 cells were preincubated 24 h with CUR and then coincubated 48 h with CUR and 8 mM GM. Treatment with CUR attenuated GM-induced drop in cell viability and led to an increase in nuclear factor (erythroid-2)-related factor 2 (Nrf2) nuclear accumulation and peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) cell expression attenuating GM-induced losses in these proteins. In vivo, Wistar rats were injected subcutaneously with GM (75 mg/Kg/12 h) during 7 days to develop kidney mitochondrial alterations. CUR (400 mg/Kg/day) was administered orally 5 days before and during the GM exposure. The GM-induced mitochondrial alterations in ultrastructure and bioenergetics as well as decrease in activities of respiratory complexes I and IV and induction of calcium-dependent permeability transition were mostly attenuated by CUR. Protection of CUR against GM-induced nephrotoxicity could be in part mediated by maintenance of mitochondrial functions and biogenesis with some participation of the nuclear factor Nrf2. PMID:26345660

  20. The Interaction of Mitochondrial Biogenesis and Fission/Fusion Mediated by PGC-1α Regulates Rotenone-Induced Dopaminergic Neurotoxicity.

    PubMed

    Peng, Kaige; Yang, Likui; Wang, Jian; Ye, Feng; Dan, Guorong; Zhao, Yuanpeng; Cai, Ying; Cui, Zhihong; Ao, Lin; Liu, Jinyi; Zou, Zhongmin; Sai, Yan; Cao, Jia

    2016-06-07

    Parkinson's disease is a common neurodegenerative disease in the elderly, and mitochondrial defects underlie the pathogenesis of PD. Impairment of mitochondrial homeostasis results in reactive oxygen species formation, which in turn can potentiate the accumulation of dysfunctional mitochondria, forming a vicious cycle in the neuron. Mitochondrial fission/fusion and biogenesis play important roles in maintaining mitochondrial homeostasis. It has been reported that PGC-1α is a powerful transcription factor that is widely involved in the regulation of mitochondrial biogenesis, oxidative stress, and other processes. Therefore, we explored mitochondrial biogenesis, mitochondrial fission/fusion, and especially PGC-1α as the key point in the signaling mechanism of their interaction in rotenone-induced dopamine neurotoxicity. The results showed that mitochondrial number and mass were reduced significantly, accompanied by alterations in proteins known to regulate mitochondrial fission/fusion (MFN2, OPA1, Drp1, and Fis1) and mitochondrial biogenesis (PGC-1α and mtTFA). Further experiments proved that inhibition of mitochondrial fission or promotion of mitochondrial fusion has protective effects in rotenone-induced neurotoxicity and also promotes mitochondrial biogenesis. By establishing cell models of PGC-1α overexpression and reduced expression, we found that PGC-1α can regulate MFN2 and Drp1 protein expression and phosphorylation to influence mitochondrial fission/fusion. In summary, it can be concluded that PGC-1α-mediated cross talk between mitochondrial biogenesis and fission/fusion contributes to rotenone-induced dopaminergic neurodegeneration.

  1. The effect of ethidium bromide and chloramphenicol on mitochondrial biogenesis in primary human fibroblasts

    SciTech Connect

    Kao, Li-Pin; Ovchinnikov, Dmitry; Wolvetang, Ernst

    2012-05-15

    The expression of mitochondrial components is controlled by an intricate interplay between nuclear transcription factors and retrograde signaling from mitochondria. The role of mitochondrial DNA (mtDNA) and mtDNA-encoded proteins in mitochondrial biogenesis is, however, poorly understood and thus far has mainly been studied in transformed cell lines. We treated primary human fibroblasts with ethidium bromide (EtBr) or chloramphenicol for six weeks to inhibit mtDNA replication or mitochondrial protein synthesis, respectively, and investigated how the cells recovered from these insults two weeks after removal of the drugs. Although cellular growth and mitochondrial gene expression were severely impaired after both inhibitor treatments we observed marked differences in mitochondrial structure, membrane potential, glycolysis, gene expression, and redox status between fibroblasts treated with EtBr and chloramphenicol. Following removal of the drugs we further detected clear differences in expression of both mtDNA-encoded genes and nuclear transcription factors that control mitochondrial biogenesis, suggesting that the cells possess different compensatory mechanisms to recover from drug-induced mitochondrial dysfunction. Our data reveal new aspects of the interplay between mitochondrial retrograde signaling and the expression of nuclear regulators of mitochondrial biogenesis, a process with direct relevance to mitochondrial diseases and chloramphenicol toxicity in humans. -- Highlights: ► Cells respond to certain environmental toxins by increasing mitochondrial biogenesis. ► We investigated the effect of Chloramphenicol and EtBr in primary human fibroblasts. ► Inhibiting mitochondrial protein synthesis or DNA replication elicit different effects. ► We provide novel insights into the cellular responses toxins and antibiotics.

  2. THE UNFOLDED PROTEIN RESPONSE IN RELATION TO MITOCHONDRIAL BIOGENESIS IN SKELETAL MUSCLE CELLS.

    PubMed

    Mesbah Moosavi, Zahra S; Hood, David A

    2017-03-08

    Mitochondria are comprised of both nuclear- and mitochondrially-encoded proteins requiring precise stoichiometry for their integration into functional complexes. The augmented protein synthesis associated with mitochondrial biogenesis results in the accumulation of unfolded proteins, thus triggering cellular stress. As such, the unfolded protein responses emanating from the endoplasmic reticulum (UPR(ER)) or the mitochondrion (UPR(MT)) are triggered to ensure correct protein handling. Whether this response is necessary for mitochondrial adaptations is unknown. Two models of mitochondrial biogenesis were used: muscle differentiation and chronic contractile activity (CCA) in murine muscle cells. After 4 days of differentiation, our findings depict selective activation of the UPR(MT) in which chaperones decreased, however Sirt3 and UPR(ER) markers were elevated. To delineate the role of ER stress in mitochondrial adaptations, the ER stress inhibitor TUDCA was administered. Surprisingly, mitochondrial markers COX-I, COX-IV, and PGC-1α protein levels were augmented up to 1.5-fold above that of vehicle-treated cells. Similar results were obtained in myotubes undergoing CCA in which biogenesis was enhanced by ~2-3-fold, along with elevated UPR(MT) markers Sirt3 and CPN10. To verify whether the findings were attributable to the terminal UPRER branch directed by the transcription factor CHOP, cells were transfected with CHOP siRNA. Basally, COX-I levels increased (~20%) and COX-IV decreased (~30%), suggesting that CHOP influences mitochondrial composition. This effect was fully restored by CCA. Therefore, our results suggest that mitochondrial biogenesis is independent of the terminal UPR(ER) Under basal conditions CHOP is required for the maintenance of mitochondrial composition, but not for differentiation- or CCA-induced mitochondrial biogenesis.

  3. Reactive oxygen species mediates homocysteine-induced mitochondrial biogenesis in human endothelial cells: Modulation by antioxidants

    SciTech Connect

    Perez-de-Arce, Karen; Foncea, Rocio . E-mail: rfoncea@med.puc.cl; Leighton, Federico

    2005-12-16

    It has been proposed that homocysteine (Hcy)-induces endothelial dysfunction and atherosclerosis by generation of reactive oxygen species (ROS). A previous report has shown that Hcy promotes mitochondrial damage. Considering that oxidative stress can affect mitochondrial biogenesis, we hypothesized that Hcy-induced ROS in endothelial cells may lead to increased mitochondrial biogenesis. We found that Hcy-induced ROS (1.85-fold), leading to a NF-{kappa}B activation and increase the formation of 3-nitrotyrosine. Furthermore, expression of the mitochondrial biogenesis factors, nuclear respiratory factor-1 and mitochondrial transcription factor A, was significantly elevated in Hcy-treated cells. These changes were accompanied by increase in mitochondrial mass and higher mRNA and protein expression of the subunit III of cytochrome c oxidase. These effects were significantly prevented by pretreatment with the antioxidants, catechin and trolox. Taken together, our results suggest that ROS is an important mediator of mitochondrial biogenesis induced by Hcy, and that modulation of oxidative stress by antioxidants may protect against the adverse vascular effects of Hcy.

  4. The effects of NAD+ on apoptotic neuronal death and mitochondrial biogenesis and function after glutamate excitotoxicity.

    PubMed

    Wang, Xiaowan; Li, Hailong; Ding, Shinghua

    2014-11-07

    NAD+ is an essential co-enzyme for cellular energy metabolism and is also involved as a substrate for many cellular enzymatic reactions. It has been shown that NAD+ has a beneficial effect on neuronal survival and brain injury in in vitro and in vivo ischemic models. However, the effect of NAD+ on mitochondrial biogenesis and function in ischemia has not been well investigated. In the present study, we used an in vitro glutamate excitotoxicity model of primary cultured cortical neurons to study the effect of NAD+ on apoptotic neuronal death and mitochondrial biogenesis and function. Our results show that supplementation of NAD+ could effectively reduce apoptotic neuronal death, and apoptotic inducing factor translocation after neurons were challenged with excitotoxic glutamate stimulation. Using different approaches including confocal imaging, mitochondrial DNA measurement and Western blot analysis of PGC-1 and NRF-1, we also found that NAD+ could significantly attenuate glutamate-induced mitochondrial fragmentation and the impairment of mitochondrial biogenesis. Furthermore, NAD+ treatment effectively inhibited mitochondrial membrane potential depolarization and NADH redistribution after excitotoxic glutamate stimulation. Taken together, our results demonstrated that NAD+ is capable of inhibiting apoptotic neuronal death after glutamate excitotoxicity via preserving mitochondrial biogenesis and integrity. Our findings provide insights into potential neuroprotective strategies in ischemic stroke.

  5. Phosphoinositide Dependent Protein Kinase 1 is Required for Exercise-induced Cardiac Hypertrophy but not the Associated Mitochondrial Adaptations

    PubMed Central

    Noh, Junghyun; Wende, Adam R.; Olsen, Curtis D; Kim, Bumjun; Bevins, Jack; Zhu, Yi; Zhang, Quan-Jiang; Riehle, Christian; Abel, E. Dale

    2015-01-01

    Phosphoinositide-dependent protein kinase-1 (PDPK1) is an important mediator of phosphatidylinositol 3-kinase (PI3K) signaling. We previously reported that PI3K but not Akt signaling mediates the increase of mitochondrial oxidative capacity to physiological cardiac hypertrophy. To determine if PDPK1 regulates these metabolic adaptations we examined mice with cardiomyocyte-specific heterozygous knockout of PDPK1 (cPDPK1+/−) after 5 wk. exercise swim training. Akt phosphorylation at Thr308 increased by 43% in wildtype (WT) mice but not in cPDPK1+/− mice following exercise training. Ventricular contractile function was not different between WT and cPDPK1+/− mice at baseline. In addition, exercise did not influence ventricular function in WT or cPDPK1+/− mice. Heart weight normalized to tibia length ratios increased by 13.8% in WT mice (6.2 ± 0.2 vs. 7.1 ± 0.2, P=0.001), but not in cPDPK1+/− (6.2 ± 0.3 vs. 6.5 ± 0.2, P=0.20) mice after swim training. Diastolic LV dimension increased in WT mice (3.7 ± 0.1 vs. 4.0 ± 0.1 mm, P=0.01) but not in cPDPK1+/− (3.8 ± 0.1 vs. 3.7 ± 0.1 mm, P=0.56) following swim training. Maximal mitochondrial oxygen consumption (VADP, nmol/min/mg) using palmitoyl carnitine as a substrate was significantly increased in mice of all genotypes following swim training (WT: 13.6 ± 0.6 vs.16.1 ± 0.9, P=0.04; cPDPK1+/−: 12.4 ± 0.6 vs.15.9 ± 1.2, P=0.04). These findings suggest that PDPK1 is required for exercise-induced cardiac hypertrophy but does not contribute to exercise-induced increases in mitochondrial function. PMID:26476238

  6. Phosphoinositide dependent protein kinase 1 is required for exercise-induced cardiac hypertrophy but not the associated mitochondrial adaptations.

    PubMed

    Noh, Junghyun; Wende, Adam R; Olsen, Curtis D; Kim, Bumjun; Bevins, Jack; Zhu, Yi; Zhang, Quan-Jiang; Riehle, Christian; Abel, E Dale

    2015-12-01

    Phosphoinositide-dependent protein kinase-1 (PDPK1) is an important mediator of phosphatidylinositol 3-kinase (PI3K) signaling. We previously reported that PI3K but not Akt signaling mediates the increase in mitochondrial oxidative capacity following physiological cardiac hypertrophy. To determine if PDPK1 regulates these metabolic adaptations we examined mice with cardiomyocyte-specific heterozygous knockout of PDPK1 (cPDPK1(+/-)) after 5 wk. exercise swim training. Akt phosphorylation at Thr308 increased by 43% in wildtype (WT) mice but not in cPDPK1(+/-) mice following exercise training. Ventricular contractile function was not different between WT and cPDPK1(+/-) mice at baseline. In addition, exercise did not influence ventricular function in WT or cPDPK1(+/-) mice. Heart weight normalized to tibia length ratios increased by 13.8% in WT mice (6.2±0.2 vs. 7.1±0.2, P=0.001), but not in cPDPK1(+/-) (6.2±0.3 vs. 6.5±0.2, P=0.20) mice after swim training. Diastolic LV dimension increased in WT mice (3.7±0.1 vs. 4.0±0.1 mm, P=0.01) but not in cPDPK1(+/-) (3.8±0.1 vs. 3.7±0.1 mm, P=0.56) following swim training. Maximal mitochondrial oxygen consumption (VADP, nmol/min/mg) using palmitoyl carnitine as a substrate was significantly increased in mice of all genotypes following swim training (WT: 13.6±0.6 vs.16.1±0.9, P=0.04; cPDPK1(+/-): 12.4±0.6 vs.15.9±1.2, P=0.04). These findings suggest that PDPK1 is required for exercise-induced cardiac hypertrophy but does not contribute to exercise-induced increases in mitochondrial function.

  7. Chronic Arsenic Exposure-Induced Oxidative Stress is Mediated by Decreased Mitochondrial Biogenesis in Rat Liver.

    PubMed

    Prakash, Chandra; Kumar, Vijay

    2016-09-01

    The present study was executed to study the effect of chronic arsenic exposure on generation of mitochondrial oxidative stress and biogenesis in rat liver. Chronic sodium arsenite treatment (25 ppm for 12 weeks) decreased mitochondrial complexes activity in rat liver. There was a decrease in mitochondrial superoxide dismutase (MnSOD) activity in arsenic-treated rats that might be responsible for increased protein and lipid oxidation as observed in our study. The messenger RNA (mRNA) expression of mitochondrial and nuclear-encoded subunits of complexes I (ND1 and ND2) and IV (COX I and COX IV) was downregulated in arsenic-treated rats only. The protein and mRNA expression of MnSOD was reduced suggesting increased mitochondrial oxidative damage after arsenic treatment. There was activation of Bax and caspase-3 followed by release of cytochrome c from mitochondria suggesting induction of apoptotic pathway under oxidative stress. The entire phenomenon was associated with decrease in mitochondrial biogenesis as evident by decreased protein and mRNA expression of nuclear respiratory factor 1 (NRF-1), nuclear respiratory factor 2 (NRF-2), peroxisome proliferator activator receptor gamma-coactivator 1α (PGC-1α), and mitochondrial transcription factor A (Tfam) in arsenic-treated rat liver. The results of the present study indicate that arsenic-induced mitochondrial oxidative stress is associated with decreased mitochondrial biogenesis in rat liver that may present one of the mechanisms for arsenic-induced hepatotoxicity.

  8. Artemisinin mimics calorie restriction to trigger mitochondrial biogenesis and compromise telomere shortening in mice.

    PubMed

    Wang, Da-Ting; He, Jiang; Wu, Ming; Li, Si-Ming; Gao, Qian; Zeng, Qing-Ping

    2015-01-01

    Calorie restriction is known to extend lifespan among organisms by a debating mechanism underlying nitric oxide-driven mitochondrial biogenesis. We report here that nitric oxide generators including artemisinin, sodium nitroprusside, and L-arginine mimics calorie restriction and resembles hydrogen peroxide to initiate the nitric oxide signaling cascades and elicit the global antioxidative responses in mice. The large quantities of antioxidant enzymes are correlated with the low levels of reactive oxygen species, which allow the down-regulation of tumor suppressors and accessory DNA repair partners, eventually leading to the compromise of telomere shortening. Accompanying with the up-regulation of signal transducers and respiratory chain signatures, mitochondrial biogenesis occurs with the elevation of adenosine triphosphate levels upon exposure of mouse skeletal muscles to the mimetics of calorie restriction. In conclusion, calorie restriction-triggered nitric oxide provides antioxidative protection and alleviates telomere attrition via mitochondrial biogenesis, thereby maintaining chromosomal stability and integrity, which are the hallmarks of longevity.

  9. Mitochondrial iron-sulfur cluster biogenesis from molecular understanding to clinical disease.

    PubMed

    Alfadhel, Majid; Nashabat, Marwan; Abu Ali, Qais; Hundallah, Khalid

    2017-01-01

    Iron_sulfur clusters (ISCs) are known to play a major role in various protein functions. Located in the mitochondria, cytosol, endoplasmic reticulum and nucleus, they contribute to various core cellular functions. Until recently, only a few human diseases related to mitochondrial ISC biogenesis defects have been described. Such diseases include Friedreich ataxia, combined oxidative phosphorylation deficiency 19, infantile complex II/III deficiency defect, hereditary myopathy with lactic acidosis and mitochondrial muscle myopathy, lipoic acid biosynthesis defects, multiple mitochondrial dysfunctions syndromes and non ketotic hyperglycinemia due to glutaredoxin 5 gene defect. Disorders of mitochondrial import, export and translation, including sideroblastic anemia with ataxia, EVEN-PLUS syndrome and mitochondrial complex I deficiency due to nucleotide-binding protein-like protein gene defect, have also been implicated in ISC biogenesis defects. With advances in next generation sequencing technologies, more disorders related to ISC biogenesis defects are expected to be elucidated. In this article, we aim to shed the light on mitochondrial ISC biogenesis, related proteins and their function, pathophysiology, clinical phenotypes of related disorders, diagnostic approach, and future implications.

  10. Mitochondrial biogenesis in epithelial cancer cells promotes breast cancer tumor growth and confers autophagy resistance.

    PubMed

    Salem, Ahmed F; Whitaker-Menezes, Diana; Howell, Anthony; Sotgia, Federica; Lisanti, Michael P

    2012-11-15

    Here, we set out to test the novel hypothesis that increased mitochondrial biogenesis in epithelial cancer cells would "fuel" enhanced tumor growth. For this purpose, we generated MDA-MB-231 cells (a triple-negative human breast cancer cell line) overexpressing PGC-1α and MitoNEET, which are established molecules that drive mitochondrial biogenesis and increased mitochondrial oxidative phosphorylation (OXPHOS). Interestingly, both PGC-1α and MitoNEET increased the abundance of OXPHOS protein complexes, conferred autophagy resistance under conditions of starvation and increased tumor growth by up to ~3-fold. However, this increase in tumor growth was independent of neo-angiogenesis, as assessed by immunostaining and quantitation of vessel density using CD31 antibodies. Quantitatively similar increases in tumor growth were also observed by overexpression of PGC-1β and POLRMT in MDA-MB-231 cells, which are also responsible for mediating increased mitochondrial biogenesis. Thus, we propose that increased mitochondrial "power" in epithelial cancer cells oncogenically promotes tumor growth by conferring autophagy resistance. As such, PGC-1α, PGC-1β, mitoNEET and POLRMT should all be considered as tumor promoters or "metabolic oncogenes." Our results are consistent with numerous previous clinical studies showing that metformin (a weak mitochondrial "poison") prevents the onset of nearly all types of human cancers in diabetic patients. Therefore, metformin (a complex I inhibitor) and other mitochondrial inhibitors should be developed as novel anticancer therapies, targeting mitochondrial metabolism in cancer cells.

  11. N-acetylcysteine inhibits the up-regulation of mitochondrial biogenesis genes in livers from rats fed ethanol chronically

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Background: Chronic ethanol (EtOH) administration to experimental animals induces hepatic oxidative stress and up-regulates mitochondrial biogenesis. The mechanisms by which chronic EtOH up-regulates mitochondrial biogenesis have not been fully explored. In this work, we hypothesized that oxidative ...

  12. Age associated low mitochondrial biogenesis may be explained by lack of response of PGC-1α to exercise training.

    PubMed

    Derbré, Frederic; Gomez-Cabrera, Mari Carmen; Nascimento, Ana Lucia; Sanchis-Gomar, Fabian; Martinez-Bello, Vladimir Essau; Tresguerres, Jesus A F; Fuentes, Teresa; Gratas-Delamarche, Arlette; Monsalve, Maria; Viña, Jose

    2012-06-01

    Low mitochondriogenesis is critical to explain loss of muscle function in aging and in the development of frailty. The aim of this work was to explain the mechanism by which mitochondriogenesis is decreased in aging and to determine to which extent it may be prevented by exercise training. We used aged rats and compared them with peroxisome proliferator-activated receptor-γ coactivator-1α deleted mice (PGC-1α KO). PGC-1α KO mice showed a significant decrease in the mitochondriogenic pathway in muscle. In aged rats, we found a loss of exercise-induced expression of PGC-1α, nuclear respiratory factor-1 (NRF-1), and of cytochrome C. Thus muscle mitochondriogenesis, which is activated by exercise training in young animals, is not in aged or PGC-1α KO ones. Other stimuli to increase PGC-1α synthesis apart from exercise training, namely cold induction or thyroid hormone treatment, were effective in young rats but not in aged ones. To sum up, the low mitochondrial biogenesis associated with aging may be due to the lack of response of PGC-1α to different stimuli. Aged rats behave as PGC-1α KO mice. Results reported here highlight the role of PGC-1α in the loss of mitochondriogenesis associated with aging and point to this important transcriptional coactivator as a target for pharmacological interventions to prevent age-associated sarcopenia.

  13. A new live-cell reporter strategy to simultaneously monitor mitochondrial biogenesis and morphology.

    PubMed

    Hodneland Nilsson, Linn Iren; Nitschke Pettersen, Ina Katrine; Nikolaisen, Julie; Micklem, David; Avsnes Dale, Hege; Vatne Røsland, Gro; Lorens, James; Tronstad, Karl Johan

    2015-11-24

    Changes in mitochondrial amount and shape are intimately linked to maintenance of cell homeostasis via adaptation of vital functions. Here, we developed a new live-cell reporter strategy to simultaneously monitor mitochondrial biogenesis and morphology. This was achieved by making a genetic reporter construct where a master regulator of mitochondrial biogenesis, nuclear respiratory factor 1 (NRF-1), controls expression of mitochondria targeted green fluorescent protein (mitoGFP). HeLa cells with the reporter construct demonstrated inducible expression of mitoGFP upon activation of AMP-dependent protein kinase (AMPK) with AICAR. We established stable reporter cells where the mitoGFP reporter activity corresponded with mitochondrial biogenesis both in magnitude and kinetics, as confirmed by biochemical markers and confocal microscopy. Quantitative 3D image analysis confirmed accordant increase in mitochondrial biomass, in addition to filament/network promoting and protecting effects on mitochondrial morphology, after treatment with AICAR. The level of mitoGFP reversed upon removal of AICAR, in parallel with decrease in mtDNA. In summary, we here present a new GFP-based genetic reporter strategy to study mitochondrial regulation and dynamics in living cells. This combinatorial reporter concept can readily be transferred to other cell models and contexts to address specific physiological mechanisms.

  14. Melatonin enhances mitophagy and mitochondrial biogenesis in rats with carbon tetrachloride-induced liver fibrosis.

    PubMed

    Kang, Jung-Woo; Hong, Jeong-Min; Lee, Sun-Mee

    2016-05-01

    Liver fibrosis leads to liver cirrhosis and failure, and no effective treatment is currently available. Growing evidence supports a link between mitochondrial dysfunction and liver fibrogenesis and mitochondrial quality control-based therapy has emerged as a new therapeutic target. We investigated the protective mechanisms of melatonin against mitochondrial dysfunction-involved liver fibrosis, focusing on mitophagy and mitochondrial biogenesis. Rats were treated with carbon tetrachloride (CCl4) dissolved in olive oil (0.5 mL/kg, twice a week, i.p.) for 8 wk. Melatonin was administered orally at 2.5, 5, and 10 mg/kg once a day. Chronic CCl4 exposure induced collagen deposition, hepatocellular damage, and oxidative stress, and melatonin attenuated these increases. Increases in mRNA and protein expression levels of transforming growth factor β1 and α-smooth muscle actin in response to CCl4 were attenuated by melatonin. Melatonin attenuated hallmarks of mitochondrial dysfunction, such as mitochondrial swelling and glutamate dehydrogenase release. Chronic CCl4 exposure impaired mitophagy and mitochondrial biogenesis, and melatonin attenuated this impairment, as indicated by increases in mitochondrial DNA and in protein levels of PTEN-induced putative kinase 1 (PINK1); Parkin; peroxisome proliferator-activated receptor-gamma coactivator 1α (PGC-1α); nuclear respiratory factor 1 (NRF1); and transcription factor A, mitochondrial (TFAM). CCl4-mediated decreases in mitochondrial fission- and fusion-related proteins, such as dynamin-related protein 1 (DRP1) and mitofusin 2, were also attenuated by melatonin. Moreover, melatonin induced AMP-activated protein kinase (AMPK) phosphorylation. These results suggest that melatonin protects against liver fibrosis via upregulation of mitophagy and mitochondrial biogenesis, and may be useful as an anti-fibrotic treatment.

  15. SIRT1 is required for mitochondrial biogenesis reprogramming in hypoxic human pulmonary arteriolar smooth muscle cells.

    PubMed

    Li, Pengyun; Liu, Yan; Burns, Nana; Zhao, Ke-Seng; Song, Rui

    2017-03-22

    Although recent studies have reported that mitochondria are putative oxygen sensors underlying hypoxic pulmonary vasoconstriction, little is known concerning the sirtuin 1 (SIRT1)-mediated mitochondrial biogenesis regulatory program in pulmonary arteriolar smooth muscle cells (PASMCs) during hypoxia/reoxygenation (H/R). We investigated the epigenetic regulatory mechanism of mitochondrial biogenesis and function in human PASMCs during H/R. Human PASMCs were exposed to hypoxia of 24-48 h and reoxygenation of 24-48 h. The expression of SIRT1 was reduced in a time-dependent manner. Mitochondrial transcription factor A (TFAM) expression was increased during hypoxia and decreased during reoxygenation, while the release of TFAM was increased in a time-dependent manner. Lentiviral overexpression of SIRT1 preserved SIRT3 deacetylase activity in human PASMCs exposed to H/R. Knockdown of PGC-1α suppressed the effect of SIRT1 on SIRT3 activity. Knockdown of SIRT3 abrogated SIRT1-mediated deacetylation of cyclophilin D (CyPD). Notably, knockdown of SIRT3 or PGC-1α suppressed the incremental effect of SIRT1 on mitochondrial TFAM, mitochondrial DNA (mtDNA) content and cellular ATP levels. Importantly, polydatin restored SIRT1 levels in human PASMCs exposed to H/R. Knockdown of SIRT1 suppressed the effect of polydatin on mitochondrial TFAM, mtDNA content and cellular ATP levels. In conclusion, SIRT1 expression is decreased in human PASMCs during H/R. TFAM expression in mitochondria is reduced and the release of TFAM is increased by H/R. PGC-1α/SIRT3/CyPD mediates the protective effect of SIRT1 on expression and release of TFAM and mitochondrial biogenesis and function. Polydatin improves mitochondrial biogenesis and function by enhancing SIRT1 expression in hypoxic human PASMCs.

  16. Mitochondrial OXA Translocase Plays a Major Role in Biogenesis of Inner-Membrane Proteins.

    PubMed

    Stiller, Sebastian B; Höpker, Jan; Oeljeklaus, Silke; Schütze, Conny; Schrempp, Sandra G; Vent-Schmidt, Jens; Horvath, Susanne E; Frazier, Ann E; Gebert, Natalia; van der Laan, Martin; Bohnert, Maria; Warscheid, Bettina; Pfanner, Nikolaus; Wiedemann, Nils

    2016-05-10

    The mitochondrial inner membrane harbors three protein translocases. Presequence translocase and carrier translocase are essential for importing nuclear-encoded proteins. The oxidase assembly (OXA) translocase is required for exporting mitochondrial-encoded proteins; however, different views exist about its relevance for nuclear-encoded proteins. We report that OXA plays a dual role in the biogenesis of nuclear-encoded mitochondrial proteins. First, a systematic analysis of OXA-deficient mitochondria led to an unexpected expansion of the spectrum of OXA substrates imported via the presequence pathway. Second, biogenesis of numerous metabolite carriers depends on OXA, although they are not imported by the presequence pathway. We show that OXA is crucial for the biogenesis of the Tim18-Sdh3 module of the carrier translocase. The export translocase OXA is thus required for the import of metabolite carriers by promoting assembly of the carrier translocase. We conclude that OXA is of central importance for the biogenesis of the mitochondrial inner membrane.

  17. Efficient mitochondrial biogenesis drives incomplete penetrance in Leber's hereditary optic neuropathy.

    PubMed

    Giordano, Carla; Iommarini, Luisa; Giordano, Luca; Maresca, Alessandra; Pisano, Annalinda; Valentino, Maria Lucia; Caporali, Leonardo; Liguori, Rocco; Deceglie, Stefania; Roberti, Marina; Fanelli, Francesca; Fracasso, Flavio; Ross-Cisneros, Fred N; D'Adamo, Pio; Hudson, Gavin; Pyle, Angela; Yu-Wai-Man, Patrick; Chinnery, Patrick F; Zeviani, Massimo; Salomao, Solange R; Berezovsky, Adriana; Belfort, Rubens; Ventura, Dora Fix; Moraes, Milton; Moraes Filho, Milton; Barboni, Piero; Sadun, Federico; De Negri, Annamaria; Sadun, Alfredo A; Tancredi, Andrea; Mancini, Massimiliano; d'Amati, Giulia; Loguercio Polosa, Paola; Cantatore, Palmiro; Carelli, Valerio

    2014-02-01

    Leber's hereditary optic neuropathy is a maternally inherited blinding disease caused as a result of homoplasmic point mutations in complex I subunit genes of mitochondrial DNA. It is characterized by incomplete penetrance, as only some mutation carriers become affected. Thus, the mitochondrial DNA mutation is necessary but not sufficient to cause optic neuropathy. Environmental triggers and genetic modifying factors have been considered to explain its variable penetrance. We measured the mitochondrial DNA copy number and mitochondrial mass indicators in blood cells from affected and carrier individuals, screening three large pedigrees and 39 independently collected smaller families with Leber's hereditary optic neuropathy, as well as muscle biopsies and cells isolated by laser capturing from post-mortem specimens of retina and optic nerves, the latter being the disease targets. We show that unaffected mutation carriers have a significantly higher mitochondrial DNA copy number and mitochondrial mass compared with their affected relatives and control individuals. Comparative studies of fibroblasts from affected, carriers and controls, under different paradigms of metabolic demand, show that carriers display the highest capacity for activating mitochondrial biogenesis. Therefore we postulate that the increased mitochondrial biogenesis in carriers may overcome some of the pathogenic effect of mitochondrial DNA mutations. Screening of a few selected genetic variants in candidate genes involved in mitochondrial biogenesis failed to reveal any significant association. Our study provides a valuable mechanism to explain variability of penetrance in Leber's hereditary optic neuropathy and clues for high throughput genetic screening to identify the nuclear modifying gene(s), opening an avenue to develop predictive genetic tests on disease risk and therapeutic strategies.

  18. Order within a mosaic distribution of mitochondrial c-type cytochrome biogenesis systems?

    PubMed

    Allen, James W A; Jackson, Andrew P; Rigden, Daniel J; Willis, Antony C; Ferguson, Stuart J; Ginger, Michael L

    2008-05-01

    Mitochondrial cytochromes c and c(1) are present in all eukaryotes that use oxygen as the terminal electron acceptor in the respiratory chain. Maturation of c-type cytochromes requires covalent attachment of the heme cofactor to the protein, and there are at least five distinct biogenesis systems that catalyze this post-translational modification in different organisms and organelles. In this study, we use biochemical data, comparative genomic and structural bioinformatics investigations to provide a holistic view of mitochondrial c-type cytochrome biogenesis and its evolution. There are three pathways for mitochondrial c-type cytochrome maturation, only one of which is present in prokaryotes. We analyze the evolutionary distribution of these biogenesis systems, which include the Ccm system (System I) and the enzyme heme lyase (System III). We conclude that heme lyase evolved once and, in many lineages, replaced the multicomponent Ccm system (present in the proto-mitochondrial endosymbiont), probably as a consequence of lateral gene transfer. We find no evidence of a System III precursor in prokaryotes, and argue that System III is incompatible with multi-heme cytochromes common to bacteria, but absent from eukaryotes. The evolution of the eukaryotic-specific protein heme lyase is strikingly unusual, given that this protein provides a function (thioether bond formation) that is also ubiquitous in prokaryotes. The absence of any known c-type cytochrome biogenesis system from the sequenced genomes of various trypanosome species indicates the presence of a third distinct mitochondrial pathway. Interestingly, this system attaches heme to mitochondrial cytochromes c that contain only one cysteine residue, rather than the usual two, within the heme-binding motif. The isolation of single-cysteine-containing mitochondrial cytochromes c from free-living kinetoplastids, Euglena and the marine flagellate Diplonema papillatum suggests that this unique form of heme attachment

  19. Augmentation of aerobic respiration and mitochondrial biogenesis in skeletal muscle by hypoxia preconditioning with cobalt chloride.

    PubMed

    Saxena, Saurabh; Shukla, Dhananjay; Bansal, Anju

    2012-11-01

    High altitude/hypoxia training is known to improve physical performance in athletes. Hypoxia induces hypoxia inducible factor-1 (HIF-1) and its downstream genes that facilitate hypoxia adaptation in muscle to increase physical performance. Cobalt chloride (CoCl₂), a hypoxia mimetic, stabilizes HIF-1, which otherwise is degraded in normoxic conditions. We studied the effects of hypoxia preconditioning by CoCl₂ supplementation on physical performance, glucose metabolism, and mitochondrial biogenesis using rodent model. The results showed significant increase in physical performance in cobalt supplemented rats without (two times) or with training (3.3 times) as compared to control animals. CoCl₂ supplementation in rats augmented the biological activities of enzymes of TCA cycle, glycolysis and cytochrome c oxidase (COX); and increased the expression of glucose transporter-1 (Glut-1) in muscle showing increased glucose metabolism by aerobic respiration. There was also an increase in mitochondrial biogenesis in skeletal muscle observed by increased mRNA expressions of mitochondrial biogenesis markers which was further confirmed by electron microscopy. Moreover, nitric oxide production increased in skeletal muscle in cobalt supplemented rats, which seems to be the major reason for peroxisome proliferator activated receptor-gamma coactivator-1α (PGC-1α) induction and mitochondrial biogenesis. Thus, in conclusion, we state that hypoxia preconditioning by CoCl₂ supplementation in rats increases mitochondrial biogenesis, glucose uptake and metabolism by aerobic respiration in skeletal muscle, which leads to increased physical performance. The significance of this study lies in understanding the molecular mechanism of hypoxia adaptation and improvement of work performance in normal as well as extreme conditions like hypoxia via hypoxia preconditioning.

  20. Nebivolol stimulates mitochondrial biogenesis in 3T3-L1 adipocytes

    SciTech Connect

    Huang, Chenglin; Chen, Dongrui; Xie, Qihai; Yang, Ying; Shen, Weili

    2013-08-16

    Highlights: •Nebivolol may act as a partial agonist of β3-adrenergic receptor (AR). •Nebivolol stimulates mitochondrial DNA replication and protein expression. •Nebivolol promotes mitochondrial synthesis via activation of eNOS by β3-AR. -- Abstract: Nebivolol is a third-generation β-adrenergic receptor (β-AR) blocker with additional beneficial effects, including the improvement of lipid and glucose metabolism in obese individuals. However, the underlying mechanism of nebivolol’s role in regulating the lipid profile remains largely unknown. In this study, we investigated the role of nebivolol in mitochondrial biogenesis in 3T3-L1 adipocytes. Exposure of 3T3-L1 cells to nebivolol for 24 h increased mitochondrial DNA copy number, mitochondrial protein levels and the expression of transcription factors involved in mitochondrial biogenesis, including PPAR-γ coactivator-1α (PGC-1α), Sirtuin 3 (Sirt3), mitochondrial transcription factor A (Tfam) and nuclear related factor 1 (Nrf1). These changes were accompanied by an increase in oxygen consumption and in the expression of genes involved in fatty acid oxidation and antioxidant enzymes in 3T3-L1 adipocytes, including nebivolol-induced endothelial nitric oxide synthase (eNOS), as well as an increase in the formation of cyclic guanosine monophosphate (cGMP). Pretreatment with NG-nitro-L-arginine methyl ester (l-NAME) attenuated nebivolol-induced mitochondrial biogenesis, as did the soluble guanylate cyclase inhibitor, ODQ. Treatment with nebivolol and β3-AR blocker SR59230A markedly attenuated PGC-1α, Sirt3 and manganese superoxide dismutase (MnSOD) protein levels in comparison to treatment with nebivolol alone. These data indicate that the mitochondrial synthesis and metabolism in adipocytes that is promoted by nebivolol is primarily mediated through the eNOS/cGMP-dependent pathway and is initiated by the activation of β3-AR receptors.

  1. Leucine Modulates Mitochondrial Biogenesis and SIRT1-AMPK Signaling in C2C12 Myotubes

    PubMed Central

    Liang, Chunzi; Curry, Benjamin J.; Brown, Patricia L.; Zemel, Michael B.

    2014-01-01

    Previous studies from this laboratory demonstrate that dietary leucine protects against high fat diet-induced mitochondrial impairments and stimulates mitochondrial biogenesis and energy partitioning from adipocytes to muscle cells through SIRT1-mediated mechanisms. Moreover, β-hydroxy-β-methyl butyrate (HMB), a metabolite of leucine, has been reported to activate AMPK synergistically with resveratrol in C2C12 myotubes. Therefore, we hypothesize that leucine-induced activation of SIRT1 and AMPK is the central event that links the upregulated mitochondrial biogenesis and fatty acid oxidation in skeletal muscle. Thus, C2C12 myotubes were treated with leucine (0.5 mM), alanine (0.5 mM), valine (0.5 mM), EX527 (SIRT1 inhibitor, 25 μM), and Compound C (AMPK inhibitor, 25 μM) alone or in combination to determine the roles of AMPK and SIRT1 in leucine-modulation of energy metabolism. Leucine significantly increased mitochondrial content, mitochondrial biogenesis-related genes expression, fatty acid oxidation, SIRT1 activity and gene expression, and AMPK phosphorylation in C2C12 myotubes compared to the controls, while EX527 and Compound C markedly attenuated these effects. Furthermore, leucine treatment for 24 hours resulted in time-dependent increases in cellular NAD+, SIRT1 activity, and p-AMPK level, with SIRT1 activation preceding that of AMPK, indicating that leucine activation of SIRT1, rather than AMPK, is the primary event. PMID:25400942

  2. Exercise-Induced Bronchoconstriction

    MedlinePlus

    ... Conditions & Treatments ▸ Conditions Dictionary ▸ Exercise-Induced Bronchoconstriction Share | Exercise-Induced Bronchoconstriction (EIB) « Back to A to Z Listing Exercise-Induced Bronchoconstriction, (EIB), often known as exercise-induced ...

  3. Altered skeletal muscle mitochondrial biogenesis but improved endurance capacity in trained OPA1-deficient mice

    PubMed Central

    Caffin, F; Prola, A; Piquereau, J; Novotova, M; David, DJ; Garnier, A; Fortin, D; Alavi, MV; Veksler, V; Ventura-Clapier, R; Joubert, F

    2013-01-01

    The role of OPA1, a GTPase dynamin protein mainly involved in the fusion of inner mitochondrial membranes, has been studied in many cell types, but only a few studies have been conducted on adult differentiated tissues such as cardiac or skeletal muscle cells. Yet OPA1 is highly expressed in these cells, and could play different roles, especially in response to an environmental stress like exercise. Endurance exercise increases energy demand in skeletal muscle and repeated activity induces mitochondrial biogenesis and activation of fusion–fission cycles for the synthesis of new mitochondria. But currently no study has clearly shown a link between mitochondrial dynamics and biogenesis. Using a mouse model of haploinsufficiency for the Opa1 gene (Opa1+/−), we therefore studied the impact of OPA1 deficiency on the adaptation ability of fast skeletal muscles to endurance exercise training. Our results show that, surprisingly, Opa1+/− mice were able to perform the same physical activity as control mice. However, the adaptation strategies of both strains after training differed: while in control mice mitochondrial biogenesis was increased as expected, in Opa1+/− mice this process was blunted. Instead, training in Opa1+/− mice led to an increase in endurance capacity, and a specific adaptive response involving a metabolic remodelling towards enhanced fatty acid utilization. In conclusion, OPA1 appears necessary for the normal adaptive response and mitochondrial biogenesis of skeletal muscle to training. This work opens new perspectives on the role of mitochondrial dynamics in skeletal muscle cells and during adaptation to stress. PMID:24042504

  4. Cilostazol promotes mitochondrial biogenesis in human umbilical vein endothelial cells through activating the expression of PGC-1α

    SciTech Connect

    Zuo, Luning; Li, Qiang; Sun, Bei; Xu, Zhiying; Ge, Zhiming

    2013-03-29

    Highlights: ► First time to show that cilostazol promotes the expressions of PGC-1α. ► First time to show that cilostazol stimulates mitochondrial biogenesis in HUVECs. ► PKA/CREB pathway mediates the effect of cilostazol on PGC-1α expression. ► Suggesting the roles of cilostazol in mitochondrial dysfunction related disease. -- Abstract: Mitochondrial dysfunction is frequently observed in vascular diseases. Cilostazol is a drug approved by the US Food and Drug Administration for the treatment of intermittent claudication. Cilostazol increases intracellular cyclic adenosine monophosphate (cAMP) levels through inhibition of type III phosphodiesterase. The effects of cilostazol in mitochondrial biogenesis in human umbilical vein endothelial cells (HUVECs) were investigated in this study. Cilostazol treated HUVECs displayed increased levels of ATP, mitochondrial DNA/nuclear DNA ratio, expressions of cytochrome B, and mitochondrial mass, suggesting an enhanced mitochondrial biogenesis induced by cilostazol. The promoted mitochondrial biogenesis could be abolished by Protein kinase A (PKA) specific inhibitor H-89, implying that PKA pathway played a critical role in increased mitochondrial biogenesis after cilostazol treatment. Indeed, expression levels of peroxisome proliferator activator receptor gamma-coactivator 1α (PGC-1α), NRF 1 and mitochondrial transcription factor A (TFAM) were significantly increased in HUVECs after incubation with cilostazol at both mRNA levels and protein levels. Importantly, knockdown of PGC-1α could abolish cilostazol-induced mitochondrial biogenesis. Enhanced expression of p-CREB and PGC-1α induced by cilostazol could be inhibited by H-89. Moreover, the increased expression of PGC-1α induced by cilostazol could be inhibited by downregulation of CREB using CREB siRNA at both mRNA and protein levels. All the results indicated that cilostazol promoted mitochondrial biogenesis through activating the expression of PGC-1α in

  5. Alternative NF-κB Regulates RANKL-induced Osteoclast Differentiation and Mitochondrial Biogenesis via Independent Mechanisms

    PubMed Central

    Zeng, Rong; Faccio, Roberta; Novack, Deborah V

    2016-01-01

    Mitochondrial biogenesis, the generation of new mitochondrial DNA and proteins, has been linked to osteoclast (OC) differentiation and function. In this study we used mice with mutations in key alternative NF-κB pathway proteins, RelB and NIK, to dissect the complex relationship between mitochondrial biogenesis and osteoclastogenesis. OC precursors lacking either NIK or RelB, RANKL were unable to increase mitochondrial DNA or OxPhos protein expression, associated with lower oxygen consumption rates. Transgenic OC precursors expressing constitutively active NIK showed normal RANKL-induced mitochondrial biogenesis (OxPhos expression and mitochondria copy number) compared to controls, but larger mitochondrial dimensions and increased oxygen consumption rates, suggesting increased mitochondrial function. To deduce the mechanism for mitochondrial biogenesis defects in NIK- and RelB-deficient precursors, we examined expression of genes known to control this process. PGC-1β (Ppargc1b) expression, but not PGC-1α, PPRC1 or ERRα, was significantly reduced in RelB−/− and NIK−/− OCs. Because PGC-1β has been reported to positively regulate both mitochondrial biogenesis and differentiation in OCs, we retrovirally overexpressed PGC-1β in RelB−/− cells, but surprisingly found that it did not affect differentiation, nor restore RANKL-induced mitochondrial biogenesis. To determine whether the blockade in osteoclastogenesis in RelB-deficient cells precludes mitochondrial biogenesis, we rescued RelB−/− differentiation via overexpression of NFATc1. Mitochondrial parameters in neither WT nor RelB-deficient cultures were affected by NFATc1 overexpression, and bone resorption in RelB −/− was not restored. Furthermore, NFATc1 co-overexpression with PGC-1β, while allowing OC differentiation, did not rescue mitochondrial biogenesis or bone resorption in RelB−/− OCs, by CTX-I levels. Thus, our results indicate that the alternative NF-κB pathway plays dual, but

  6. Augmentation of aerobic respiration and mitochondrial biogenesis in skeletal muscle by hypoxia preconditioning with cobalt chloride

    SciTech Connect

    Saxena, Saurabh; Shukla, Dhananjay; Bansal, Anju

    2012-11-01

    High altitude/hypoxia training is known to improve physical performance in athletes. Hypoxia induces hypoxia inducible factor-1 (HIF-1) and its downstream genes that facilitate hypoxia adaptation in muscle to increase physical performance. Cobalt chloride (CoCl{sub 2}), a hypoxia mimetic, stabilizes HIF-1, which otherwise is degraded in normoxic conditions. We studied the effects of hypoxia preconditioning by CoCl{sub 2} supplementation on physical performance, glucose metabolism, and mitochondrial biogenesis using rodent model. The results showed significant increase in physical performance in cobalt supplemented rats without (two times) or with training (3.3 times) as compared to control animals. CoCl{sub 2} supplementation in rats augmented the biological activities of enzymes of TCA cycle, glycolysis and cytochrome c oxidase (COX); and increased the expression of glucose transporter-1 (Glut-1) in muscle showing increased glucose metabolism by aerobic respiration. There was also an increase in mitochondrial biogenesis in skeletal muscle observed by increased mRNA expressions of mitochondrial biogenesis markers which was further confirmed by electron microscopy. Moreover, nitric oxide production increased in skeletal muscle in cobalt supplemented rats, which seems to be the major reason for peroxisome proliferator activated receptor-gamma coactivator-1α (PGC-1α) induction and mitochondrial biogenesis. Thus, in conclusion, we state that hypoxia preconditioning by CoCl{sub 2} supplementation in rats increases mitochondrial biogenesis, glucose uptake and metabolism by aerobic respiration in skeletal muscle, which leads to increased physical performance. The significance of this study lies in understanding the molecular mechanism of hypoxia adaptation and improvement of work performance in normal as well as extreme conditions like hypoxia via hypoxia preconditioning. -- Highlights: ► We supplemented rats with CoCl{sub 2} for 15 days along with training. ► Co

  7. Interfacing mitochondrial biogenesis and elimination to enhance host pathogen defense and longevity

    PubMed Central

    Palikaras, Konstantinos; Lionaki, Eirini; Tavernarakis, Nektarios

    2015-01-01

    Mitochondria are highly dynamic and semi-autonomous organelles, essential for many fundamental cellular processes, including energy production, metabolite synthesis and calcium homeostasis, among others. Alterations in mitochondrial activity not only influence individual cell function but also, through non-cell autonomous mechanisms, whole body metabolism, healthspan and lifespan. Energy homeostasis is orchestrated by the complex interplay between mitochondrial biogenesis and mitochondria-selective autophagy (mitophagy). However, the cellular and molecular pathways that coordinate these 2 opposing processes remained obscure. In our recent study, we demonstrate that DCT-1, the Caenorhabditis elegans homolog of the mammalian BNIP3 and BNIP3L/NIX, is a key mediator of mitophagy, and functions in the same genetic pathway with PINK-1 and PDR-1 (the nematode homologs of PINK1 and Parkin respectively) to promote longevity and prevent cell damage under stress conditions. Interestingly, accumulation of damaged mitochondria activates SKN-1 (SKiNhead-1), the nematode homolog of NRF2, which in turn initiates a compensatory retrograde signaling response that impinges on both mitochondrial biogenesis and removal. In this commentary, we discuss the implications of these new findings in the context of innate immunity and aging. Unraveling the regulatory network that governs the crosstalk between mitochondrial biogenesis and mitophagy will enhance our understanding of the molecular mechanisms that link aberrant energy metabolism to aging and disease. PMID:26430570

  8. Interfacing mitochondrial biogenesis and elimination to enhance host pathogen defense and longevity.

    PubMed

    Palikaras, Konstantinos; Lionaki, Eirini; Tavernarakis, Nektarios

    2015-01-01

    Mitochondria are highly dynamic and semi-autonomous organelles, essential for many fundamental cellular processes, including energy production, metabolite synthesis and calcium homeostasis, among others. Alterations in mitochondrial activity not only influence individual cell function but also, through non-cell autonomous mechanisms, whole body metabolism, healthspan and lifespan. Energy homeostasis is orchestrated by the complex interplay between mitochondrial biogenesis and mitochondria-selective autophagy (mitophagy). However, the cellular and molecular pathways that coordinate these 2 opposing processes remained obscure. In our recent study, we demonstrate that DCT-1, the Caenorhabditis elegans homolog of the mammalian BNIP3 and BNIP3L/NIX, is a key mediator of mitophagy, and functions in the same genetic pathway with PINK-1 and PDR-1 (the nematode homologs of PINK1 and Parkin respectively) to promote longevity and prevent cell damage under stress conditions. Interestingly, accumulation of damaged mitochondria activates SKN-1 (SKiNhead-1), the nematode homolog of NRF2, which in turn initiates a compensatory retrograde signaling response that impinges on both mitochondrial biogenesis and removal. In this commentary, we discuss the implications of these new findings in the context of innate immunity and aging. Unraveling the regulatory network that governs the crosstalk between mitochondrial biogenesis and mitophagy will enhance our understanding of the molecular mechanisms that link aberrant energy metabolism to aging and disease.

  9. Sulforaphane induces differential modulation of mitochondrial biogenesis and dynamics in normal cells and tumor cells.

    PubMed

    Negrette-Guzmán, Mario; Huerta-Yepez, Sara; Vega, Mario I; León-Contreras, Juan Carlos; Hernández-Pando, Rogelio; Medina-Campos, Omar Noel; Rodríguez, Esteban; Tapia, Edilia; Pedraza-Chaverri, José

    2017-02-01

    Antioxidant-based chemotherapy has been intensely debated. Herein, we show that sulforaphane (SFN) induced mitochondrial biogenesis followed by mitochondrial fusion in a kidney cell line commonly used in nephroprotective models. At the same concentration and exposure time, SFN induced cell death in prostate cancer cells accompanied by mitochondrial biogenesis and fragmentation. Stabilization of the nuclear factor E2-related factor-2 (Nrf2) could be associated with these effects in the tumor cell line. An increase in the peroxisome proliferator-activated receptor-γ co-activator-1α (PGC1α) level and a decrease in the hypoxia-inducible factor-1α (HIF1α) level would suggest a possible metabolic shift. The knockdown in the nuclear respiratory factor-1 (NRF1) attenuated the SFN-induced effect on prostate cancer cells demonstrating that mitochondrial biogenesis plays an important role in cell death for this kind of tumor cells. This evidence supports SFN as a potential antineoplastic agent that could inhibit tumor development and could protect normal tissues by modulating common processes.

  10. Mitochondrial biogenesis and proteome remodeling promotes one carbon metabolism for T cell activation

    PubMed Central

    Ron-Harel, Noga; Santos, Daniel; Ghergurovich, Jonathan M.; Sage, Peter T.; Reddy, Anita; Lovitch, Scott B.; Dephoure, Noah; Satterstrom, F. Kyle; Sheffer, Michal; Spinelli, Jessica B.; Gygi, Steven; Rabinowitz, Joshua D.; Sharpe, Arlene H.; Haigis, Marcia C.

    2017-01-01

    Summary Naïve T cell stimulation activates anabolic metabolism to fuel the transition from quiescence to growth and proliferation. Here we show that naïve CD4+ T cell activation induces a unique program of mitochondrial biogenesis and remodeling. Using mass spectrometry, we quantified protein dynamics during T cell activation. We identified substantial remodeling of the mitochondrial proteome over the first 24 hr of T cell activation to generate mitochondria with a distinct metabolic signature, with one carbon metabolism as the most induced pathway. Salvage pathways and mitochondrial one carbon metabolism, fed by serine, contribute to purine and thymidine synthesis to enable T cell proliferation and survival. Genetic inhibition of the mitochondrial serine catabolic enzyme SHMT2 impaired T cell survival in culture, and antigen-specific T cell abundance in vivo. Thus, during T cell activation, mitochondrial proteome remodeling generates specialized mitochondria with enhanced one carbon metabolism that is critical for T cell activation and survival. PMID:27411012

  11. Respiration and Mitochondrial Biogenesis in Germinating Embryos of Maize 1

    PubMed Central

    Ehrenshaft, Marilyn; Brambl, Robert

    1990-01-01

    Function of the cyanide-sensitive mitochondrial electron transport system was required for germination of the Zea mays embryo. Respiration of the standard electron transport system (rather than the alternate oxidase) began immediately upon initiation of imbibition. This respiration depended upon cytochrome c oxidase and ATPase that were conserved in an active form in the quiescent embryo rather than upon newly synthesized or assembled enzyme complexes. Immunoprecipitation of radiolabeled subunits of these enzymes showed that the initiation of mitochondrial biogenetic activities, including de novo synthesis of nuclear- and mitochondrial-encoded enzyme subunit peptides, was strongly induced after 6 hours of embryo germination. Undetectable or very low levels of transcripts for subunits 1 and 2 of the F1-ATPase and subunit 2 of cytochrome c oxidase were present in the quiescent embryo; these transcripts accumulated rapidly between 6 and 12 hours of germination and their translation products were rapidly synthesized between 6 and 24 hours. An exception was the gene for subunit 9 of the ATPase; transcripts of this mitochondrial gene were abundant in the dry embryo and rapidly accumulated further upon initiation of imbibition; they were translated actively during the first 6 hours. We isolated and sequenced a near full-length cDNA for subunit 2 (beta) of the F1-ATPase, and we compared the deduced protein sequence with related sequences of other organisms. Images Figure 2 Figure 3 Figure 5 PMID:16667450

  12. Shear stress-induced mitochondrial biogenesis decreases the release of microparticles from endothelial cells

    PubMed Central

    Kim, Ji-Seok; Kim, Boa; Lee, Hojun; Thakkar, Sunny; Babbitt, Dianne M.; Eguchi, Satoru; Brown, Michael D.

    2015-01-01

    The concept of enhancing structural integrity of mitochondria has emerged as a novel therapeutic option for cardiovascular disease. Flow-induced increase in laminar shear stress is a potent physiological stimulant associated with exercise, which exerts atheroprotective effects in the vasculature. However, the effect of laminar shear stress on mitochondrial remodeling within the vascular endothelium and its related functional consequences remain largely unknown. Using in vitro and in vivo complementary studies, here, we report that aerobic exercise alleviates the release of endothelial microparticles in prehypertensive individuals and that these salutary effects are, in part, mediated by shear stress-induced mitochondrial biogenesis. Circulating levels of total (CD31+/CD42a−) and activated (CD62E+) microparticles released by endothelial cells were significantly decreased (∼40% for both) after a 6-mo supervised aerobic exercise training program in individuals with prehypertension. In cultured human endothelial cells, laminar shear stress reduced the release of endothelial microparticles, which was accompanied by an increase in mitochondrial biogenesis through a sirtuin 1 (SIRT1)-dependent mechanism. Resveratrol, a SIRT1 activator, treatment showed similar effects. SIRT1 knockdown using small-interfering RNA completely abolished the protective effect of shear stress. Disruption of mitochondrial integrity by either antimycin A or peroxisome proliferator-activated receptor-γ coactivator-1α small-interfering RNA significantly increased the number of total, and activated, released endothelial microparticles, and shear stress restored these back to basal levels. Collectively, these data demonstrate a critical role of endothelial mitochondrial integrity in preserving endothelial homeostasis. Moreover, prolonged laminar shear stress, which is systemically elevated during aerobic exercise in the vessel wall, mitigates endothelial dysfunction by promoting mitochondrial

  13. Cannabidiol Protects against Doxorubicin-Induced Cardiomyopathy by Modulating Mitochondrial Function and Biogenesis.

    PubMed

    Hao, Enkui; Mukhopadhyay, Partha; Cao, Zongxian; Erdélyi, Katalin; Holovac, Eileen; Liaudet, Lucas; Lee, Wen-Shin; Haskó, György; Mechoulam, Raphael; Pacher, Pál

    2015-01-06

    Doxorubicin (DOX) is a widely used, potent chemotherapeutic agent; however, its clinical application is limited because of its dose-dependent cardiotoxicity. DOX's cardiotoxicity involves increased oxidative/nitrative stress, impaired mitochondrial function in cardiomyocytes/endothelial cells and cell death. Cannabidiol (CBD) is a nonpsychotropic constituent of marijuana, which is well tolerated in humans, with antioxidant, antiinflammatory and recently discovered antitumor properties. We aimed to explore the effects of CBD in a well-established mouse model of DOX-induced cardiomyopathy. DOX-induced cardiomyopathy was characterized by increased myocardial injury (elevated serum creatine kinase and lactate dehydrogenase levels), myocardial oxidative and nitrative stress (decreased total glutathione content and glutathione peroxidase 1 activity, increased lipid peroxidation, 3-nitrotyrosine formation and expression of inducible nitric oxide synthase mRNA), myocardial cell death (apoptotic and poly[ADP]-ribose polymerase 1 [PARP]-dependent) and cardiac dysfunction (decline in ejection fraction and left ventricular fractional shortening). DOX also impaired myocardial mitochondrial biogenesis (decreased mitochondrial copy number, mRNA expression of peroxisome proliferator-activated receptor γ coactivator 1-alpha, peroxisome proliferator-activated receptor alpha, estrogen-related receptor alpha), reduced mitochondrial function (attenuated complex I and II activities) and decreased myocardial expression of uncoupling protein 2 and 3 and medium-chain acyl-CoA dehydrogenase mRNA. Treatment with CBD markedly improved DOX-induced cardiac dysfunction, oxidative/nitrative stress and cell death. CBD also enhanced the DOX-induced impaired cardiac mitochondrial function and biogenesis. These data suggest that CBD may represent a novel cardioprotective strategy against DOX-induced cardiotoxicity, and the above-described effects on mitochondrial function and biogenesis may

  14. Turn up the power –pharmacological activation of mitochondrial biogenesis in mouse models

    PubMed Central

    Komen, J C; Thorburn, D R

    2014-01-01

    The oxidative phosphorylation (OXPHOS) system in mitochondria is responsible for the generation of the majority of cellular energy in the form of ATP. Patients with genetic OXPHOS disorders form the largest group of inborn errors of metabolism. Unfortunately, there is still a lack of efficient therapies for these disorders other than management of symptoms. Developing therapies has been complicated because, although the total group of OXPHOS patients is relatively large, there is enormous clinical and genetic heterogeneity within this patient population. Thus there has been a lot of interest in generating relevant mouse models for the different kinds of OXPHOS disorders. The most common treatment strategies tested in these mouse models have aimed to up-regulate mitochondrial biogenesis, in order to increase the residual OXPHOS activity present in affected animals and thereby to ameliorate the energy deficiency. Drugs such as bezafibrate, resveratrol and AICAR target the master regulator of mitochondrial biogenesis PGC-1α either directly or indirectly to manipulate mitochondrial metabolism. This review will summarize the outcome of preclinical treatment trials with these drugs in mouse models of OXPHOS disorders and discuss similar treatments in a number of mouse models of common diseases in which pathology is closely linked to mitochondrial dysfunction. In the majority of these studies the pharmacological activation of the PGC-1α axis shows true potential as therapy; however, other effects besides mitochondrial biogenesis may be contributing to this as well. Linked Articles This article is part of a themed issue on Mitochondrial Pharmacology: Energy, Injury & Beyond. To view the other articles in this issue visit http://dx.doi.org/10.1111/bph.2014.171.issue-8 PMID:24102298

  15. MKK3 regulates mitochondrial biogenesis and mitophagy in sepsis-induced lung injury.

    PubMed

    Mannam, Praveen; Shinn, Amanda S; Srivastava, Anup; Neamu, Radu F; Walker, Wendy E; Bohanon, Michael; Merkel, Jane; Kang, Min-Jong; Dela Cruz, Charles S; Ahasic, Amy M; Pisani, Margaret A; Trentalange, Mark; West, A Phillip; Shadel, Gerald S; Elias, Jack A; Lee, Patty J

    2014-04-01

    Sepsis is a systemic inflammatory response to infection and a major cause of death worldwide. Because specific therapies to treat sepsis are limited, and underlying pathogenesis is unclear, current medical care remains purely supportive. Therefore targeted therapies to treat sepsis need to be developed. Although an important mediator of sepsis is thought to be mitochondrial dysfunction, the underlying molecular mechanism is unclear. Modulation of mitochondrial processes may be an effective therapeutic strategy in sepsis. Here, we investigated the role of the kinase MKK3 in regulation of mitochondrial function in sepsis. Using clinically relevant animal models, we examined mitochondrial function in primary mouse lung endothelial cells exposed to LPS. MKK3 deficiency reduces lethality of sepsis in mice and by lowering levels of lung and mitochondrial injury as well as reactive oxygen species. Furthermore, MKK3 deficiency appeared to simultaneously increase mitochondrial biogenesis and mitophagy through the actions of Sirt1, Pink1, and Parkin. This led to a more robust mitochondrial network, which we propose provides protection against sepsis. We also detected higher MKK3 activation in isolated peripheral blood mononuclear cells from septic patients compared with nonseptic controls. Our findings demonstrate a critical role for mitochondria in the pathogenesis of sepsis that involves a previously unrecognized function of MKK3 in mitochondrial quality control. This mitochondrial pathway may help reveal new diagnostic markers and therapeutic targets against sepsis.

  16. Optimizing Intramuscular Adaptations to Aerobic Exercise: Effects of Carbohydrate Restriction and Protein Supplementation on Mitochondrial Biogenesis12

    PubMed Central

    Margolis, Lee M.; Pasiakos, Stefan M.

    2013-01-01

    Mitochondrial biogenesis is a critical metabolic adaptation to aerobic exercise training that results in enhanced mitochondrial size, content, number, and activity. Recent evidence has shown that dietary manipulation can further enhance mitochondrial adaptations to aerobic exercise training, which may delay skeletal muscle fatigue and enhance exercise performance. Specifically, studies have demonstrated that combining carbohydrate restriction (endogenous and exogenous) with a single bout of aerobic exercise potentiates the beneficial effects of exercise on markers of mitochondrial biogenesis. Additionally, studies have demonstrated that high-quality protein supplementation enhances anabolic skeletal muscle intracellular signaling and mitochondrial protein synthesis following a single bout of aerobic exercise. Mitochondrial biogenesis is stimulated by complex intracellular signaling pathways that appear to be primarily regulated by 5′AMP-activated protein kinase and p38 mitogen-activated protein kinase mediated through proliferator-activated γ receptor co-activator 1 α activation, resulting in increased mitochondrial DNA expression and enhanced skeletal muscle oxidative capacity. However, the mechanisms by which concomitant carbohydrate restriction and dietary protein supplementation modulates mitochondrial adaptations to aerobic exercise training remains unclear. This review summarizes intracellular regulation of mitochondrial biogenesis and the effects of carbohydrate restriction and protein supplementation on mitochondrial adaptations to aerobic exercise. PMID:24228194

  17. 14,15-EET promotes mitochondrial biogenesis and protects cortical neurons against oxygen/glucose deprivation-induced apoptosis

    SciTech Connect

    Wang, Lai; Chen, Man; Yuan, Lin; Xiang, Yuting; Zheng, Ruimao; Zhu, Shigong

    2014-07-18

    Highlights: • 14,15-EET inhibits OGD-induced apoptosis in cortical neurons. • Mitochondrial biogenesis of cortical neurons is promoted by 14,15-EET. • 14,15-EET preserves mitochondrial function of cortical neurons under OGD. • CREB mediates effect of 14,15-EET on mitochondrial biogenesis and function. - Abstract: 14,15-Epoxyeicosatrienoic acid (14,15-EET), a metabolite of arachidonic acid, is enriched in the brain cortex and exerts protective effect against neuronal apoptosis induced by ischemia/reperfusion. Although apoptosis has been well recognized to be closely associated with mitochondrial biogenesis and function, it is still unclear whether the neuroprotective effect of 14,15-EET is mediated by promotion of mitochondrial biogenesis and function in cortical neurons under the condition of oxygen–glucose deprivation (OGD). In this study, we found that 14,15-EET improved cell viability and inhibited apoptosis of cortical neurons. 14,15-EET significantly increased the mitochondrial mass and the ratio of mitochondrial DNA to nuclear DNA. Key makers of mitochondrial biogenesis, peroxisome proliferator activator receptor gamma-coactivator 1 alpha (PGC-1α), nuclear respiratory factor 1 (NRF-1) and mitochondrial transcription factor A (TFAM), were elevated at both mRNA and protein levels in the cortical neurons treated with 14,15-EET. Moreover, 14,15-EET markedly attenuated the decline of mitochondrial membrane potential, reduced ROS, while increased ATP synthesis. Knockdown of cAMP-response element binding protein (CREB) by siRNA blunted the up-regulation of PGC-1α and NRF-1 stimulated by 14,15-EET, and consequently abolished the neuroprotective effect of 14,15-EET. Our results indicate that 14,15-EET protects neurons from OGD-induced apoptosis by promoting mitochondrial biogenesis and function through CREB mediated activation of PGC-1α and NRF-1.

  18. Mitophagy is required for mitochondrial biogenesis and myogenic differentiation of C2C12 myoblasts.

    PubMed

    Sin, Jon; Andres, Allen M; Taylor, David J R; Weston, Thomas; Hiraumi, Yoshimi; Stotland, Aleksandr; Kim, Brandon J; Huang, Chengqun; Doran, Kelly S; Gottlieb, Roberta A

    2016-01-01

    Myogenesis is a crucial process governing skeletal muscle development and homeostasis. Differentiation of primitive myoblasts into mature myotubes requires a metabolic switch to support the increased energetic demand of contractile muscle. Skeletal myoblasts specifically shift from a highly glycolytic state to relying predominantly on oxidative phosphorylation (OXPHOS) upon differentiation. We have found that this phenomenon requires dramatic remodeling of the mitochondrial network involving both mitochondrial clearance and biogenesis. During early myogenic differentiation, autophagy is robustly upregulated and this coincides with DNM1L/DRP1 (dynamin 1-like)-mediated fragmentation and subsequent removal of mitochondria via SQSTM1 (sequestosome 1)-mediated mitophagy. Mitochondria are then repopulated via PPARGC1A/PGC-1α (peroxisome proliferator-activated receptor gamma, coactivator 1 alpha)-mediated biogenesis. Mitochondrial fusion protein OPA1 (optic atrophy 1 [autosomal dominant]) is then briskly upregulated, resulting in the reformation of mitochondrial networks. The final product is a myotube replete with new mitochondria. Respirometry reveals that the constituents of these newly established mitochondrial networks are better primed for OXPHOS and are more tightly coupled than those in myoblasts. Additionally, we have found that suppressing autophagy with various inhibitors during differentiation interferes with myogenic differentiation. Together these data highlight the integral role of autophagy and mitophagy in myogenic differentiation.

  19. Berberine protects against high fat diet-induced dysfunction in muscle mitochondria by inducing SIRT1-dependent mitochondrial biogenesis

    PubMed Central

    Gomes, Ana P.; Duarte, Filipe V.; Nunes, Patricia; Hubbard, Basil P.; Teodoro, João S.; Varela, Ana T.; Jones, John G.; Sinclair, David A.; Palmeira, Carlos M.; Rolo, Anabela P.

    2012-01-01

    Berberine (BBR) has recently been shown to improve insulin sensitivity in rodent models of insulin resistance. Although this effect was explained partly through an observed activation of AMP-activated protein kinase (AMPK), the upstream and downstream mediators of this phenotype were not explored. Here, we show that BBR supplementation reverts mitochondrial dysfunction induced by High Fat Diet (HFD) and hyperglycemia in skeletal muscle, in part due to an increase in mitochondrial biogenesis. Furthermore, we observe that the prevention of mitochondrial dysfunction by BBR, the increase in mitochondrial biogenesis, as well as BBR-induced AMPK activation, are blocked in cells in which SIRT1 has been knocked-down. Taken together, these data reveal an important role for SIRT1 and mitochondrial biogenesis in the preventive effects of BBR on diet-induced insulin resistance. PMID:22027215

  20. Neural stem cell transplantation enhances mitochondrial biogenesis in a transgenic mouse model of Alzheimer's disease-like pathology.

    PubMed

    Zhang, Wei; Gu, Guo-Jun; Shen, Xing; Zhang, Qi; Wang, Gang-Min; Wang, Pei-Jun

    2015-03-01

    Mitochondrial dysfunction, especially a defect in mitochondrial biogenesis, is an early and prominent feature of Alzheimer's disease (AD). Previous studies demonstrated that the number of mitochondria is significantly reduced in susceptible hippocampal neurons from AD patients. Neural stem cell (NSC) transplantation in AD-like mice can compensate for the neuronal loss resulting from amyloid-beta protein deposition. The effects of NSC transplantation on mitochondrial biogenesis and cognitive function in AD-like mice, however, are poorly understood. In this study, we injected NSCs or vehicle into 12-month-old amyloid precursor protein (APP)/PS1 transgenic mice, a mouse model of AD-like pathology. The effects of NSC transplantation on cognitive function, the amount of mitochondrial DNA, the expression of mitochondrial biogenesis factors and mitochondria-related proteins, and mitochondrial morphology were investigated. Our results show that in NSC-injected APP/PS1 (Tg-NSC) mice, the cognitive function, number of mitochondria, and expression of mitochondria-related proteins, specifically the mitochondrial fission factors (dynamin-related protein 1 [Drp1] and fission 1 [Fis1]) and the mitochondrial fusion factor optic atrophy 1 (OPA1), were significantly increased compared with those in age-matched vehicle-injected APP/PS1 (Tg-Veh) mice, whereas the expression of mitochondrial fusion factors mitofusion 1 (Mfn1) and Mfn2 was significantly decreased. These data indicate that NSC transplantation may enhance mitochondria biogenesis and further rescue cognitive deficits in AD-like mice.

  1. The role of AMPK in controlling metabolism and mitochondrial biogenesis during exercise.

    PubMed

    Marcinko, Katarina; Steinberg, Gregory R

    2014-12-01

    Insulin resistance is associated with defects in skeletal muscle fatty acid (FA) metabolism that contribute to the development of type 2 diabetes. Endurance exercise increases FA and glucose metabolism, muscle mitochondrial content and insulin sensitivity. In skeletal muscle, basal rates of FA oxidation are dependent on AMP-activated protein kinase (AMPK) phosphorylation of acetyl-CoA carboxylase 2, the rate-limiting enzyme controlling the production of the metabolic intermediate malonyl-CoA. Likewise, AMPK is essential for maintaining muscle mitochondrial content in untrained mice; effects that may be mediated through regulation of the peroxisome proliferator-activated receptor γ co-activator-1α. However, the importance of AMPK in regulating glucose and FA uptake, FA oxidation and mitochondrial biogenesis during and following endurance exercise training is not fully understood. A better understanding of the mechanisms by which endurance exercise regulates substrate utilization and mitochondrial biogenesis may lead to improved therapeutic and preventative strategies for the treatment of insulin resistance and type 2 diabetes.

  2. Defects in Mitochondrial Fatty Acid Synthesis Result in Failure of Multiple Aspects of Mitochondrial Biogenesis in Saccharomyces cerevisiae

    PubMed Central

    Kursu, V. A. Samuli; Pietikäinen, Laura P.; Fontanesi, Flavia; Aaltonen, Mari J.; Suomi, Fumi; Nair, Remya Raghavan; Schonauer, Melissa S.; Dieckmann, Carol L.; Barrientos, Antoni; Hiltunen, J. Kalervo; Kastaniotis, Alexander J.

    2014-01-01

    Summary Mitochondrial fatty acid synthesis (mtFAS) shares acetyl-CoA with the Krebs cycle as a common substrate and is required for the production of octanoic acid (C8) precursors of lipoic acid (LA) in mitochondria. MtFAS is a conserved pathway essential for respiration. In a genetic screen in Saccharomyces cerevisiae designed to further elucidate the physiological role of mtFAS, we isolated mutants with defects in mitochondrial post-translational gene expression processes, indicating a novel link to mitochondrial gene expression and respiratory chain biogenesis. In our ensuing analysis, we show that mtFAS, but not lipoylation per se, is required for respiratory competence. We demonstrate that mtFAS is required for mRNA splicing, mitochondrial translation and respiratory complex assembly, and provide evidence that not LA per se, but fatty acids longer than C8 play a role in these processes. We also show that mtFAS- and LA-deficient strains suffer from a mild heme deficiency that may contribute to the respiratory complex assembly defect. Based on our data and previously published information, we propose a model implicating mtFAS as a sensor for mitochondrial acetyl-CoA availability and a coordinator of nuclear and mitochondrial gene expression by adapting the mitochondrial compartment to changes in the metabolic status of the cell. PMID:24102902

  3. Amla Enhances Mitochondrial Spare Respiratory Capacity by Increasing Mitochondrial Biogenesis and Antioxidant Systems in a Murine Skeletal Muscle Cell Line.

    PubMed

    Yamamoto, Hirotaka; Morino, Katsutaro; Mengistu, Lemecha; Ishibashi, Taishi; Kiriyama, Kohei; Ikami, Takao; Maegawa, Hiroshi

    2016-01-01

    Amla is one of the most important plants in Indian traditional medicine and has been shown to improve various age-related disorders while decreasing oxidative stress. Mitochondrial dysfunction is a proposed cause of aging through elevated oxidative stress. In this study, we investigated the effects of Amla on mitochondrial function in C2C12 myotubes, a murine skeletal muscle cell model with abundant mitochondria. Based on cell flux analysis, treatment with an extract of Amla fruit enhanced mitochondrial spare respiratory capacity, which enables cells to overcome various stresses. To further explore the mechanisms underlying these effects on mitochondrial function, we analyzed mitochondrial biogenesis and antioxidant systems, both proposed regulators of mitochondrial spare respiratory capacity. We found that Amla treatment stimulated both systems accompanied by AMPK and Nrf2 activation. Furthermore, we found that Amla treatment exhibited cytoprotective effects and lowered reactive oxygen species (ROS) levels in cells subjected to t-BHP-induced oxidative stress. These effects were accompanied by increased oxygen consumption, suggesting that Amla protected cells against oxidative stress by using enhanced spare respiratory capacity to produce more energy. Thus we identified protective effects of Amla, involving activation of mitochondrial function, which potentially explain its various effects on age-related disorders.

  4. Amla Enhances Mitochondrial Spare Respiratory Capacity by Increasing Mitochondrial Biogenesis and Antioxidant Systems in a Murine Skeletal Muscle Cell Line

    PubMed Central

    Yamamoto, Hirotaka; Morino, Katsutaro; Mengistu, Lemecha; Ishibashi, Taishi; Kiriyama, Kohei; Ikami, Takao; Maegawa, Hiroshi

    2016-01-01

    Amla is one of the most important plants in Indian traditional medicine and has been shown to improve various age-related disorders while decreasing oxidative stress. Mitochondrial dysfunction is a proposed cause of aging through elevated oxidative stress. In this study, we investigated the effects of Amla on mitochondrial function in C2C12 myotubes, a murine skeletal muscle cell model with abundant mitochondria. Based on cell flux analysis, treatment with an extract of Amla fruit enhanced mitochondrial spare respiratory capacity, which enables cells to overcome various stresses. To further explore the mechanisms underlying these effects on mitochondrial function, we analyzed mitochondrial biogenesis and antioxidant systems, both proposed regulators of mitochondrial spare respiratory capacity. We found that Amla treatment stimulated both systems accompanied by AMPK and Nrf2 activation. Furthermore, we found that Amla treatment exhibited cytoprotective effects and lowered reactive oxygen species (ROS) levels in cells subjected to t-BHP-induced oxidative stress. These effects were accompanied by increased oxygen consumption, suggesting that Amla protected cells against oxidative stress by using enhanced spare respiratory capacity to produce more energy. Thus we identified protective effects of Amla, involving activation of mitochondrial function, which potentially explain its various effects on age-related disorders. PMID:27340504

  5. Short term exercise induces PGC-1α, ameliorates inflammation and increases mitochondrial membrane proteins but fails to increase respiratory enzymes in aging diabetic hearts.

    PubMed

    Botta, Amy; Laher, Ismail; Beam, Julianne; Decoffe, Daniella; Brown, Kirsty; Halder, Swagata; Devlin, Angela; Gibson, Deanna L; Ghosh, Sanjoy

    2013-01-01

    PGC-1α, a transcriptional coactivator, controls inflammation and mitochondrial gene expression in insulin-sensitive tissues following exercise intervention. However, attributing such effects to PGC-1α is counfounded by exercise-induced fluctuations in blood glucose, insulin or bodyweight in diabetic patients. The goal of this study was to investigate the role of PGC-1α on inflammation and mitochondrial protein expressions in aging db/db mice hearts, independent of changes in glycemic parameters. In 8-month-old db/db mice hearts with diabetes lasting over 22 weeks, short-term, moderate-intensity exercise upregulated PGC-1α without altering body weight or glycemic parameters. Nonetheless, such a regimen lowered both cardiac (macrophage infiltration, iNOS and TNFα) and systemic (circulating chemokines and cytokines) inflammation. Curiously, such an anti-inflammatory effect was also linked to attenuated expression of downstream transcription factors of PGC-1α such as NRF-1 and several respiratory genes. Such mismatch between PGC-1α and its downstream targets was associated with elevated mitochondrial membrane proteins like Tom70 but a concurrent reduction in oxidative phosphorylation protein expressions in exercised db/db hearts. As mitochondrial oxidative stress was predominant in these hearts, in support of our in vivo data, increasing concentrations of H2O2 dose-dependently increased PGC-1α expression while inhibiting expression of inflammatory genes and downstream transcription factors in H9c2 cardiomyocytes in vitro. We conclude that short-term exercise-induced oxidative stress may be key in attenuating cardiac inflammatory genes and impairing PGC-1α mediated gene transcription of downstream transcription factors in type 2 diabetic hearts at an advanced age.

  6. Exercise-Induced Asthma

    MedlinePlus

    ... Old Feeding Your 1- to 2-Year-Old Exercise-Induced Asthma KidsHealth > For Parents > Exercise-Induced Asthma ... they choose. previous continue Tips for Kids With Exercise-Induced Asthma For the most part, kids with ...

  7. Perm1 enhances mitochondrial biogenesis, oxidative capacity, and fatigue resistance in adult skeletal muscle.

    PubMed

    Cho, Yoshitake; Hazen, Bethany C; Gandra, Paulo G; Ward, Samuel R; Schenk, Simon; Russell, Aaron P; Kralli, Anastasia

    2016-02-01

    Skeletal muscle mitochondrial content and oxidative capacity are important determinants of muscle function and whole-body health. Mitochondrial content and function are enhanced by endurance exercise and impaired in states or diseases where muscle function is compromised, such as myopathies, muscular dystrophies, neuromuscular diseases, and age-related muscle atrophy. Hence, elucidating the mechanisms that control muscle mitochondrial content and oxidative function can provide new insights into states and diseases that affect muscle health. In past studies, we identified Perm1 (PPARGC1- and ESRR-induced regulator, muscle 1) as a gene induced by endurance exercise in skeletal muscle, and regulating mitochondrial oxidative function in cultured myotubes. The capacity of Perm1 to regulate muscle mitochondrial content and function in vivo is not yet known. In this study, we use adeno-associated viral (AAV) vectors to increase Perm1 expression in skeletal muscles of 4-wk-old mice. Compared to control vector, AAV1-Perm1 leads to significant increases in mitochondrial content and oxidative capacity (by 40-80%). Moreover, AAV1-Perm1-transduced muscles show increased capillary density and resistance to fatigue (by 33 and 31%, respectively), without prominent changes in fiber-type composition. These findings suggest that Perm1 selectively regulates mitochondrial biogenesis and oxidative function, and implicate Perm1 in muscle adaptations that also occur in response to endurance exercise.

  8. Developmental regulation of mitochondrial biogenesis and function in the mouse mammary gland during a prolonged lactation cycle

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The regulation of mitochondrial biogenesis and function in the lactating mammary cell is poorly understood. The goal of this study was to use proteomics to relate temporal changes in mammary cell mitochondrial function during lactation to changes in the proteins that make up this organelle. The hypo...

  9. Aluminium induced oxidative stress results in decreased mitochondrial biogenesis via modulation of PGC-1α expression.

    PubMed

    Sharma, Deep Raj; Sunkaria, Aditya; Wani, Willayat Yousuf; Sharma, Reeta Kumari; Kandimalla, Ramesh J L; Bal, Amanjit; Gill, Kiran Dip

    2013-12-01

    The present investigation was carried out to elucidate a possible molecular mechanism related to the effects of aluminium-induced oxidative stress on various mitochondrial respiratory complex subunits with special emphasis on the role of Peroxisome proliferator activated receptor gamma co-activator 1α (PGC-1α) and its downstream targets i.e. Nuclear respiratory factor-1(NRF-1), Nuclear respiratory factor-2(NRF-2) and Mitochondrial transcription factor A (Tfam) in mitochondrial biogenesis. Aluminium lactate (10mg/kgb.wt./day) was administered intragastrically to rats for 12 weeks. After 12 weeks of exposure, we found an increase in ROS levels, mitochondrial DNA oxidation and decrease in citrate synthase activity in the Hippocampus (HC) and Corpus striatum (CS) regions of rat brain. On the other hand, there was a decrease in the mRNA levels of the mitochondrial encoded subunits-NADH dehydrogenase (ND) subunits i.e. ND1, ND2, ND3, Cytochrome b (Cytb), Cytochrome oxidase (COX) subunits i.e. COX1, COX3, ATP synthase (ATPase) subunit 6 along with reduced expression of nuclear encoded subunits COX4, COX5A, COX5B of Electron transport chain (ETC). Besides, a decrease in mitochondrial DNA copy number and mitochondrial content in both regions of rat brain was observed. The PGC-1α was down-regulated in aluminium treated rats along with NRF-1, NRF-2 and Tfam, which act downstream from PGC-1α in aluminium treated rats. Electron microscopy results revealed a significant increase in the mitochondrial swelling, loss of cristae, chromatin condensation and decreases in mitochondrial number in case of aluminium treated rats as compared to control. So, PGC-1α seems to be a potent target for aluminium neurotoxicity, which makes it an almost ideal target to control or limit the damage that has been associated with the defective mitochondrial function seen in neurodegenerative diseases.

  10. Eriocitrin ameliorates diet-induced hepatic steatosis with activation of mitochondrial biogenesis

    PubMed Central

    Hiramitsu, Masanori; Shimada, Yasuhito; Kuroyanagi, Junya; Inoue, Takashi; Katagiri, Takao; Zang, Liqing; Nishimura, Yuhei; Nishimura, Norihiro; Tanaka, Toshio

    2014-01-01

    Lemon (Citrus limon) contains various bioactive flavonoids, and prevents obesity and obesity-associated metabolic diseases. We focused on eriocitrin (eriodictyol 7-rutinoside), a powerful antioxidative flavonoid in lemon with lipid-lowering effects in a rat model of high-fat diet. To investigate the mechanism of action of eriocitrin, we conducted feeding experiments on zebrafish with diet-induced obesity. Oral administration of eriocitrin (32 mg/kg/day for 28 days) improved dyslipidaemia and decreased lipid droplets in the liver. DNA microarray analysis revealed that eriocitrin increased mRNA of mitochondrial biogenesis genes, such as mitochondria transcription factor, nuclear respiratory factor 1, cytochrome c oxidase subunit 4, and ATP synthase. In HepG2 cells, eriocitrin also induced the corresponding orthologues, and reduced lipid accumulation under conditions of lipid loading. Eriocitrin increased mitochondrial size and mtDNA content, which resulted in ATP production in HepG2 cells and zebrafish. In summary, dietary eriocitrin ameliorates diet-induced hepatic steatosis with activation of mitochondrial biogenesis. PMID:24424211

  11. cGMP-selective phosphodiesterase inhibitors stimulate mitochondrial biogenesis and promote recovery from acute kidney injury.

    PubMed

    Whitaker, Ryan M; Wills, Lauren P; Stallons, L Jay; Schnellmann, Rick G

    2013-12-01

    Recent studies demonstrate that mitochondrial dysfunction is a mediator of acute kidney injury (AKI). Consequently, restoration of mitochondrial function after AKI may be key to the recovery of renal function. Mitochondrial function can be restored through the generation of new, functional mitochondria in a process called mitochondrial biogenesis (MB). Despite its potential therapeutic significance, very few pharmacological agents have been identified to induce MB. To examine the efficacy of phosphodiesterase (PDE) inhibitors (PDE3: cAMP and cGMP activity; and PDE4: cAMP activity) in stimulating MB, primary cultures of renal proximal tubular cells (RPTCs) were treated with a panel of inhibitors for 24 hours. PDE3, but not PDE4, inhibitors increased the FCCP-uncoupled oxygen consumption rate (OCR), a marker of MB. Exposure of RPTCs to the PDE3 inhibitors, cilostamide and trequinsin, for 24 hours increased peroxisome proliferator-activated receptor γ coactivator-1α, and multiple mitochondrial electron transport chain genes. Cilostamide and trequinsin also increased mRNA expression of mitochondrial genes and mitochondrial DNA copy number in mice renal cortex. Consistent with these experiments, 8-Br-cGMP increased FCCP-uncoupled OCR and mitochondrial gene expression, whereas 8-Br-cAMP had no effect. The cGMP-specific PDE5 inhibitor sildenafil also induced MB in RPTCs and in vivo in mouse renal cortex. Treatment of mice with sildenafil after folic acid-induced AKI promoted restoration of MB and renal recovery. These data provide strong evidence that specific PDE inhibitors that increase cGMP are inducers of MB in vitro and in vivo, and suggest their potential efficacy in AKI and other diseases characterized by mitochondrial dysfunction and suppressed MB.

  12. Sudachitin, a polymethoxylated flavone, improves glucose and lipid metabolism by increasing mitochondrial biogenesis in skeletal muscle

    PubMed Central

    2014-01-01

    Background Obesity is a major risk factor for insulin resistance, type 2 diabetes, and stroke. Flavonoids are effective antioxidants that protect against these chronic diseases. In this study, we evaluated the effects of sudachitin, a polymethoxylated flavonoid found in the skin of the Citrus sudachi fruit, on glucose, lipid, and energy metabolism in mice with high-fat diet-induced obesity and db/db diabetic mice. In our current study, we show that sudachitin improves metabolism and stimulates mitochondrial biogenesis, thereby increasing energy expenditure and reducing weight gain. Methods C57BL/6 J mice fed a high-fat diet (40% fat) and db/db mice fed a normal diet were treated orally with 5 mg/kg sudachitin or vehicle for 12 weeks. Following treatment, oxygen expenditure was assessed using indirect calorimetry, while glucose tolerance, insulin sensitivity, and indices of dyslipidemia were assessed by serum biochemistry. Quantitative polymerase chain reaction was used to determine the effect of sudachitin on the transcription of key metabolism-regulating genes in the skeletal muscle, liver, and white and brown adipose tissues. Primary myocytes were also prepared to examine the signaling mechanisms targeted by sudachitin in vitro. Results Sudachitin improved dyslipidemia, as evidenced by reduction in triglyceride and free fatty acid levels, and improved glucose tolerance and insulin resistance. It also enhanced energy expenditure and fatty acid β-oxidation by increasing mitochondrial biogenesis and function. The in vitro assay results suggest that sudachitin increased Sirt1 and PGC-1α expression in the skeletal muscle. Conclusions Sudachitin may improve dyslipidemia and metabolic syndrome by improving energy metabolism. Furthermore, it also induces mitochondrial biogenesis to protect against metabolic disorders. PMID:25114710

  13. Aluminium induced oxidative stress results in decreased mitochondrial biogenesis via modulation of PGC-1α expression

    SciTech Connect

    Sharma, Deep Raj; Sunkaria, Aditya; Wani, Willayat Yousuf; Sharma, Reeta Kumari; Kandimalla, Ramesh J.L.; Bal, Amanjit; Gill, Kiran Dip

    2013-12-01

    The present investigation was carried out to elucidate a possible molecular mechanism related to the effects of aluminium-induced oxidative stress on various mitochondrial respiratory complex subunits with special emphasis on the role of Peroxisome proliferator activated receptor gamma co-activator 1α (PGC-1α) and its downstream targets i.e. Nuclear respiratory factor-1(NRF-1), Nuclear respiratory factor-2(NRF-2) and Mitochondrial transcription factor A (Tfam) in mitochondrial biogenesis. Aluminium lactate (10 mg/kg b.wt./day) was administered intragastrically to rats for 12 weeks. After 12 weeks of exposure, we found an increase in ROS levels, mitochondrial DNA oxidation and decrease in citrate synthase activity in the Hippocampus (HC) and Corpus striatum (CS) regions of rat brain. On the other hand, there was a decrease in the mRNA levels of the mitochondrial encoded subunits–NADH dehydrogenase (ND) subunits i.e. ND1, ND2, ND3, Cytochrome b (Cytb), Cytochrome oxidase (COX) subunits i.e. COX1, COX3, ATP synthase (ATPase) subunit 6 along with reduced expression of nuclear encoded subunits COX4, COX5A, COX5B of Electron transport chain (ETC). Besides, a decrease in mitochondrial DNA copy number and mitochondrial content in both regions of rat brain was observed. The PGC-1α was down-regulated in aluminium treated rats along with NRF-1, NRF-2 and Tfam, which act downstream from PGC-1α in aluminium treated rats. Electron microscopy results revealed a significant increase in the mitochondrial swelling, loss of cristae, chromatin condensation and decreases in mitochondrial number in case of aluminium treated rats as compared to control. So, PGC-1α seems to be a potent target for aluminium neurotoxicity, which makes it an almost ideal target to control or limit the damage that has been associated with the defective mitochondrial function seen in neurodegenerative diseases. - Highlights: • Aluminium decreases the mRNA levels of mitochondrial and nuclear encoded

  14. Mitochondrial biogenesis and degradation are induced by CCCP treatment of porcine oocytes.

    PubMed

    Itami, N; Shiratsuki, S; Shirasuna, K; Kuwayama, T; Iwata, H

    2015-08-01

    In this study, we investigated the mitochondrial quality control system in porcine oocytes during meiotic maturation. Cumulus cell oocyte complexes (COCs) collected from gilt ovaries were treated with 10  μM carbonyl cyanide-m-chlorophenylhydrazone (CCCP; a mitochondrial uncoupler) for 2  h. The CCCP treatment was found to significantly reduce ATP content, increase the amount of phosphorylated AMP-activated protein kinase and elevate reactive oxygen species levels in oocytes. When the CCCP-treated COCs were cultured further for 44  h in maturation medium, the ATP levels were restored and the parthenogenetic developmental rate of oocytes to the blastocyst stage was comparable with that of untreated COCs. To examine the effects of CCCP treatment of oocytes on the kinetics of mitochondrial DNA copy number (Mt number), COCs treated with 0 or 10  μM CCCP were cultured for 44  h, after which the Mt number was determined by RT-PCR. CCCP treatment was found to increase the Mt number in the modified maturation medium in which mitochondrial degradation was inhibited by MG132, whereas CCCP treatment did not affect the Mt number in the maturation medium lacking MG132. The relative gene expression of TFAM was furthermore shown to be significantly higher in CCCP-treated oocytes than in untreated oocytes. Taken together, the finding presented here suggest that when the mitochondria are injured, mitochondrial biogenesis and degradation are induced, and that these processes may contribute to the recuperation of oocytes.

  15. Mitochondria: Biogenesis and mitophagy balance in segregation and clonal expansion of mitochondrial DNA mutations.

    PubMed

    Carelli, Valerio; Maresca, Alessandra; Caporali, Leonardo; Trifunov, Selena; Zanna, Claudia; Rugolo, Michela

    2015-06-01

    Mitochondria are cytoplasmic organelles containing their own multi-copy genome. They are organized in a highly dynamic network, resulting from balance between fission and fusion, which maintains homeostasis of mitochondrial mass through mitochondrial biogenesis and mitophagy. Mitochondrial DNA (mtDNA) mutates much faster than nuclear DNA. In particular, mtDNA point mutations and deletions may occur somatically and accumulate with aging, coexisting with the wild type, a condition known as heteroplasmy. Under specific circumstances, clonal expansion of mutant mtDNA may occur within single cells, causing a wide range of severe human diseases when mutant overcomes wild type. Furthermore, mtDNA deletions accumulate and clonally expand as a consequence of deleterious mutations in nuclear genes involved in mtDNA replication and maintenance, as well as in mitochondrial fusion genes (mitofusin-2 and OPA1), possibly implicating mtDNA nucleoids segregation. We here discuss how the intricacies of mitochondrial homeostasis impinge on the intracellular propagation of mutant mtDNA. This article is part of a Directed Issue entitled: Energy Metabolism Disorders and Therapies.

  16. Dual control of mitochondrial biogenesis by sirtuin 1 and sirtuin 3.

    PubMed

    Brenmoehl, Julia; Hoeflich, Andreas

    2013-11-01

    In this review, we discuss the dual control of mitochondrial biogenesis and energy metabolism by silent information regulator-1 and -3 (SIRT1 and SIRT3). SIRT1 activates the peroxisome proliferator activated receptor γ co-activator 1α (PGC-1α)-mediated transcription of nuclear and mitochondrial genes encoding for proteins promoting mitochondria proliferation, oxidative phosphorylation and energy production, whereas SIRT3 directly acts as an activator of proteins important for oxidative phosphorylation, tricarboxylic acid (TCA) cycle and fatty-acid oxidation and indirectly of PGC-1α and AMP-activated protein kinase (AMPK). The complex network involves different cellular compartments, transcriptional activation, post-translational modification and a plethora of secondary effectors. Overall, the mode of interaction between both sirtuin family members may be considered as a prominent case of molecular job-sharing.

  17. Oxaloacetate activates brain mitochondrial biogenesis, enhances the insulin pathway, reduces inflammation and stimulates neurogenesis.

    PubMed

    Wilkins, Heather M; Harris, Janna L; Carl, Steven M; E, Lezi; Lu, Jianghua; Eva Selfridge, J; Roy, Nairita; Hutfles, Lewis; Koppel, Scott; Morris, Jill; Burns, Jeffrey M; Michaelis, Mary L; Michaelis, Elias K; Brooks, William M; Swerdlow, Russell H

    2014-12-15

    Brain bioenergetic function declines in some neurodegenerative diseases, this may influence other pathologies and administering bioenergetic intermediates could have therapeutic value. To test how one intermediate, oxaloacetate (OAA) affects brain bioenergetics, insulin signaling, inflammation and neurogenesis, we administered intraperitoneal OAA, 1-2 g/kg once per day for 1-2 weeks, to C57Bl/6 mice. OAA altered levels, distributions or post-translational modifications of mRNA and proteins (proliferator-activated receptor-gamma coactivator 1α, PGC1 related co-activator, nuclear respiratory factor 1, transcription factor A of the mitochondria, cytochrome oxidase subunit 4 isoform 1, cAMP-response element binding, p38 MAPK and adenosine monophosphate-activated protein kinase) in ways that should promote mitochondrial biogenesis. OAA increased Akt, mammalian target of rapamycin and P70S6K phosphorylation. OAA lowered nuclear factor κB nucleus-to-cytoplasm ratios and CCL11 mRNA. Hippocampal vascular endothelial growth factor mRNA, doublecortin mRNA, doublecortin protein, doublecortin-positive neuron counts and neurite length increased in OAA-treated mice. (1)H-MRS showed OAA increased brain lactate, GABA and glutathione thereby demonstrating metabolic changes are detectable in vivo. In mice, OAA promotes brain mitochondrial biogenesis, activates the insulin signaling pathway, reduces neuroinflammation and activates hippocampal neurogenesis.

  18. SIRT1 facilitates hepatocellular carcinoma metastasis by promoting PGC-1α-mediated mitochondrial biogenesis.

    PubMed

    Li, Yuming; Xu, Shangcheng; Li, Jing; Zheng, Lu; Feng, Min; Wang, Xiaoya; Han, Keqiang; Pi, Huifeng; Li, Min; Huang, Xiaobing; You, Nan; Tian, Yewang; Zuo, Guohua; Li, Hongyan; Zhao, Hongzhi; Deng, Ping; Yu, Zhengping; Zhou, Zhou; Liang, Ping

    2016-05-17

    SIRT1 is a multifaceted NAD+-dependent protein deacetylase known to act as a tumor promoter or suppressor in different cancers. Here, we describe a novel mechanism of SIRT1-induced hepatocellular carcinoma (HCC) metastasis. SIRT1 overexpression was frequently detected in human HCC specimens and was associated with microvascular invasion (P = 0.0039), advanced tumor node metastasis (TNM) stages (P = 0.0016), HCC recurrence (P = 0.021) and poor outcomes (P = 0.039). Lentivirus-mediated knockdown of SIRT1 in MHCC97H cells reduced invasion and metastasis in vitro and in vivo. SIRT1 depletion attenuated mitochondrial biogenesis and adenosine triphosphate (ATP) production but did not affect epithelial-mesenchymal transition. Elevated SIRT1 expression strongly correlated with the upregulation of PGC-1α in HCC specimens, and ectopic expression of SIRT1 increased PGC-1α levels. In cell assays and an orthotopic transplantation model, PGC-1α overexpression reversed the inhibitory effects of SIRT1 depletion on invasion and metastasis by enhancing mitochondrial biogenesis. These findings reveal the involvement of SIRT1 in HCC metastasis and provide a rationale for exploring therapeutic targets against the SIRT1/PGC-1α axis.

  19. Cardiac mitochondrial damage and biogenesis in a chronic model of type 1 diabetes.

    PubMed

    Shen, Xia; Zheng, Shirong; Thongboonkerd, Visith; Xu, Ming; Pierce, William M; Klein, Jon B; Epstein, Paul N

    2004-11-01

    Diabetic cardiomyopathy is a common complication leading to heightened risk of heart failure and death. In the present report, we performed proteomic analysis on total cardiac proteins from the OVE26 mouse model of type 1 diabetes to identify protein changes that may contribute to diabetic cardiomyopathy. This analysis revealed that a surprising high proportion (12 of 20) of the altered proteins that could be identified by mass spectrometry were of mitochondrial origin. All but one of these proteins were upregulated by diabetes. Quantitative RT-PCR, performed for two of these proteins, indicated that part of the upregulation was attributed to increased messenger RNA levels. Morphological study of diabetic hearts showed significantly increased mitochondrial area and number as well as focal regions with severe damage to mitochondria. Diabetic mitochondria also showed reduced respiratory control ratio (9.63 +/- 0.20 vs. 6.13 +/- 0.41, P < 0.0001), apparently due to reduced state 3 rate, and diminished GSH level (5.5 +/- 0.9 vs. 8.2 +/- 2.5 micromol/mg protein, P < 0.05), indicating impaired mitochondrial function and increased oxidative stress. Further examination revealed increased mitochondrial DNA (1.03 +/- 0.18 vs. 0.69 +/- 0.13 relative copy number, P < 0.001) and a tendency to higher protein yield in OVE26 cardiac mitochondria, as well as increased mRNA level for mitochondrial transcription factor A and two mitochondrial encoded proteins. Taken together, these results show that mitochondria are a primary target in the diabetic heart, probably due to oxidative stress, and that this damage coincides with and may stimulate mitochondrial biogenesis.

  20. Metastasis suppressor KISS1 seems to reverse the Warburg effect by enhancing mitochondrial biogenesis.

    PubMed

    Liu, Wen; Beck, Benjamin H; Vaidya, Kedar S; Nash, Kevin T; Feeley, Kyle P; Ballinger, Scott W; Pounds, Keke M; Denning, Warren L; Diers, Anne R; Landar, Aimee; Dhar, Animesh; Iwakuma, Tomoo; Welch, Danny R

    2014-02-01

    Cancer cells tend to utilize aerobic glycolysis even under normoxic conditions, commonly called the "Warburg effect." Aerobic glycolysis often directly correlates with malignancy, but its purpose, if any, in metastasis remains unclear. When wild-type KISS1 metastasis suppressor is expressed, aerobic glycolysis decreases and oxidative phosphorylation predominates. However, when KISS1 is missing the secretion signal peptide (ΔSS), invasion and metastasis are no longer suppressed and cells continue to metabolize using aerobic glycolysis. KISS1-expressing cells have 30% to 50% more mitochondrial mass than ΔSS-expressing cells, which are accompanied by correspondingly increased mitochondrial gene expression and higher expression of PGC1α, a master coactivator that regulates mitochondrial mass and metabolism. PGC1α-mediated downstream pathways (i.e., fatty acid synthesis and β-oxidation) are differentially regulated by KISS1, apparently reliant upon direct KISS1 interaction with NRF1, a major transcription factor involved in mitochondrial biogenesis. Since the downstream effects could be reversed using short hairpin RNA to KISS1 or PGC1α, these data appear to directly connect changes in mitochondria mass, cellular glucose metabolism, and metastasis.

  1. Metastasis suppressor KISS1 appears to reverse the Warburg effect by enhancing mitochondrial biogenesis

    PubMed Central

    Liu, Wen; Beck, Benjamin H.; Vaidya, Kedar S.; Nash, Kevin T.; Feeley, Kyle P.; Ballinger, Scott W.; Pounds, Keke M.; Denning, Warren L.; Diers, Anne R.; Landar, Aimee; Dhar, Animesh; Iwakuma, Tomoo; Welch, Danny R.

    2014-01-01

    Cancer cells tend to utilize aerobic glycolysis even under normoxic conditions, commonly called the “Warburg Effect.” Aerobic glycolysis often directly correlates with malignancy, but its purpose, if any, in metastasis remains unclear. When wild-type KISS1 metastasis suppressor is expressed, aerobic glycolysis decreases and oxidative phosphorylation predominates. However, when KISS1 is missing the secretion signal peptide (ΔSS), invasion and metastasis are no longer suppressed and cells continue to metabolize using aerobic glycolysis. KISS1-expressing cells have 30–50% more mitochondrial mass than ΔSS-expressing cells, which is accompanied by correspondingly increased mitochondrial gene expression and higher expression of PGC1α, a master co-activator that regulates mitochondrial mass and metabolism. PGC1α-mediated downstream pathways (i.e. fatty acid synthesis and β-oxidation) are differentially regulated by KISS1, apparently reliant upon direct KISS1 interaction with NRF1, a major transcription factor involved in mitochondrial biogenesis. Since the downstream effects could be reversed using shRNA to KISS1 or PGC1α, these data appear to directly connect changes in mitochondria mass, cellular glucose metabolism and metastasis. PMID:24351292

  2. The role of AAA+ proteases in mitochondrial protein biogenesis, homeostasis and activity control.

    PubMed

    Voos, Wolfgang; Ward, Linda A; Truscott, Kaye N

    2013-01-01

    Mitochondria are specialised organelles that are structurally and functionally integrated into cells in the vast majority of eukaryotes. They are the site of numerous enzymatic reactions, some of which are essential for life. The double lipid membrane of the mitochondrion, that spatially defines the organelle and is necessary for some functions, also creates a physical but semi-permeable barrier to the rest of the cell. Thus to ensure the biogenesis, regulation and maintenance of a functional population of proteins, an autonomous protein handling network within mitochondria is required. This includes resident mitochondrial protein translocation machinery, processing peptidases, molecular chaperones and proteases. This review highlights the contribution of proteases of the AAA+ superfamily to protein quality and activity control within the mitochondrion. Here they are responsible for the degradation of unfolded, unassembled and oxidatively damaged proteins as well as the activity control of some enzymes. Since most knowledge about these proteases has been gained from studies in the eukaryotic microorganism Saccharomyces cerevisiae, much of the discussion here centres on their role in this organism. However, reference is made to mitochondrial AAA+ proteases in other organisms, particularly in cases where they play a unique role such as the mitochondrial unfolded protein response. As these proteases influence mitochondrial function in both health and disease in humans, an understanding of their regulation and diverse activities is necessary.

  3. PGC-1α controls mitochondrial biogenesis and dynamics in lead-induced neurotoxicity

    PubMed Central

    Dabrowska, Aleksandra; Venero, Jose Luis; Iwasawa, Ryota; Hankir, Mohammed-khair; Rahman, Sunniyat; Boobis, Alan; Hajji, Nabil

    2015-01-01

    Due to its role in regulation of mitochondrial function, PGC1α is emerging as an important player in ageing and neurodegenerative disorders. PGC1α exerts its neuroprotective effects by promoting mitochondrial biogenesis (MB) and functioning. However, the precise regulatory role of PGC1α in the control of mitochondrial dynamics (MD) and neurotoxicity is still unknown. Here we elucidate the role of PGC1α in vitro and in vivo in the regulatory context of MB and MD in response to lead (II) acetate as a relevant model of neurotoxicity. We show that there is an adaptive response (AR) to lead, orchestrated by the BAP31-calcium signalling system operating between the ER and mitochondria. We find that this hormetic response is controlled by a cell-tolerated increase of PGC1α expression, which in turn induces a balanced expression of fusion/fission genes by binding to their promoters and implying its direct role in regulation of MD. However, dysregulation of PGC1α expression through either stable downregulation or overexpression, renders cells more susceptible to lead insult leading to mitochondrial fragmentation and cell death. Our data provide novel evidence that PGC1α expression is a key regulator of MD and the maintenance of tolerated PGC1α expression may offer a promising strategy for neuroprotective therapies. PMID:26363853

  4. PGC-1α controls mitochondrial biogenesis and dynamics in lead-induced neurotoxicity.

    PubMed

    Dabrowska, Aleksandra; Venero, Jose Luis; Iwasawa, Ryota; Hankir, Mohammed-Khair; Rahman, Sunniyat; Boobis, Alan; Hajji, Nabil

    2015-09-01

    Due to its role in regulation of mitochondrial function, PGC1α is emerging as an important player in ageing and neurodegenerative disorders. PGC1α exerts its neuroprotective effects by promoting mitochondrial biogenesis (MB) and functioning. However, the precise regulatory role of PGC1α in the control of mitochondrial dynamics (MD) and neurotoxicity is still unknown. Here we elucidate the role of PGC1αin vitro and in vivo in the regulatory context of MB and MD in response to lead (II) acetate as a relevant model of neurotoxicity. We show that there is an adaptive response (AR) to lead, orchestrated by the BAP31-calcium signalling system operating between the ER and mitochondria. We find that this hormetic response is controlled by a cell-tolerated increase of PGC1α expression, which in turn induces a balanced expression of fusion/fission genes by binding to their promoters and implying its direct role in regulation of MD. However, dysregulation of PGC1α expression through either stable downregulation or overexpression, renders cells more susceptible to lead insult leading to mitochondrial fragmentation and cell death. Our data provide novel evidence that PGC1α expression is a key regulator of MD and the maintenance of tolerated PGC1α expression may offer a promising strategy for neuroprotective therapies.

  5. 14,15-EET promotes mitochondrial biogenesis and protects cortical neurons against oxygen/glucose deprivation-induced apoptosis.

    PubMed

    Wang, Lai; Chen, Man; Yuan, Lin; Xiang, Yuting; Zheng, Ruimao; Zhu, Shigong

    2014-07-18

    14,15-Epoxyeicosatrienoic acid (14,15-EET), a metabolite of arachidonic acid, is enriched in the brain cortex and exerts protective effect against neuronal apoptosis induced by ischemia/reperfusion. Although apoptosis has been well recognized to be closely associated with mitochondrial biogenesis and function, it is still unclear whether the neuroprotective effect of 14,15-EET is mediated by promotion of mitochondrial biogenesis and function in cortical neurons under the condition of oxygen-glucose deprivation (OGD). In this study, we found that 14,15-EET improved cell viability and inhibited apoptosis of cortical neurons. 14,15-EET significantly increased the mitochondrial mass and the ratio of mitochondrial DNA to nuclear DNA. Key makers of mitochondrial biogenesis, peroxisome proliferator activator receptor gamma-coactivator 1 alpha (PGC-1α), nuclear respiratory factor 1 (NRF-1) and mitochondrial transcription factor A (TFAM), were elevated at both mRNA and protein levels in the cortical neurons treated with 14,15-EET. Moreover, 14,15-EET markedly attenuated the decline of mitochondrial membrane potential, reduced ROS, while increased ATP synthesis. Knockdown of cAMP-response element binding protein (CREB) by siRNA blunted the up-regulation of PGC-1α and NRF-1 stimulated by 14,15-EET, and consequently abolished the neuroprotective effect of 14,15-EET. Our results indicate that 14,15-EET protects neurons from OGD-induced apoptosis by promoting mitochondrial biogenesis and function through CREB mediated activation of PGC-1α and NRF-1.

  6. Gene expression of key regulators of mitochondrial biogenesis is sex dependent in mice with growth hormone receptor deletion in liver

    PubMed Central

    Zawada, Ilona; Masternak, Michal M.; List, Edward O.; Stout, Michael B.; Berryman, Darlene E.; Lewinski, Andrzej; Kopchick, John J.; Bartke, Andrzej; Karbownik-Lewinska, Malgorzata; Gesing, Adam

    2015-01-01

    Mitochondrial biogenesis is an essential process for cell viability. Mice with disruption of the growth hormone receptor (GHR) gene (Ghr gene) in the liver (LiGHRKO), in contrast to long-lived mice with global deletion of the Ghr gene (GHRKO), are characterized by lack of improved insulin sensitivity and severe hepatic steatosis. Tissue-specific disruption of the GHR in liver results in a mouse model with dramatically altered GH/IGF1 axis. We have previously shown increased levels of key regulators of mitochondrial biogenesis in insulin-sensitive GHRKO mice. The aim of the present study is to assess, using real-time PCR, the gene expression of key regulators of mitochondrial biogenesis (Pgc1α, Ampk, Sirt1, Nrf2 and Mfn2) and a marker of mitochondrial activity (CoxIV) in brains, kidneys and livers of male and female LiGHRKO and wild-type (WT) mice. There were significant differences between males and females. In the brain, expression of Pgc1α, Ampk, Sirt1, Nrf2 and Mfn2 was lower in pooled females compared to pooled males. In the kidneys, expression of Ampk and Sirt1 was also lower in female mice. In the liver, no differences between males and females were observed. Sexual dimorphism may play an important role in regulating the biogenesis of mitochondria. PMID:25855408

  7. Gene expression of key regulators of mitochondrial biogenesis is sex dependent in mice with growth hormone receptor deletion in liver.

    PubMed

    Zawada, Ilona; Masternak, Michal M; List, Edward O; Stout, Michael B; Berryman, Darlene E; Lewinski, Andrzej; Kopchick, John J; Bartke, Andrzej; Karbownik-Lewinska, Malgorzata; Gesing, Adam

    2015-03-01

    Mitochondrial biogenesis is an essential process for cell viability. Mice with disruption of the growth hormone receptor (GHR) gene (Ghr gene) in the liver (LiGHRKO), in contrast to long-lived mice with global deletion of the Ghr gene (GHRKO), are characterized by lack of improved insulin sensitivity and severe hepatic steatosis. Tissue-specific disruption of the GHR in liver results in a mouse model with dramatically altered GH/IGF1 axis. We have previously shown increased levels of key regulators of mitochondrial biogenesis in insulin-sensitive GHRKO mice. The aim of the present study is to assess, using real-time PCR, the gene expression of key regulators of mitochondrial biogenesis (Pgc1α, Ampk, Sirt1, Nrf2 and Mfn2) and a marker of mitochondrial activity (CoxIV) in brains, kidneys and livers of male and female LiGHRKO and wild-type (WT) mice. There were significant differences between males and females. In the brain, expression of Pgc1α, Ampk, Sirt1, Nrf2 and Mfn2 was lower in pooled females compared to pooled males. In the kidneys, expression of Ampk and Sirt1 was also lower in female mice. In the liver, no differences between males and females were observed. Sexual dimorphism may play an important role in regulating the biogenesis of mitochondria.

  8. Carbon Monoxide Improves Neurologic Outcomes by Mitochondrial Biogenesis after Global Cerebral Ischemia Induced by Cardiac Arrest in Rats

    PubMed Central

    Wang, Peng; Yao, Lan; Zhou, Li-li; Liu, Yuan-shan; Chen, Ming-di; Wu, Hai-dong; Chang, Rui-ming; Li, Yi; Zhou, Ming-gen; Fang, Xiang-shao; Yu, Tao; Jiang, Long-yuan; Huang, Zi-tong

    2016-01-01

    Mitochondrial dysfunction contributes to brain injury following global cerebral ischemia after cardiac arrest. Carbon monoxide treatment has shown potent cytoprotective effects in ischemia/reperfusion injury. This study aimed to investigate the effects of carbon monoxide-releasing molecules on brain mitochondrial dysfunction and brain injury following resuscitation after cardiac arrest in rats. A rat model of cardiac arrest was established by asphyxia. The animals were randomly divided into the following 3 groups: cardiac arrest and resuscitation group, cardiac arrest and resuscitation plus carbon monoxide intervention group, and sham control group (no cardiac arrest). After the return of spontaneous circulation, neurologic deficit scores (NDS) and S-100B levels were significantly decreased at 24, 48, and 72 h, but carbon monoxide treatment improved the NDS and S-100B levels at 24 h and the 3-day survival rates of the rats. This treatment also decreased the number of damaged neurons in the hippocampus CA1 area and increased the brain mitochondrial activity. In addition, it increased mitochondrial biogenesis by increasing the expression of biogenesis factors including peroxisome proliferator-activated receptor-γ coactivator-1α, nuclear respiratory factor-1, nuclear respiratory factor-2 and mitochondrial transcription factor A. Thus, this study showed that carbon monoxide treatment alleviated brain injury after cardiac arrest in rats by increased brain mitochondrial biogenesis. PMID:27489503

  9. Gamma rays induce a p53-independent mitochondrial biogenesis that is counter-regulated by HIF1α.

    PubMed

    Bartoletti-Stella, A; Mariani, E; Kurelac, I; Maresca, A; Caratozzolo, M F; Iommarini, L; Carelli, V; Eusebi, L H; Guido, A; Cenacchi, G; Fuccio, L; Rugolo, M; Tullo, A; Porcelli, A M; Gasparre, G

    2013-06-13

    Mitochondrial biogenesis is an orchestrated process that presides to the regulation of the organelles homeostasis within a cell. We show that γ-rays, at doses commonly used in the radiation therapy for cancer treatment, induce an increase in mitochondrial mass and function, in response to a genotoxic stress that pushes cells into senescence, in the presence of a functional p53. Although the main effector of the response to γ-rays is the p53-p21 axis, we demonstrated that mitochondrial biogenesis is only indirectly regulated by p53, whose activation triggers a murine double minute 2 (MDM2)-mediated hypoxia-inducible factor 1α (HIF1α) degradation, leading to the release of peroxisome-proliferator activated receptor gamma co-activator 1β inhibition by HIF1α, thus promoting mitochondrial biogenesis. Mimicking hypoxia by HIF1α stabilization, in fact, blunts the mitochondrial response to γ-rays as well as the induction of p21-mediated cell senescence, indicating prevalence of the hypoxic over the genotoxic response. Finally, we also show in vivo that post-radiotherapy mitochondrial DNA copy number increase well correlates with lack of HIF1α increase in the tissue, concluding this may be a useful molecular tool to infer the trigger of a hypoxic response during radiotherapy, which may lead to failure of activation of cell senescence.

  10. Nuclear recruitment of neuronal nitric-oxide synthase by α-syntrophin is crucial for the induction of mitochondrial biogenesis.

    PubMed

    Aquilano, Katia; Baldelli, Sara; Ciriolo, Maria R

    2014-01-03

    Neuronal nitric-oxide synthase (nNOS) has various splicing variants and different subcellular localizations. nNOS can be found also in the nucleus; however, its exact role in this compartment is still not completely defined. In this report, we demonstrate that the PDZ domain allows the recruitment of nNOS to nuclei, thus favoring local NO production, nuclear protein S-nitrosylation, and induction of mitochondrial biogenesis. In particular, overexpression of PDZ-containing nNOS (nNOSα) increases S-nitrosylated CREB with consequent augmented binding on cAMP response element consensus sequence on peroxisome proliferator-activated receptor γ co-activator (PGC)-1α promoter. The resulting PGC-1α induction is accompanied by the expression of mitochondrial genes (e.g., TFAM, MtCO1) and increased mitochondrial mass. Importantly, full active nNOS lacking PDZ domain (nNOSβ) does not localize in nuclei and fails in inducing the expression of PGC-1α. Moreover, we substantiate that the mitochondrial biogenesis normally accompanying myogenesis is associated with nuclear translocation of nNOS. We demonstrate that α-Syntrophin, which resides in nuclei of myocytes, functions as the upstream mediator of nuclear nNOS translocation and nNOS-dependent mitochondrial biogenesis. Overall, our results indicate that altered nNOS splicing and nuclear localization could be contributing factors in human muscular diseases associated with mitochondrial impairment.

  11. Epigallocatechin-3-gallate prevents oxidative phosphorylation deficit and promotes mitochondrial biogenesis in human cells from subjects with Down's syndrome.

    PubMed

    Valenti, Daniela; De Rasmo, Domenico; Signorile, Anna; Rossi, Leonardo; de Bari, Lidia; Scala, Iris; Granese, Barbara; Papa, Sergio; Vacca, Rosa Anna

    2013-04-01

    A critical role for mitochondrial dysfunction has been proposed in the pathogenesis of Down's syndrome (DS), a human multifactorial disorder caused by trisomy of chromosome 21, associated with mental retardation and early neurodegeneration. Previous studies from our group demonstrated in DS cells a decreased capacity of the mitochondrial ATP production system and overproduction of reactive oxygen species (ROS) in mitochondria. In this study we have tested the potential of epigallocatechin-3-gallate (EGCG) - a natural polyphenol component of green tea - to counteract the mitochondrial energy deficit found in DS cells. We found that EGCG, incubated with cultured lymphoblasts and fibroblasts from DS subjects, rescued mitochondrial complex I and ATP synthase catalytic activities, restored oxidative phosphorylation efficiency and counteracted oxidative stress. These effects were associated with EGCG-induced promotion of PKA activity, related to increased cellular levels of cAMP and PKA-dependent phosphorylation of the NDUFS4 subunit of complex I. In addition, EGCG strongly promoted mitochondrial biogenesis in DS cells, as associated with increase in Sirt1-dependent PGC-1α deacetylation, NRF-1 and T-FAM protein levels and mitochondrial DNA content. In conclusion, this study shows that EGCG is a promoting effector of oxidative phosphorylation and mitochondrial biogenesis in DS cells, acting through modulation of the cAMP/PKA- and sirtuin-dependent pathways. EGCG treatment promises thus to be a therapeutic approach to counteract mitochondrial energy deficit and oxidative stress in DS.

  12. AKT3 controls mitochondrial biogenesis and autophagy via regulation of the major nuclear export protein CRM-1.

    PubMed

    Corum, Daniel G; Tsichlis, Philip N; Muise-Helmericks, Robin C

    2014-01-01

    Our previous work has shown that Akt3 is required for mitochondrial biogenesis in primary human endothelial cells (ECs) and in Akt3-null mice; Akt3 affects subcellular localization of peroxisome proliferator-activated receptor γ coactivator-1 (PGC-1α), the master regulator of mitochondrial biogenesis. The purpose of this study is to determine the mechanism by which Akt3 controls the subcellular distribution of PGC-1α and to explore the effect on mitochondrial biogenesis and turnover during angiogenesis. Here we use standard biochemical analyses and Akt3-knockdown strategies to show that Akt3 controls the stabilization of chromosome maintenance region-1 (CRM-1), the major nuclear export receptor. Site-directed mutagenesis and association analyses show that PGC-1α nuclear export is CRM-1 dependent. Akt3 knockdown and CRM-1 overexpression cause 3-fold reductions in PGC-1α target gene expression, compared to control levels. Akt3 inhibition causes autophagy, as measured by autophagosome formation, in a CRM-1-dependent, Akt1/mTOR-independent pathway. In vivo, Akt3-null and heterozygous mice show dose-dependent decreases in angiogenesis compared to wild-type littermates (~5- and 2.5-fold decreases, respectively), as assessed by Matrigel plug assays. This correlates with an ~1.5-fold decrease in mitochondrial Cox IV expression. Our studies suggest that Akt3 is a regulator of mitochondrial dynamics in the vasculature via regulation of CRM-1-dependent nuclear export.

  13. AMPK maintains energy homeostasis and survival in cancer cells via regulating p38/PGC-1α-mediated mitochondrial biogenesis

    PubMed Central

    Chaube, B; Malvi, P; Singh, S V; Mohammad, N; Viollet, B; Bhat, M K

    2015-01-01

    Cancer cells exhibit unique metabolic response and adaptation to the fluctuating microenvironment, yet molecular and biochemical events imprinting this phenomenon are unclear. Here, we show that metabolic homeostasis and adaptation to metabolic stress in cancer cells are primarily achieved by an integrated response exerted by the activation of AMPK. We provide evidence that AMPK-p38-PGC-1α axis, by regulating energy homeostasis, maintains survival in cancer cells under glucose-limiting conditions. Functioning as a molecular switch, AMPK promotes glycolysis by activating PFK2, and facilitates mitochondrial metabolism of non-glucose carbon sources thereby maintaining cellular ATP level. Interestingly, we noted that AMPK can promote oxidative metabolism via increasing mitochondrial biogenesis and OXPHOS capacity via regulating expression of PGC-1α through p38MAPK activation. Taken together, our study signifies the fundamental role of AMPK in controlling cellular bioenergetics and mitochondrial biogenesis in cancer cells. PMID:27551487

  14. Differentiation of Human Neural Stem Cells into Motor Neurons Stimulates Mitochondrial Biogenesis and Decreases Glycolytic Flux

    PubMed Central

    Keeney, Paula M.

    2015-01-01

    Differentiation of human pluripotent stem cells (hPSCs) in vitro offers a way to study cell types that are not accessible in living patients. Previous research suggests that hPSCs generate ATP through anaerobic glycolysis, in contrast to mitochondrial oxidative phosphorylation (OXPHOS) in somatic cells; however, specialized cell types have not been assessed. To test if mitobiogenesis is increased during motor neuron differentiation, we differentiated human embryonic stem cell (hESC)- and induced pluripotent stem cell-derived human neural stem cells (hNSCs) into motor neurons. After 21 days of motor neuron differentiation, cells increased mRNA and protein levels of genes expressed by postmitotic spinal motor neurons. Electrophysiological analysis revealed voltage-gated currents characteristic of excitable cells and action potential formation. Quantitative PCR revealed an increase in peroxisome proliferator-activated receptor gamma coactivator 1-α (PGC-1α), an upstream regulator of transcription factors involved in mitobiogenesis, and several of its downstream targets in hESC-derived cultures. This correlated with an increase in protein expression of respiratory subunits, but no increase in protein reflecting mitochondrial mass in either cell type. Respiration analysis revealed a decrease in glycolytic flux in both cell types on day 21 (D21), suggesting a switch from glycolysis to OXPHOS. Collectively, our findings suggest that mitochondrial biogenesis, but not mitochondrial mass, is increased during differentiation of hNSCs into motor neurons. These findings help us to understand human motor neuron mitobiogenesis, a process impaired in amyotrophic lateral sclerosis, a neurodegenerative disease characterized by death of motor neurons in the brain and spinal cord. PMID:25892363

  15. Dynamin-dependent biogenesis, cell cycle regulation and mitochondrial association of peroxisomes in fission yeast.

    PubMed

    Jourdain, Isabelle; Sontam, Dharani; Johnson, Chad; Dillies, Clément; Hyams, Jeremy S

    2008-03-01

    Peroxisomes were visualized for the first time in living fission yeast cells. In small, newly divided cells, the number of peroxisomes was low but increased in parallel with the increase in cell length/volume that accompanies cell cycle progression. In cells grown in oleic acid, both the size and the number of peroxisomes increased. The peroxisomal inventory of cells lacking the dynamin-related proteins Dnm1 or Vps1 was similar to that in wild type. By contrast, cells of the double mutant dnm1Delta vps1Delta contained either no peroxisomes at all or a small number of morphologically aberrant organelles. Peroxisomes exhibited either local Brownian movement or longer-range linear displacements, which continued in the absence of either microtubules or actin filaments. On the contrary, directed peroxisome motility appeared to occur in association with mitochondria and may be an indirect function of intrinsic mitochondrial dynamics. We conclude that peroxisomes are present in fission yeast and that Dnm1 and Vps1 act redundantly in peroxisome biogenesis, which is under cell cycle control. Peroxisome movement is independent of the cytoskeleton but is coupled to mitochondrial dynamics.

  16. Quercetin protects against aluminium induced oxidative stress and promotes mitochondrial biogenesis via activation of the PGC-1α signaling pathway.

    PubMed

    Sharma, Deep Raj; Sunkaria, Aditya; Wani, Willayat Yousuf; Sharma, Reeta Kumari; Verma, Deepika; Priyanka, Kumari; Bal, Amanjit; Gill, Kiran Dip

    2015-12-01

    The present investigation was carried out to elucidate a possible molecular mechanism related to the protective effect of quercetin administration against aluminium-induced oxidative stress on various mitochondrial respiratory complex subunits with special emphasis on the role of PGC-1α and its downstream targets, i.e. NRF-1, NRF-2 and Tfam in mitochondrial biogenesis. Aluminium lactate (10mg/kg b.wt./day) was administered intragastrically to rats, which were pre-treated with quercetin 6h before aluminium (10mg/kg b.wt./day, intragastrically) for 12 weeks. We found a decrease in ROS levels, mitochondrial DNA oxidation and citrate synthase activity in the hippocampus (HC) and corpus striatum (CS) regions of rat brain treated with quercetin. Besides this an increase in the mRNA levels of the mitochondrial encoded subunits - ND1, ND2, ND3, Cyt b, COX1, COX3 and ATPase6 along with increased expression of nuclear encoded subunits COX4, COX5A and COX5B of electron transport chain (ETC). In quercetin treated group an increase in the mitochondrial DNA copy number and mitochondrial content in both the regions of rat brain was observed. The PGC-1α was up regulated in quercetin treated rats along with NRF-1, NRF-2 and Tfam, which act downstream from PGC-1α. Electron microscopy results revealed a significant decrease in the mitochondrial cross-section area, mitochondrial perimeter length and increase in mitochondrial number in case of quercetin treated rats as compared to aluminium treated ones. Therefore it seems quercetin increases mitochondrial biogenesis and makes it an almost ideal flavanoid to control or limit the damage that has been associated with the defective mitochondrial function seen in many neurodegenerative diseases.

  17. Moderate superoxide production is an early promoter of mitochondrial biogenesis in differentiating N2a neuroblastoma cells.

    PubMed

    Valero, T; Moschopoulou, G; Mayor-Lopez, L; Kintzios, S

    2012-12-01

    Reactive oxygen species (ROS) have been widely considered as harmful for cell development and as promoters of cell aging by increasing oxidative stress. However, ROS have an important role in cell signaling and they have been demonstrated to be beneficial by triggering hormetic signals, which could protect the organism from later insults. In the present study, N2a murine neuroblastoma cells were used as a paradigm of cell-specific (neural) differentiation partly mediated by ROS. Differentiation was triggered by the established treatments of serum starvation, forskolin or dibutyryl cyclic AMP. A marked differentiation, expressed as the development of neurites, was detected by fixation and staining with coomassie brilliant blue after 48 h treatment. This was accompanied by an increase in mitochondrial mass detected by mitotracker green staining, an increased expression of the peroxisome proliferator-activated receptor gamma (PPARγ) coactivator 1-alpha (PGC-1α) and succinate dehydrogenase activity as detected by MTT. In line with these results, an increase in free radicals, specifically superoxide anion, was detected in differentiating cells by flow cytometry. Superoxide scavenging by MnTBAP and MAPK inhibition by PD98059 partially reversed differentiation and mitochondrial biogenesis. In this way, we demonstrated that mitochondrial biogenesis and differentiation are mediated by superoxide and MAPK cues. Our data suggest that differentiation and mitochondrial biogenesis in N2a cells are part of a hormetic response which is triggered by a modest increase of superoxide anion concentration within the mitochondria.

  18. Mitochondrial biogenesis is decreased in skeletal muscle of pig fetuses exposed to maternal high-energy diets.

    PubMed

    Zou, T D; Yu, B; Yu, J; Mao, X B; Zheng, P; He, J; Huang, Z Q; He, D T; Chen, D W

    2017-01-01

    Mitochondria plays an important role in the regulation of energy homeostasis. Moreover, mitochondrial biogenesis accompanies skeletal myogenesis, and we previously reported that maternal high-energy diet repressed skeletal myogenesis in pig fetuses. Therefore, the aim of this study was to evaluate the effects of moderately increased maternal energy intake on skeletal muscle mitochondrial biogenesis and function of the pig fetuses. Primiparous purebred Large White sows were allocated to a normal energy intake group (NE) as recommended by the National Research Council (NRC) and a high energy intake group (HE, 110% of NRC recommendations). On day 90 of gestation, fetal umbilical vein blood and longissimus (LM) muscle were collected. Results showed that the weight gain of sows fed HE diet was higher than NE sows on day 90 of gestation (P<0.05). Maternal HE diet increased fetal umbilical vein serum triglyceride and insulin concentrations (P<0.05), and tended to increase the homeostasis model assessment index (P=0.08). Furthermore, HE fetuses exhibited increased malondialdehyde concentration (P<0.05), and decreased activities of antioxidative enzymes (P<0.05) and intracellular NAD+ level (P<0.05) in LM muscle. These alterations in metabolic traits of HE fetuses were accompanied by reduced mitochondrial DNA amount (P<0.05) and down-regulated messenger RNA expression levels of genes responsible for mitochondrial biogenesis and function (P<0.05). Our results suggest that moderately increased energy supply during gestation decreases mitochondrial biogenesis, function and antioxidative capacity in skeletal muscle of pig fetuses.

  19. Impaired Nrf2 regulation of mitochondrial biogenesis in rostral ventrolateral medulla on hypertension induced by systemic inflammation.

    PubMed

    Wu, Kay L H; Wu, Chih-Wei; Chao, Yung-Mei; Hung, Chun-Ying; Chan, Julie Y H

    2016-08-01

    Oxidative stress in rostral ventrolateral medulla (RVLM), where sympathetic premotor neurons reside, is involved in the development of hypertension under systemic inflammation. Mitochondrial dysfunction contributes to tissue oxidative stress. In this study, we sought to investigate whether hypertension developed under systemic inflammation is attributable to impaired mitochondrial biogenesis in RVLM. In normotensive Sprague-Dawley rats, intraperitoneal infusion of a low dose Escherichia coli lipopolysaccharide (LPS) for 7 days promoted a pressor response, alongside a decrease in mitochondrial DNA (mtDNA) copy number, reductions in protein expression of nuclear DNA-encoded transcription factors for mitochondrial biogenesis, including mitochondrial transcription factor A (TFAM) and nuclear factor erythroid-derived 2-like 2 (Nrf2), and suppression of nuclear translocation of the phosphorylated Nrf2 (p-Nrf2) in RVLM neurons; all of which were abrogated by treatment with intracisternal infusion of an interleukin-1β (IL-1β) blocker, IL-1Ra, or a mobile mitochondrial electron carrier, coenzyme Q10 (CoQ10). Microinjection into RVLM of IL-1β suppressed the expressions of p-Nrf2 and TFAM, and evoked a pressor response; conversely, the Nrf2 inducer, tert-butylhydroquinone, lessened the LPS-induced suppression of TFAM expression and pressor response. At cellular level, exposure of neuronal N2a cells to IL-1β decreased mtDNA copy number, increased protein interaction of Nrf2 to its negative regulator, kelch-like ECH-associated protein 1 (Keap1), and reduced DNA binding activity of p-Nrf2 to Tfam gene. Together these results indicate that defect mitochondrial biogenesis in RVLM neurons entailing redox-sensitive and IL-1β-dependent suppression of TFAM because of the increase in the formation of Keap1/Nrf2 complex, reductions in nuclear translocation of the activated Nrf2 and its binding to the Tfam gene promoter may underlie hypertension developed under the LPS

  20. Hyaluronan Upregulates Mitochondrial Biogenesis and Reduces Adenoside Triphosphate Production for Efficient Mitochondrial Function in Slow-Proliferating Human Mesenchymal Stem Cells.

    PubMed

    Solis, Mairim Alexandra; Wei, Yau-Huei; Chang, Chiung-Hsin; Yu, Chen-Hsiang; Kuo, Pao-Lin; Huang, Lynn L H

    2016-10-01

    Hyaluronan-coated surfaces preserve the proliferation and differentiation potential of mesenchymal stem cells by prolonging their G1-phase transit, which maintains cells in a slow-proliferative mode. Mitochondria are known to play a crucial role in stem cell self-renewal and differentiation. In this study, for the first time, the metabolic mechanism underlying the hyaluronan-regulated slow-proliferative maintenance of stem cells was investigated by evaluating mitochondrial functions. Human placenta-derived mesenchymal stem cells (PDMSCs) cultured on hyaluronan-coated surfaces at 0.5, 3.0, 5.0, and 30 µg/cm(2) were found to have an average 58% higher mitochondrial mass and an increase in mitochondrial DNA copy number compared to noncoated tissue culture surfaces (control), as well as a threefold increase in the gene expression of the mitochondrial biogenesis-related gene PGC-1α. Increase in mitochondrial biogenesis led to a hyaluronan dose-dependent increase in mitochondrial membrane potential, ATP content, and oxygen consumption rate, with reactive oxygen species levels shown to be at least three times lower compared to the control. Although hyaluronan seemed to favor mitochondrial function, cell entry into a hyaluronan-regulated slow-proliferative mode led to a fivefold reduction in ATP production and coupling efficiency levels. Together, these results suggest that hyaluronan-coated surfaces influence the metabolic proliferative state of stem cells by upregulating mitochondrial biogenesis and function with controlled ATP production. This more efficiently meets the energy requirements of slow-proliferating PDMSCs. A clear understanding of the metabolic mechanism induced by hyaluronan in stem cells will allow future applications that may overcome the current limitations faced in stem cell culture. Stem Cells 2016;34:2512-2524.

  1. NADPH Oxidase 4 (Nox4) Suppresses Mitochondrial Biogenesis and Bioenergetics in Lung Fibroblasts via a Nuclear Factor Erythroid-derived 2-like 2 (Nrf2)-dependent Pathway.

    PubMed

    Bernard, Karen; Logsdon, Naomi J; Miguel, Veronica; Benavides, Gloria A; Zhang, Jianhua; Carter, A Brent; Darley-Usmar, Victor M; Thannickal, Victor J

    2017-02-17

    Mitochondrial bioenergetics are critical for cellular homeostasis and stress responses. The reactive oxygen species-generating enzyme, NADPH oxidase 4 (Nox4), regulates a number of physiological and pathological processes, including cellular differentiation, host defense, and tissue fibrosis. In this study we explored the role of constitutive Nox4 activity in regulating mitochondrial function. An increase in mitochondrial oxygen consumption and reserve capacity was observed in murine and human lung fibroblasts with genetic deficiency (or silencing) of Nox4. Inhibition of Nox4 expression/activity by genetic or pharmacological approaches resulted in stimulation of mitochondrial biogenesis, as evidenced by elevated mitochondrial-to-nuclear DNA ratio and increased expression of the mitochondrial markers transcription factor A (TFAM), citrate synthase, voltage-dependent anion channel (VDAC), and cytochrome c oxidase subunit 4 (COX IV). Induction of mitochondrial biogenesis was dependent on TFAM up-regulation but was independent of the activation of the peroxisome proliferator-activated receptor γ coactivator 1-α (PGC-1α). The enhancement of mitochondrial bioenergetics as well as the increase in mitochondrial proteins in Nox4-deficient lung fibroblasts is inhibited by silencing of nuclear factor erythroid-derived 2-like 2 (Nrf2), supporting a key role for Nrf2 in control of mitochondrial biogenesis. Together, these results indicate a critical role for both Nox4 and Nrf2 in counter-regulation of mitochondrial biogenesis and metabolism.

  2. The MIA pathway: a key regulator of mitochondrial oxidative protein folding and biogenesis.

    PubMed

    Mordas, Amelia; Tokatlidis, Kostas

    2015-08-18

    Mitochondria are fundamental intracellular organelles with key roles in important cellular processes like energy production, Fe/S cluster biogenesis, and homeostasis of lipids and inorganic ions. Mitochondrial dysfunction is consequently linked to many human pathologies (cancer, diabetes, neurodegeneration, stroke) and apoptosis. Mitochondrial biogenesis relies on protein import as most mitochondrial proteins (about 10-15% of the human proteome) are imported after their synthesis in the cytosol. Over the last several years many mitochondrial translocation pathways have been discovered. Among them, the import pathway that targets proteins to the intermembrane space (IMS) stands out as it is the only one that couples import to folding and oxidation and results in the covalent modification of the incoming precursor that adopt internal disulfide bonds in the process (the MIA pathway). The discovery of this pathway represented a significant paradigm shift as it challenged the prevailing dogma that the endoplasmic reticulum is the only compartment of eukaryotic cells where oxidative folding can occur. The concept of the oxidative folding pathway was first proposed on the basis of folding and import data for the small Tim proteins that have conserved cysteine motifs and must adopt intramolecular disulfides after import so that they are retained in the organelle. The introduction of disulfides in the IMS is catalyzed by Mia40 that functions as a chaperone inducing their folding. The sulfhydryl oxidase Erv1 generates the disulfide pairs de novo using either molecular oxygen or, cytochrome c and other proteins as terminal electron acceptors that eventually link this folding process to respiration. The solution NMR structure of Mia40 (and supporting biochemical experiments) showed that Mia40 is a novel type of disulfide donor whose recognition capacity for its substrates relies on a hydrophobic binding cleft found adjacent to a thiol active CPC motif. Targeting of the

  3. The MIA Pathway: A Key Regulator of Mitochondrial Oxidative Protein Folding and Biogenesis

    PubMed Central

    2015-01-01

    Conspectus Mitochondria are fundamental intracellular organelles with key roles in important cellular processes like energy production, Fe/S cluster biogenesis, and homeostasis of lipids and inorganic ions. Mitochondrial dysfunction is consequently linked to many human pathologies (cancer, diabetes, neurodegeneration, stroke) and apoptosis. Mitochondrial biogenesis relies on protein import as most mitochondrial proteins (about 10–15% of the human proteome) are imported after their synthesis in the cytosol. Over the last several years many mitochondrial translocation pathways have been discovered. Among them, the import pathway that targets proteins to the intermembrane space (IMS) stands out as it is the only one that couples import to folding and oxidation and results in the covalent modification of the incoming precursor that adopt internal disulfide bonds in the process (the MIA pathway). The discovery of this pathway represented a significant paradigm shift as it challenged the prevailing dogma that the endoplasmic reticulum is the only compartment of eukaryotic cells where oxidative folding can occur. The concept of the oxidative folding pathway was first proposed on the basis of folding and import data for the small Tim proteins that have conserved cysteine motifs and must adopt intramolecular disulfides after import so that they are retained in the organelle. The introduction of disulfides in the IMS is catalyzed by Mia40 that functions as a chaperone inducing their folding. The sulfhydryl oxidase Erv1 generates the disulfide pairs de novo using either molecular oxygen or, cytochrome c and other proteins as terminal electron acceptors that eventually link this folding process to respiration. The solution NMR structure of Mia40 (and supporting biochemical experiments) showed that Mia40 is a novel type of disulfide donor whose recognition capacity for its substrates relies on a hydrophobic binding cleft found adjacent to a thiol active CPC motif. Targeting

  4. Regulation of Mitochondrial Respiratory Chain Biogenesis by Estrogens/Estrogen Receptors and Physiological, Pathological and Pharmacological Implications

    PubMed Central

    Chen, Jin-Qiang; Cammarata, Patrick R.; Baines, Christopher P.; Yager, James D.

    2009-01-01

    There has been increasing evidence pointing to the mitochondrial respiratory chain (MRC) as a novel and important target for the actions of 17β-estradiol(E2) and estrogen receptors (ER) in a number of cell types and tissues that have high demands for mitochondrial energy metabolism. This novel E2-mediated mitochondrial pathway involves the cooperation of both nuclear and mitochondrial ERα and ERβ and their co-activators on the coordinate regulation of both nuclear DNA- and mitochondrial DNA-encoded genes for MRC proteins. In this paper, we have: 1) comprehensively reviewed studies that reveal a novel role of estrogens and ERs in the regulation of MRC biogenesis; 2) discussed their physiological, pathological and pharmacological implications in the control of cell proliferation and apoptosis in relation to estrogen-mediated carcinogenesis, anticancer drug resistance in human breast cancer cells, neuro-protection for Alzheimer’s disease and Parkinson’s disease in brain, cardiovascular protection in human heart and their beneficial effects in lens physiology related to cataract in the eye; and 3) pointed out new research directions to address the key questions in this important and newly emerging area. We also suggest a novel conceptual approach that will contribute to innovative regimines for the prevention or treatment of a wide variety of medical complications based on E2/ER-mediated MRC biogenesis pathway. PMID:19559056

  5. Supplementing the maternal diet of rats with butyrate enhances mitochondrial biogenesis in the skeletal muscles of weaned offspring.

    PubMed

    Huang, Yanping; Gao, Shixing; Jun, Guo; Zhao, Ruqian; Yang, Xiaojing

    2017-01-01

    The present study aimed to investigate the effects of maternal dietary butyrate supplementation on energy metabolism and mitochondrial biogenesis in offspring skeletal muscle and the possible mediating mechanisms. Virgin female rats were randomly assigned to either control or butyrate diets (1 % butyrate sodium) throughout gestation and lactation. At the end of lactation (21 d), the offspring were killed by exsanguination from the abdominal aorta under anaesthesia. The results showed that maternal butyrate supplementation throughout gestation and lactation did not affect offspring body weight. However, the protein expressions of G-protein-coupled receptors (GPR) 43 and 41 were significantly enhanced in offspring skeletal muscle of the maternal butyrate-supplemented group. The ATP content, most of mitochondrial DNA-encoded gene expressions, the cytochrome c oxidase subunit 1 and 4 protein contents and the mitochondrial DNA copy number were significantly higher in the butyrate group than in the control group. Meanwhile, the protein expressions of type 1 myosin heavy chain, mitochondrial transcription factor A, PPAR-coactivator-1α (PGC-1α) and uncoupling protein 3 were significantly increased in the gastrocnemius muscle of the treatment group compared with the control group. These results indicate for the first time that maternal butyrate supplementation during the gestation and lactation periods influenced energy metabolism and mitochondrial biogenesis through the GPR and PGC-1α pathways in offspring skeletal muscle at weaning.

  6. Mitochondrial disease genes COA6, COX6B and SCO2 have overlapping roles in COX2 biogenesis

    PubMed Central

    Ghosh, Alok; Pratt, Anthony T.; Soma, Shivatheja; Theriault, Sarah G.; Griffin, Aaron T.; Trivedi, Prachi P.; Gohil, Vishal M.

    2016-01-01

    Biogenesis of cytochrome c oxidase (CcO), the terminal enzyme of the mitochondrial respiratory chain, is a complex process facilitated by several assembly factors. Pathogenic mutations were recently reported in one such assembly factor, COA6, and our previous work linked Coa6 function to mitochondrial copper metabolism and expression of Cox2, a copper-containing subunit of CcO. However, the precise role of Coa6 in Cox2 biogenesis remained unknown. Here we show that yeast Coa6 is an orthologue of human COA6, and like Cox2, is regulated by copper availability, further implicating it in copper delivery to Cox2. In order to place Coa6 in the Cox2 copper delivery pathway, we performed a comprehensive genetic epistasis analysis in the yeast Saccharomyces cerevisiae and found that simultaneous deletion of Coa6 and Sco2, a mitochondrial copper metallochaperone, or Coa6 and Cox12/COX6B, a structural subunit of CcO, completely abrogates Cox2 biogenesis. Unlike Coa6 deficient cells, copper supplementation fails to rescue Cox2 levels of these double mutants. Overexpression of Cox12 or Sco proteins partially rescues the coa6Δ phenotype, suggesting their overlapping but non-redundant roles in copper delivery to Cox2. These genetic data are strongly corroborated by biochemical studies demonstrating physical interactions between Coa6, Cox2, Cox12 and Sco proteins. Furthermore, we show that patient mutations in Coa6 disrupt Coa6–Cox2 interaction, providing the biochemical basis for disease pathogenesis. Taken together, these results place COA6 in the copper delivery pathway to CcO and, surprisingly, link it to a previously unidentified function of CcO subunit Cox12 in Cox2 biogenesis. PMID:26669719

  7. Coordinated Upregulation of Mitochondrial Biogenesis and Autophagy in Breast Cancer Cells: The Role of Dynamin Related Protein-1 and Implication for Breast Cancer Treatment

    PubMed Central

    Zou, Peng; Liu, Longhua; Zheng, Louise D.; Payne, Kyle K.; Idowu, Michael O.; Zhang, Jinfeng; Schmelz, Eva M.

    2016-01-01

    Overactive mitochondrial fission was shown to promote cell transformation and tumor growth. It remains elusive how mitochondrial quality is regulated in such conditions. Here, we show that upregulation of mitochondrial fission protein, dynamin related protein-1 (Drp1), was accompanied with increased mitochondrial biogenesis markers (PGC1α, NRF1, and Tfam) in breast cancer cells. However, mitochondrial number was reduced, which was associated with lower mitochondrial oxidative capacity in breast cancer cells. This contrast might be owing to enhanced mitochondrial turnover through autophagy, because an increased population of autophagic vacuoles engulfing mitochondria was observed in the cancer cells. Consistently, BNIP3 (a mitochondrial autophagy marker) and autophagic flux were significantly upregulated, indicative of augmented mitochondrial autophagy (mitophagy). The upregulation of Drp1 and BNIP3 was also observed in vivo (human breast carcinomas). Importantly, inhibition of Drp1 significantly suppressed mitochondrial autophagy, metabolic reprogramming, and cancer cell viability. Together, this study reveals coordinated increase of mitochondrial biogenesis and mitophagy in which Drp1 plays a central role regulating breast cancer cell metabolism and survival. Given the emerging evidence of PGC1α contributing to tumor growth, it will be of critical importance to target both mitochondrial biogenesis and mitophagy for effective cancer therapeutics. PMID:27746856

  8. Mia40 and MINOS act in parallel with Ccs1 in the biogenesis of mitochondrial Sod1.

    PubMed

    Varabyova, Aksana; Topf, Ulrike; Kwiatkowska, Paulina; Wrobel, Lidia; Kaus-Drobek, Magdalena; Chacinska, Agnieszka

    2013-10-01

    Superoxide dismutase 1 (Sod1) is a major superoxide-scavenging enzyme in the eukaryotic cell, and is localized in the cytosol and intermembrane space of mitochondria. Sod1 requires its specific chaperone Ccs1 and disulfide bond formation in order to be retained in the intermembrane space. Our study identified a pool of Sod1 that is present in the reduced state in mitochondria that lack Ccs1. We created yeast mutants with mutations in highly conserved amino acid residues corresponding to human mutations that cause amyotrophic lateral sclerosis, and found that some of the mutant proteins were present in the reduced state. These mutant variants of Sod1 were efficiently localized in mitochondria. Localization of the reduced, Ccs1-independent forms of Sod1 relied on Mia40, an essential component of the mitochondrial intermembrane space import and assembly pathway that is responsible for the biogenesis of intermembrane space proteins. Furthermore, the mitochondrial inner membrane organizing system (MINOS), which is responsible for mitochondrial membrane architecture, differentially modulated the presence of reduced Sod1 in mitochondria. Thus, we identified novel mitochondrial players that are possibly involved in pathological conditions caused by changes in the biogenesis of Sod1.

  9. Enhanced oxidative stress and aberrant mitochondrial biogenesis in human neuroblastoma SH-SY5Y cells during methamphetamine induced apoptosis

    SciTech Connect

    Wu, C.-W.; Ping, Y.-H.; Yen, J.-C.; Chang, C.-Y.; Wang, S.-F.; Yeh, C.-L.; Chi, C.-W.; Lee, H.-C. . E-mail: hclee2@ym.edu.tw

    2007-05-01

    Methamphetamine (METH) is an abused drug that may cause psychiatric and neurotoxic damage, including degeneration of monoaminergic terminals and apoptosis of non-monoaminergic cells in Brain. The cellular and molecular mechanisms underlying these METH-induced neurotoxic effects remain to be clarified. In this study, we performed a time course assessment to investigate the effects of METH on intracellular oxidative stress and mitochondrial alterations in a human dopaminergic neuroblastoma SH-SY5Y cell line. We characterized that METH induces a temporal sequence of several cellular events including, firstly, a decrease in mitochondrial membrane potential within 1 h of the METH treatment, secondly, an extensive decline in mitochondrial membrane potential and increase in the level of reactive oxygen species (ROS) after 8 h of the treatment, thirdly, an increase in mitochondrial mass after the drug treatment for 24 h, and finally, a decrease in mtDNA copy number and mitochondrial proteins per mitochondrion as well as the occurrence of apoptosis after 48 h of the treatment. Importantly, vitamin E attenuated the METH-induced increases in intracellular ROS level and mitochondrial mass, and prevented METH-induced cell death. Our observations suggest that enhanced oxidative stress and aberrant mitochondrial biogenesis may play critical roles in METH-induced neurotoxic effects.

  10. Sam37 is crucial for formation of the mitochondrial TOM–SAM supercomplex, thereby promoting β-barrel biogenesis

    PubMed Central

    Wenz, Lena-Sophie; Ellenrieder, Lars; Qiu, Jian; Bohnert, Maria; Zufall, Nicole; van der Laan, Martin; Becker, Thomas

    2015-01-01

    Biogenesis of mitochondrial β-barrel proteins requires two preprotein translocases, the general translocase of the outer membrane (TOM) and the sorting and assembly machinery (SAM). TOM and SAM form a supercomplex that promotes transfer of β-barrel precursors. The SAM core complex contains the channel protein Sam50, which cooperates with Sam35 in precursor recognition, and the peripheral membrane protein Sam37. The molecular function of Sam37 has been unknown. We report that Sam37 is crucial for formation of the TOM–SAM supercomplex. Sam37 interacts with the receptor domain of Tom22 on the cytosolic side of the mitochondrial outer membrane and links TOM and SAM complexes. Sam37 thus promotes efficient transfer of β-barrel precursors to the SAM complex. We conclude that Sam37 functions as a coupling factor of the translocase supercomplex of the mitochondrial outer membrane. PMID:26416958

  11. Impaired mitochondrial biogenesis is a common feature to myocardial hypertrophy and end-stage ischemic heart failure

    PubMed Central

    Pisano, Annalinda; Cerbelli, Bruna; Perli, Elena; Pelullo, Maria; Bargelli, Valentina; Preziuso, Carmela; Mancini, Massimiliano; He, Langping; Bates, Matthew GD; Lucena, Joaquin R; Della Monica, Paola Lilla; Familiari, Giuseppe; Petrozza, Vincenzo; Nediani, Chiara; Taylor, Robert W; d’Amati, Giulia; Giordano, Carla

    2016-01-01

    Mitochondrial (mt) DNA depletion and oxidative mtDNA damage have been implicated in the process of pathological cardiac remodeling. Whether these features are present in the early phase of maladaptive cardiac remodeling, that is, during compensated cardiac hypertrophy, is still unknown. We compared the morphologic and molecular features of mt biogenesis and markers of oxidative stress in human heart from adult subjects with compensated hypertrophic cardiomyopathy and heart failure. We have shown that mtDNA depletion is a constant feature of both conditions. A quantitative loss of mtDNA content was associated with significant down-regulation of selected modulators of mt biogenesis and decreased expression of proteins involved in mtDNA maintenance. Interestingly, mtDNA depletion characterized also the end-stage phase of cardiomyopathies due to a primary mtDNA defect. Oxidative stress damage was detected only in failing myocardium. PMID:26764143

  12. Melatonin Improves Mitochondrial Function by Promoting MT1/SIRT1/PGC-1 Alpha-Dependent Mitochondrial Biogenesis in Cadmium-Induced Hepatotoxicity In Vitro

    PubMed Central

    Guo, Pan; Pi, Huifeng; Xu, Shangcheng; Zhang, Lei; Li, Yuming; Li, Min; Cao, Zhengwang; Tian, Li; Xie, Jia; Li, Renyan; He, Mindi; Lu, Yonghui; Liu, Chuan; Duan, Weixia; Yu, Zhengping; Zhou, Zhou

    2014-01-01

    Melatonin is an indolamine synthesized in the pineal gland that has a wide range of physiological functions, and it has been under clinical investigation for expanded applications. Increasing evidence demonstrates that melatonin can ameliorate cadmium-induced hepatotoxicity. However, the potentially protective effects of melatonin against cadmium-induced hepatotoxicity and the underlying mechanisms of this protection remain unclear. This study investigates the protective effects of melatonin pretreatment on cadmium-induced hepatotoxicity and elucidates the potential mechanism of melatonin-mediated protection. We exposed HepG2 cells to different concentrations of cadmium chloride (2.5, 5, and 10μM) for 12 h. We found that Cd stimulated cytotoxicity, disrupted the mitochondrial membrane potential, increased reactive oxygen species production, and decreased mitochondrial mass and mitochondrial DNA content. Consistent with this finding, Cd exposure was associated with decreased Sirtuin 1 (SIRT1) protein expression and activity, thus promoted acetylation of PGC-1 alpha, a key enzyme involved in mitochondrial biogenesis and function, although Cd did not disrupt the interaction between SIRT1 and PGC-1 alpha. However, all cadmium-induced mitochondrial oxidative injuries were efficiently attenuated by melatonin pretreatment. Moreover, Sirtinol and SIRT1 siRNA each blocked the melatonin-mediated elevation in mitochondrial function by inhibiting SIRT1/ PGC-1 alpha signaling. Luzindole, a melatonin receptor antagonist, was found to partially block the ability of melatonin to promote SIRT1/ PGC-1 alpha signaling. In summary, our results indicate that SIRT1 plays an essential role in the ability of moderate melatonin to stimulate PGC-1 alpha and improve mitochondrial biogenesis and function at least partially through melatonin receptors in cadmium-induced hepatotoxicity. PMID:25159133

  13. Exercise-induced asthma

    MedlinePlus

    Wheezing - exercise-induced; Reactive airway disease - exercise ... Having asthma symptoms when you exercise does not mean you cannot or should not exercise. But be aware of your EIA triggers. Cold or dry air may ...

  14. Idiopathic chronic fatigue in older adults is linked to impaired mitochondrial content and biogenesis signaling in skeletal muscle

    PubMed Central

    Wawrzyniak, Nicholas R.; Joseph, Anna-Maria; Levin, David G.; Gundermann, David M.; Leeuwenburgh, Christiaan; Sandesara, Bhanuprasad; Manini, Todd M.; Adhihetty, Peter J.

    2016-01-01

    Fatigue is a symptom of many diseases, but it can also manifest as a unique medical condition, such as idiopathic chronic fatigue (ICF). While the prevalence of ICF increases with age, mitochondrial content and function decline with age, which may contribute to ICF. The purpose of this study was to determine whether skeletal muscle mitochondrial dysregulation and oxidative stress is linked to ICF in older adults. Sedentary, old adults (n = 48, age 72.4 ± 5.3 years) were categorized into ICF and non-fatigued (NF) groups based on the FACIT-Fatigue questionnaire. ICF individuals had a FACIT score one standard deviation below the mean for non-anemic adults > 65 years and were excluded according to CDC diagnostic criteria for ICF. Vastus lateralis muscle biopsies were analyzed, showing reductions in mitochondrial content and suppression of mitochondrial regulatory proteins Sirt3, PGC-1α, NRF-1, and cytochrome c in ICF compared to NF. Additionally, mitochondrial morphology proteins, antioxidant enzymes, and lipid peroxidation were unchanged in ICF individuals. Our data suggests older adults with ICF have reduced skeletal muscle mitochondrial content and biogenesis signaling that cannot be accounted for by increased oxidative damage. PMID:27447862

  15. PGC-1α mediates mitochondrial biogenesis and oxidative phosphorylation in cancer cells to promote metastasis.

    PubMed

    LeBleu, Valerie S; O'Connell, Joyce T; Gonzalez Herrera, Karina N; Wikman, Harriet; Pantel, Klaus; Haigis, Marcia C; de Carvalho, Fernanda Machado; Damascena, Aline; Domingos Chinen, Ludmilla Thome; Rocha, Rafael M; Asara, John M; Kalluri, Raghu

    2014-10-01

    Cancer cells can divert metabolites into anabolic pathways to support their rapid proliferation and to accumulate the cellular building blocks required for tumour growth. However, the specific bioenergetic profile of invasive and metastatic cancer cells is unknown. Here we report that migratory/invasive cancer cells specifically favour mitochondrial respiration and increased ATP production. Invasive cancer cells use the transcription coactivator peroxisome proliferator-activated receptor gamma, coactivator 1 alpha (PPARGC1A, also known as PGC-1α) to enhance oxidative phosphorylation, mitochondrial biogenesis and the oxygen consumption rate. Clinical analysis of human invasive breast cancers revealed a strong correlation between PGC-1α expression in invasive cancer cells and the formation of distant metastases. Silencing of PGC-1α in cancer cells suspended their invasive potential and attenuated metastasis without affecting proliferation, primary tumour growth or the epithelial-to-mesenchymal program. Inherent genetics of cancer cells can determine the transcriptome framework associated with invasion and metastasis, and mitochondrial biogenesis and respiration induced by PGC-1α are also essential for functional motility of cancer cells and metastasis.

  16. Decreased Levels of Proapoptotic Factors and Increased Key Regulators of Mitochondrial Biogenesis Constitute New Potential Beneficial Features of Long-lived Growth Hormone Receptor Gene–Disrupted Mice

    PubMed Central

    2013-01-01

    Decreased somatotrophic signaling is among the most important mechanisms associated with extended longevity. Mice homozygous for the targeted disruption of the growth hormone (GH) receptor gene (GH receptor knockout; GHRKO) are obese and dwarf, are characterized by a reduced weight and body size, undetectable levels of GH receptor, high concentration of serum GH, and greatly reduced plasma levels of insulin and insulin-like growth factor-I, and are remarkably long lived. Recent results suggest new features of GHRKO mice that may positively affect longevity—decreased levels of proapoptotic factors and increased levels of key regulators of mitochondrial biogenesis. The alterations in levels of the proapoptotic factors and key regulators of mitochondrial biogenesis were not further improved by two other potential life-extending interventions—calorie restriction and visceral fat removal. This may attribute the primary role to GH resistance in the regulation of apoptosis and mitochondrial biogenesis in GHRKO mice in terms of increased life span. PMID:23197187

  17. Promise of Neurorestoration and Mitochondrial Biogenesis in Parkinson's Disease with Multi Target Drugs: An Alternative to Stem Cell Therapy

    PubMed Central

    Oh, Young J.

    2013-01-01

    There is an unmet need in progressive neurodegenerative diseases such as Parkinson's and Alzheimer's diseases. The present therapeutics for these diseases at best is symptomatic and is not able to delay disease or possess disease modifying activity. Thus an approach to drug design should be made to slow or halt progressive course of a neurological disorder by interfering with a disease-specific pathogenetic process. This would entail the ability of the drug to protect neurons by blocking the common pathway for neuronal injury and cell death and the ability to promote regeneration of neurons and restoration of neuronal function. We have now developed a number of multi target drugs which possess neuroprotective, and neurorestorative activity as well as being able to active PGC-1α (peroxisome proliferator-activated receptor γ coactivator-1α), SIRT1 (NAD-dependent deacetylase protein) and NTF (mitochondrial transcription factor) that are intimately associated with mitochondrial biogenesis. PMID:24167412

  18. Mitochondrial DNA (mtDNA) biogenesis: visualization and duel incorporation of BrdU and EdU into newly synthesized mtDNA in vitro.

    PubMed

    Lentz, Stephen I; Edwards, James L; Backus, Carey; McLean, Lisa L; Haines, Kristine M; Feldman, Eva L

    2010-02-01

    Mitochondria are key regulators of cellular energy and are the focus of a large number of studies examining the regulation of mitochondrial dynamics and biogenesis in healthy and diseased conditions. One approach to monitoring mitochondrial biogenesis is to measure the rate of mitochondrial DNA (mtDNA) replication. We developed a sensitive technique to visualize newly synthesized mtDNA in individual cells to study mtDNA replication within subcellular compartments of neurons. The technique combines the incorporation of 5-bromo-2-deoxyuridine (BrdU) and/or 5-ethynyl-2'-deoxyuridine (EdU) into mtDNA, together with a tyramide signal amplification protocol. Employing this technique, we visualized and measured mtDNA biogenesis in individual cells. The labeling procedure for EdU allows for more comprehensive results by allowing the comparison of its incorporation with other intracellular markers, because it does not require the harsh acid or enzyme digests necessary to recover the BrdU epitope. In addition, the utilization of both BrdU and EdU permits sequential pulse-chase experiments to follow the intracellular localization of mtDNA replication. The ability to quantify mitochondrial biogenesis provides an essential tool for investigating the alterations in mitochondrial dynamics involved in the pathogenesis of multiple cellular disorders, including neuropathies and neurodegenerative diseases.

  19. The neurogenic basic helix-loop-helix transcription factor NeuroD6 enhances mitochondrial biogenesis and bioenergetics to confer tolerance of neuronal PC12-NeuroD6 cells to the mitochondrial stressor rotenone

    SciTech Connect

    Baxter, Kristin Kathleen; Uittenbogaard, Martine; Chiaramello, Anne

    2012-10-15

    The fundamental question of how and which neuronal specific transcription factors tailor mitochondrial biogenesis and bioenergetics to the need of developing neuronal cells has remained largely unexplored. In this study, we report that the neurogenic basic helix-loop-helix transcription factor NeuroD6 possesses mitochondrial biogenic properties by amplifying the mitochondrial DNA content and TFAM expression levels, a key regulator for mitochondrial biogenesis. NeuroD6-mediated increase in mitochondrial biogenesis in the neuronal progenitor-like PC12-NEUROD6 cells is concomitant with enhanced mitochondrial bioenergetic functions, including increased expression levels of specific subunits of respiratory complexes of the electron transport chain, elevated mitochondrial membrane potential and ATP levels produced by oxidative phosphorylation. Thus, NeuroD6 augments the bioenergetic capacity of PC12-NEUROD6 cells to generate an energetic reserve, which confers tolerance to the mitochondrial stressor, rotenone. We found that NeuroD6 induces an adaptive bioenergetic response throughout rotenone treatment involving maintenance of the mitochondrial membrane potential and ATP levels in conjunction with preservation of the actin network. In conclusion, our results support the concept that NeuroD6 plays an integrative role in regulating and coordinating the onset of neuronal differentiation with acquisition of adequate mitochondrial mass and energetic capacity to ensure energy demanding events, such as cytoskeletal remodeling, plasmalemmal expansion, and growth cone formation. -- Highlights: Black-Right-Pointing-Pointer NeuroD6 induces mitochondrial biogenesis in neuroprogenitor-like cells. Black-Right-Pointing-Pointer NeuroD6 augments the bioenergetic reserve of the neuronal PC12-NeuroD6 cells. Black-Right-Pointing-Pointer NeuroD6 increases the mitochondrial membrane potential and ATP levels. Black-Right-Pointing-Pointer NeuroD6 confers tolerance to rotenone via an adaptive

  20. A novel mechanism involved in the coupling of mitochondrial biogenesis to oxidative phosphorylation

    PubMed Central

    Ostojić, Jelena; Rago, Jean-Paul; Dujardin, Geneviève

    2014-01-01

    Mitochondria are essential organelles that are central to a multitude of cellular processes, including oxidative phosphorylation (OXPHOS), which produces most of the ATP in animal cells. Thus it is important to understand not only the mechanisms and biogenesis of this energy production machinery but also how it is regulated in both physiological and pathological contexts. A recent study by Ostojić et al. [Cell Metabolism (2013) 18, 567-577] has uncovered a regulatory loop by which the biogenesis of a major enzyme of the OXPHOS pathway, the respiratory complex III, is coupled to the energy producing activity of the mitochondria. PMID:28357209

  1. Activation of the human mitochondrial transcription factor A gene by nuclear respiratory factors: a potential regulatory link between nuclear and mitochondrial gene expression in organelle biogenesis.

    PubMed Central

    Virbasius, J V; Scarpulla, R C

    1994-01-01

    Mitochondrial transcription factor A (mtTFA), the product of a nuclear gene, stimulates transcription from the two divergent mitochondrial promoters and is likely the principal activator of mitochondrial gene expression in vertebrates. Here we establish that the proximal promoter of the human mtTFA gene is highly dependent upon recognition sites for the nuclear respiratory factors, NRF-1 and NRF-2, for activity. These factors have been previously implicated in the activation of numerous nuclear genes that contribute to mitochondrial respiratory function. The affinity-purified factors from HeLa cells specifically bind to the mtTFA NRF-1 and NRF-2 sites through guanine nucleotide contacts that are characteristic for each site. Mutations in these contacts eliminate NRF-1 and NRF-2 binding and also dramatically reduce promoter activity in transfected cells. Although both factors contribute, NRF-1 binding appears to be the major determinant of promoter function. This dependence on NRF-1 activation is confirmed by in vitro transcription using highly purified recombinant proteins that display the same binding specificities as the HeLa cell factors. The activation of the mtTFA promoter by both NRF-1 and NRF-2 therefore provides a link between the expression of nuclear and mitochondrial genes and suggests a mechanism for their coordinate regulation during organelle biogenesis. Images PMID:8108407

  2. Mitochondria "fuel" breast cancer metabolism: fifteen markers of mitochondrial biogenesis label epithelial cancer cells, but are excluded from adjacent stromal cells.

    PubMed

    Sotgia, Federica; Whitaker-Menezes, Diana; Martinez-Outschoorn, Ubaldo E; Salem, Ahmed F; Tsirigos, Aristotelis; Lamb, Rebecca; Sneddon, Sharon; Hulit, James; Howell, Anthony; Lisanti, Michael P

    2012-12-01

    Here, we present new genetic and morphological evidence that human tumors consist of two distinct metabolic compartments. First, re-analysis of genome-wide transcriptional profiling data revealed that > 95 gene transcripts associated with mitochondrial biogenesis and/or mitochondrial translation were significantly elevated in human breast cancer cells, as compared with adjacent stromal tissue. Remarkably, nearly 40 of these upregulated gene transcripts were mitochondrial ribosomal proteins (MRPs), functionally associated with mitochondrial translation of protein components of the OXPHOS complex. Second, during validation by immunohistochemistry, we observed that antibodies directed against 15 markers of mitochondrial biogenesis and/or mitochondrial translation (AKAP1, GOLPH3, GOLPH3L, MCT1, MRPL40, MRPS7, MRPS15, MRPS22, NRF1, NRF2, PGC1-α, POLRMT, TFAM, TIMM9 and TOMM70A) selectively labeled epithelial breast cancer cells. These same mitochondrial markers were largely absent or excluded from adjacent tumor stromal cells. Finally, markers of mitochondrial lipid synthesis (GOLPH3) and mitochondrial translation (POLRMT) were associated with poor clinical outcome in human breast cancer patients. Thus, we conclude that human breast cancers contain two distinct metabolic compartments-a glycolytic tumor stroma, which surrounds oxidative epithelial cancer cells-that are mitochondria-rich. The co-existence of these two compartments is indicative of metabolic symbiosis between epithelial cancer cells and their surrounding stroma. As such, epithelial breast cancer cells should be viewed as predatory metabolic "parasites," which undergo anabolic reprogramming to amplify their mitochondrial "power." This notion is consistent with the observation that the anti-malarial agent chloroquine may be an effective anticancer agent. New anticancer therapies should be developed to target mitochondrial biogenesis and/or mitochondrial translation in human cancer cells.

  3. Induction of mitochondrial biogenesis and respiration is associated with mTOR regulation in hepatocytes of rats treated with the pan-PPAR activator tetradecylthioacetic acid (TTA)

    SciTech Connect

    Hagland, Hanne R.; Nilsson, Linn I.H.; Burri, Lena; Nikolaisen, Julie; Berge, Rolf K.; Tronstad, Karl J.

    2013-01-11

    Highlights: Black-Right-Pointing-Pointer We investigated mechanisms of mitochondrial regulation in rat hepatocytes. Black-Right-Pointing-Pointer Tetradecylthioacetic acid (TTA) was employed to activate mitochondrial oxidation. Black-Right-Pointing-Pointer Mitochondrial biogenesis and respiration were induced. Black-Right-Pointing-Pointer It was confirmed that PPAR target genes were induced. Black-Right-Pointing-Pointer The mechanism involved activation mTOR. -- Abstract: The hypolipidemic effect of peroxisome proliferator-activated receptor (PPAR) activators has been explained by increasing mitochondrial fatty acid oxidation, as observed in livers of rats treated with the pan-PPAR activator tetradecylthioacetic acid (TTA). PPAR-activation does, however, not fully explain the metabolic adaptations observed in hepatocytes after treatment with TTA. We therefore characterized the mitochondrial effects, and linked this to signalling by the metabolic sensor, the mammalian target of rapamycin (mTOR). In hepatocytes isolated from TTA-treated rats, the changes in cellular content and morphology were consistent with hypertrophy. This was associated with induction of multiple mitochondrial biomarkers, including mitochondrial DNA, citrate synthase and mRNAs of mitochondrial proteins. Transcription analysis further confirmed activation of PPAR{alpha}-associated genes, in addition to genes related to mitochondrial biogenesis and function. Analysis of mitochondrial respiration revealed that the capacity of both electron transport and oxidative phosphorylation were increased. These effects coincided with activation of the stress related factor, ERK1/2, and mTOR. The protein level and phosphorylation of the downstream mTOR actors eIF4G and 4E-BP1 were induced. In summary, TTA increases mitochondrial respiration by inducing hypertrophy and mitochondrial biogenesis in rat hepatocytes, via adaptive regulation of PPARs as well as mTOR.

  4. Mitochondria “fuel” breast cancer metabolism: Fifteen markers of mitochondrial biogenesis label epithelial cancer cells, but are excluded from adjacent stromal cells

    PubMed Central

    Sotgia, Federica; Whitaker-Menezes, Diana; Martinez-Outschoorn, Ubaldo E.; Salem, Ahmed F.; Tsirigos, Aristotelis; Lamb, Rebecca; Sneddon, Sharon; Hulit, James; Howell, Anthony; Lisanti, Michael P.

    2012-01-01

    Here, we present new genetic and morphological evidence that human tumors consist of two distinct metabolic compartments. First, re-analysis of genome-wide transcriptional profiling data revealed that > 95 gene transcripts associated with mitochondrial biogenesis and/or mitochondrial translation were significantly elevated in human breast cancer cells, as compared with adjacent stromal tissue. Remarkably, nearly 40 of these upregulated gene transcripts were mitochondrial ribosomal proteins (MRPs), functionally associated with mitochondrial translation of protein components of the OXPHOS complex. Second, during validation by immunohistochemistry, we observed that antibodies directed against 15 markers of mitochondrial biogenesis and/or mitochondrial translation (AKAP1, GOLPH3, GOLPH3L, MCT1, MRPL40, MRPS7, MRPS15, MRPS22, NRF1, NRF2, PGC1-α, POLRMT, TFAM, TIMM9 and TOMM70A) selectively labeled epithelial breast cancer cells. These same mitochondrial markers were largely absent or excluded from adjacent tumor stromal cells. Finally, markers of mitochondrial lipid synthesis (GOLPH3) and mitochondrial translation (POLRMT) were associated with poor clinical outcome in human breast cancer patients. Thus, we conclude that human breast cancers contain two distinct metabolic compartments—a glycolytic tumor stroma, which surrounds oxidative epithelial cancer cells—that are mitochondria-rich. The co-existence of these two compartments is indicative of metabolic symbiosis between epithelial cancer cells and their surrounding stroma. As such, epithelial breast cancer cells should be viewed as predatory metabolic “parasites,” which undergo anabolic reprogramming to amplify their mitochondrial “power.” This notion is consistent with the observation that the anti-malarial agent chloroquine may be an effective anticancer agent. New anticancer therapies should be developed to target mitochondrial biogenesis and/or mitochondrial translation in human cancer cells. PMID

  5. Convergence of multiple signaling pathways is required to coordinately up-regulate mtDNA and mitochondrial biogenesis during T cell activation

    PubMed Central

    D’Souza, Anthony D.; Parikh, Neal; Kaech, Susan M.; Shadel, Gerald S.

    2009-01-01

    The quantity and activity of mitochondria vary dramatically in tissues and are modulated in response to changing cellular energy demands and environmental factors. The amount of mitochondrial DNA (mtDNA), which encodes essential subunits of the oxidative phosphorylation complexes required for cellular ATP production, is also tightly regulated, but by largely unknown mechanisms. Using murine T cells as a model system, we have addressed how specific signaling pathways influence mitochondrial biogenesis and mtDNA levels. T cell receptor (TCR) activation results in a large increase in mitochondrial mass and membrane potential and a corresponding increase of mtDNA copy number, indicating the vital role for mitochondrial function for the growth and proliferation of these cells. Independent activation of protein kinase C (via PMA) or calcium-related pathways (via ionomycin) had differential and sub-maximal effects on these mitochondrial parameters, as did activation of naïve T cells with proliferative cytokines. Thus, the robust mitochondrial biogenesis response observed upon TCR activation requires synergy of multiple downstream signaling pathways. One such pathway involves AMP-activated protein kinase (AMPK), which we show has an unprecedented role in negatively regulating mitochondrial biogenesis that is mammalian target of rapamycin (mTOR)-dependent. That is, inhibition of AMPK after TCR signaling commences results in excessive, but uncoordinated mitochondrial proliferation. We propose that mitochondrial biogenesis is not under control of a master regulatory circuit, but rather requires the convergence of multiple signaling pathways with distinct downstream consequences on the organelle’s structure, composition, and function. PMID:17890163

  6. Drosophila cyclin D/Cdk4 regulates mitochondrial biogenesis and aging and sensitizes animals to hypoxic stress

    PubMed Central

    Icreverzi, Amalia; Flor de la Cruz, Aida; Van Voorhies, Wayne A

    2012-01-01

    Drosophila cyclin D (CycD) is the single fly ortholog of the mammalian cyclin D1 and promotes both cell cycle progression and cellular growth. However, little is known about how CycD promotes cell growth. We show here that CycD/Cdk4 hyperactivity leads to increased mitochondrial biogenesis (mitobiogenesis), mitochondrial mass, NRF-1 activity (Tfam transcript levels) and metabolic activity in Drosophila, whereas loss of CycD/Cdk4 activity has the opposite effects. Surprisingly, both CycD/Cdk4 addition and loss of function increase mitochondrial superoxide production and decrease lifespan, indicating that an imbalance in mitobiogenesis may lead to oxidative stress and aging. In addition, we provide multiple lines of evidence indicating that CycD/Cdk4 activity affects the hypoxic status of cells and sensitizes animals to hypoxia. Both mitochondrial and hypoxia-related effects can be detected at global transcriptional level. We propose that mitobiogenesis and the hypoxic stress response have an antagonistic relationship, and that CycD/Cdk4 levels regulate mitobiogenesis contemporaneous to the cell cycle, such that only when cells are sufficiently oxygenated can they proliferate. PMID:22293404

  7. The disulfide relay system of mitochondria is required for the biogenesis of mitochondrial Ccs1 and Sod1.

    PubMed

    Reddehase, Silvia; Grumbt, Barbara; Neupert, Walter; Hell, Kai

    2009-01-16

    Cells protect themselves against oxygen stress and reactive oxygen species. An important enzyme in this process is superoxide dismutase, Sod1, which converts superoxide radicals into water and hydrogen peroxide. The biogenesis of functional Sod1 is dependent on its copper chaperone, Ccs1, which introduces a disulfide bond and a copper ion into Sod1. Ccs1 and Sod1 are present in the cytosol but are also found in the mitochondrial intermembrane space (IMS), the compartment between the outer and the inner membrane of mitochondria. Ccs1 mediates mitochondrial localization of Sod1. Here, we report on the biogenesis of the fractions of Ccs1 and Sod1 present in mitochondria of Saccharomyces cerevisiae. The IMS of mitochondria harbors a disulfide relay system consisting of the import receptor Mia40 and the thiol oxidase Erv1, which drives the import of substrates with conserved cysteine residues arranged in typical twin Cx(3)C and twin Cx(9)C motifs. We show that depletion of Mia40 results in decreased levels of Ccs1 and Sod1. On the other hand, overexpression of Mia40 increased the mitochondrial fraction of both proteins. In addition, the import rates of Ccs1 were enhanced by increased levels of Mia40 and reduced upon depletion of Mia40. Mia40 forms mixed disulfides with Ccs1, suggesting a role of Mia40 for the generation of disulfide bonds in Ccs1. We suggest that the disulfide relay system transfers disulfide bonds via Mia40 to Ccs1, which then shuttles disulfide bonds to Sod1. In conclusion, the disulfide relay system is crucial for the import of Ccs1, thereby affecting the transport of Sod1, and it can control the distribution of Ccs1 and Sod1 between the IMS of mitochondria and the cytosol.

  8. Long-term physical exercise induces changes in sirtuin 1 pathway and oxidative parameters in adult rat tissues.

    PubMed

    Bayod, S; Del Valle, J; Lalanza, J F; Sanchez-Roige, S; de Luxán-Delgado, B; Coto-Montes, A; Canudas, A M; Camins, A; Escorihuela, R M; Pallàs, M

    2012-12-01

    The protein deacetylase, sirtuin 1, is suggested as a master regulator of exercise-induced beneficial effects. Sirtuin 1 modulates mitochondrial biogenesis, primarily via its ability to deacetylate and activate proliferator-activated receptor-γ coactivator-1α (PGC-1α), interacting with AMPK kinase. Redox cell status can also influence this regulatory axis and together they form an important convergence point in hormesis during the aging process. Here, we tested whether treadmill training (36weeks), as a paradigm of long-term moderate exercise, modifies the AMPK-sirtuin 1-PGC-1α axis and redox balance in rat gastrocnemius muscle, liver and heart. Physical activity induced increases in sirtuin 1 protein levels in all the aged rat tissues studied, as well as total PGC-1α levels. However, no changes in AMPK activation or significant differences in mitochondrial biogenesis (by measuring electron transport chain protein content) were found after exercise training. Parallel to these changes, we observed an improvement of oxidative stress defenses, mainly in muscle, with modification of the antioxidant enzyme machinery resulting in a reduction in lipid peroxidation and protein carbonylation. Thus, we demonstrate that moderate long-term exercise promotes tissue adaptations, increasing muscle, liver and heart sirtuin 1 protein content and activity and increasing PGC-1α protein expression. However, AMPK activation or mitochondrial biogenesis is not modified, but it cannot be discarded that its participation in the adaptive mechanism which prevents the development of the deleterious effects of age.

  9. Role of PGC-1α during acute exercise-induced autophagy and mitophagy in skeletal muscle

    PubMed Central

    Vainshtein, Anna; Tryon, Liam D.; Pauly, Marion

    2015-01-01

    Regular exercise leads to systemic metabolic benefits, which require remodeling of energy resources in skeletal muscle. During acute exercise, the increase in energy demands initiate mitochondrial biogenesis, orchestrated by the transcriptional coactivator peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α). Much less is known about the degradation of mitochondria following exercise, although new evidence implicates a cellular recycling mechanism, autophagy/mitophagy, in exercise-induced adaptations. How mitophagy is activated and what role PGC-1α plays in this process during exercise have yet to be evaluated. Thus we investigated autophagy/mitophagy in muscle immediately following an acute bout of exercise or 90 min following exercise in wild-type (WT) and PGC-1α knockout (KO) animals. Deletion of PGC-1α resulted in a 40% decrease in mitochondrial content, as well as a 25% decline in running performance, which was accompanied by severe acidosis in KO animals, indicating metabolic distress. Exercise induced significant increases in gene transcripts of various mitochondrial (e.g., cytochrome oxidase subunit IV and mitochondrial transcription factor A) and autophagy-related (e.g., p62 and light chain 3) genes in WT, but not KO, animals. Exercise also resulted in enhanced targeting of mitochondria for mitophagy, as well as increased autophagy and mitophagy flux, in WT animals. This effect was attenuated in the absence of PGC-1α. We also identified Niemann-Pick C1, a transmembrane protein involved in lysosomal lipid trafficking, as a target of PGC-1α that is induced with exercise. These results suggest that mitochondrial turnover is increased following exercise and that this effect is at least in part coordinated by PGC-1α. Anna Vainshtein received the AJP-Cell 2015 Paper of the Year award. Listen to a podcast with Anna Vainshtein and coauthor David A. Hood at http://ajpcell.podbean.com/e/ajp-cell-paper-of-the-year-2015-award-podcast/. PMID

  10. Interferon-stimulated gene ISG12b1 inhibits adipogenic differentiation and mitochondrial biogenesis in 3T3-L1 cells.

    PubMed

    Li, Bing; Shin, Jonghyun; Lee, Kichoon

    2009-03-01

    Microarray analysis was performed to find a new group of genes or pathways that might be important in adipocyte development and metabolism. Among them, a mouse interferon-stimulated gene 12b1 (ISG12b1) is expressed at a 400-fold higher level in adipocytes compared with stromal-vascular cells. It is predominantly expressed in adipose tissue among other tissues we tested. Developmentally, ISG12b1 mRNA expression was initially inhibited followed by a dramatic induction during both in vivo and in vitro adipogenic differentiation. Adenovirus-mediated overexpression of ISG12b1 inhibited adipogenic differentiation in 3T3-L1 cells as shown by decreased lipid staining with Oil-Red-O and reduction in adipogenic marker proteins including peroxisome proliferator-activated receptor-gamma (PPARgamma), and CCAAT/enhancer-binding protein-alpha (C/EBPalpha). Our bioinformatics analysis for the predicted localization of ISG12b1 protein suggested the mitochondrial localization, which was confirmed by the colocalization of hemagglutinin-tagged ISG12b1 protein with mitochondrial marker MitoTracker. In addition, ISG12b1 protein was exclusively detected in protein extract from the fractionated mitochondria by Western blot analysis. Furthermore, overexpression of ISG12b1 in adipocytes reduced mitochondrial DNA content and gene expression of mitochondrial transcription factor A (mtTFA), nuclear respiratory factor 1 (NRF1), and cytochrome oxidase II, suggesting an inhibitory role of ISG12b1 in mitochondrial biogenesis and function. Activation of mitochondrial biogenesis and function by treatment with PPARgamma and PPARalpha agonists in 3T3-L1 cells and cold exposure in mice induced mitochondrial transcription factors and reduced ISG12 expression. These data demonstrated that mitochondrial-localized ISG12b1 protein inhibits adipocyte differentiation and mitochondrial biogenesis and function, implying the important role of mitochondrial function in adipocyte development and associated

  11. Polyphenols decreased liver NADPH oxidase activity, increased muscle mitochondrial biogenesis and decreased gastrocnemius age-dependent autophagy in aged rats.

    PubMed

    Laurent, Caroline; Chabi, Beatrice; Fouret, Gilles; Py, Guillaume; Sairafi, Badie; Elong, Cecile; Gaillet, Sylvie; Cristol, Jean Paul; Coudray, Charles; Feillet-Coudray, Christine

    2012-09-01

    This study explored major systems of reactive oxygen species (ROS) production and their consequences on oxidative stress, mitochondriogenesis and muscle metabolism in aged rats, and evaluated the efficiency of 30-day oral supplementation with a moderate dose of a red grape polyphenol extract (RGPE) on these parameters. In the liver of aged rats, NADPH oxidase activity was increased and mitochondrial respiratory chain complex activities were altered, while xanthine oxidase activity remained unchanged. In muscles, only mitochondrial activity was modified with aging. The oral intake of RGPE decreased liver NADPH oxidase activity in the aged rats without affecting global oxidative stress, suggesting that NADPH oxidase was probably not the dominant detrimental source of production of O(2)·(-) in the liver. Interestingly, RGPE supplementation increased mitochondrial biogenesis and improved antioxidant status in the gastrocnemius of aged rats, while it had no significant effect in soleus. RGPE supplementation also decreased age-dependent autophagy in gastrocnemius of aged rats. These results extended existing findings on the beneficial effects of RGPE on mitochondriogenesis and muscle metabolism in aged rats.

  12. Protective Effects of Quercetin on Mitochondrial Biogenesis in Experimental Traumatic Brain Injury via the Nrf2 Signaling Pathway

    PubMed Central

    Li, Xiang; Wang, Handong; Gao, Yongyue; Li, Liwen; Tang, Chao; Wen, Guodao; Zhou, Yuan; Zhou, Mengliang; Mao, Lei; Fan, Youwu

    2016-01-01

    The present investigation was carried out to elucidate a possible molecular mechanism related to the protective effect of quercetin administration against oxidative stress on various mitochondrial respiratory complex subunits with special emphasis on the role of nuclear factor erythroid 2-related factor 2 (Nrf2) in mitochondrial biogenesis. Recently, quercetin has been proved to have a protective effect against mitochondria damage after traumatic brain injury (TBI). However, its precise role and underlying mechanisms in traumatic brain injury are not yet fully understood. The aim of the present study was to investigate the effect of quercetin on the potential mechanism of these effects in a weight-drop model of TBI in male mice that were treated with quercetin or vehicle via intraperitoneal injection administrated 30 min after TBI. In this experiment, ICR mice were divided into four groups: A sham group, TBI group, TBI + vehicle group, and TBI + quercetin group. Brain samples were collected 24 h later for analysis. Quercetin treatment resulted in an upregulation of Nrf2 expression and cytochrome c, malondialdehyde (MDA) and superoxide dismutase (SOD) levels were restored by quercetin treatment. Quercetin markedly promoted the translocation of Nrf2 protein from the cytoplasm to the nucleus. These observations suggest that quercetin improves mitochondrial function in TBI models, possibly by activating the Nrf2 pathway. PMID:27780244

  13. Protective Effects of Quercetin on Mitochondrial Biogenesis in Experimental Traumatic Brain Injury via the Nrf2 Signaling Pathway.

    PubMed

    Li, Xiang; Wang, Handong; Gao, Yongyue; Li, Liwen; Tang, Chao; Wen, Guodao; Zhou, Yuan; Zhou, Mengliang; Mao, Lei; Fan, Youwu

    2016-01-01

    The present investigation was carried out to elucidate a possible molecular mechanism related to the protective effect of quercetin administration against oxidative stress on various mitochondrial respiratory complex subunits with special emphasis on the role of nuclear factor erythroid 2-related factor 2 (Nrf2) in mitochondrial biogenesis. Recently, quercetin has been proved to have a protective effect against mitochondria damage after traumatic brain injury (TBI). However, its precise role and underlying mechanisms in traumatic brain injury are not yet fully understood. The aim of the present study was to investigate the effect of quercetin on the potential mechanism of these effects in a weight-drop model of TBI in male mice that were treated with quercetin or vehicle via intraperitoneal injection administrated 30 min after TBI. In this experiment, ICR mice were divided into four groups: A sham group, TBI group, TBI + vehicle group, and TBI + quercetin group. Brain samples were collected 24 h later for analysis. Quercetin treatment resulted in an upregulation of Nrf2 expression and cytochrome c, malondialdehyde (MDA) and superoxide dismutase (SOD) levels were restored by quercetin treatment. Quercetin markedly promoted the translocation of Nrf2 protein from the cytoplasm to the nucleus. These observations suggest that quercetin improves mitochondrial function in TBI models, possibly by activating the Nrf2 pathway.

  14. Mitochondrial biogenesis and increased uncoupling protein 1 in brown adipose tissue of mice fed a ketone ester diet

    PubMed Central

    Srivastava, Shireesh; Kashiwaya, Yoshihiro; King, M. Todd; Baxa, Ulrich; Tam, Joseph; Niu, Gang; Chen, Xiaoyuan; Clarke, Kieran; Veech, Richard L.

    2012-01-01

    We measured the effects of a diet in which d-β-hydroxybutyrate-(R)-1,3 butanediol monoester [ketone ester (KE)] replaced equicaloric amounts of carbohydrate on 8-wk-old male C57BL/6J mice. Diets contained equal amounts of fat, protein, and micronutrients. The KE group was fed ad libitum, whereas the control (Ctrl) mice were pair-fed to the KE group. Blood d-β-hydroxybutyrate levels in the KE group were 3-5 times those reported with high-fat ketogenic diets. Voluntary food intake was reduced dose dependently with the KE diet. Feeding the KE diet for up to 1 mo increased the number of mitochondria and doubled the electron transport chain proteins, uncoupling protein 1, and mitochondrial biogenesis-regulating proteins in the interscapular brown adipose tissue (IBAT). [18F]-Fluorodeoxyglucose uptake in IBAT of the KE group was twice that in IBAT of the Ctrl group. Plasma leptin levels of the KE group were more than 2-fold those of the Ctrl group and were associated with increased sympathetic nervous system activity to IBAT. The KE group exhibited 14% greater resting energy expenditure, but the total energy expenditure measured over a 24-h period or body weights was not different. The quantitative insulin-sensitivity check index was 73% higher in the KE group. These results identify KE as a potential antiobesity supplement.—Srivastava, S., Kashiwaya, Y., King, M. T. Baxa, U., Tam, J., Niu, G., Chen, X., Clarke, K., Veech, R. L. Mitochondrial biogenesis and increased uncoupling protein 1 in brown adipose tissue of mice fed a ketone ester diet. PMID:22362892

  15. Delta-9-tetrahydrocannabinol protects against MPP+ toxicity in SH-SY5Y cells by restoring proteins involved in mitochondrial biogenesis

    PubMed Central

    Zeissler, Marie-Louise; Eastwood, Jordan; McCorry, Kieran; Hanemann, C. Oliver; Zajicek, John P.; Carroll, Camille B.

    2016-01-01

    Proliferator-activated receptor γ (PPARγ) activation can result in transcription of proteins involved in oxidative stress defence and mitochondrial biogenesis which could rescue mitochondrial dysfunction in Parkinson's disease (PD). The PPARγ agonist pioglitazone is protective in models of PD; however side effects have limited its clinical use. The cannabinoid Δ9-tetrahydrocannabinol (Δ9-THC) may have PPARγ dependent anti-oxidant properties. Here we investigate the effects of Δ9-THC and pioglitazone on mitochondrial biogenesis and oxidative stress. Differentiated SH-SY5Y neuroblastoma cells were exposed to the PD relevant mitochondrial complex 1 inhibitor 1-methyl-4-phenylpyridinium iodide (MPP+). We found that only Δ9-THC was able to restore mitochondrial content in MPP+ treated SH-SY5Y cells in a PPARγ dependent manner by increasing expression of the PPARγ co-activator 1α (PGC-1α), the mitochondrial transcription factor (TFAM) as well as mitochondrial DNA content. Co-application of Δ9-THC with pioglitazone further increased the neuroprotection against MPP+ toxicity as compared to pioglitazone treatment alone. Furthermore, using lentiviral knock down of the PPARγ receptor we showed that, unlike pioglitazone, Δ9-THC resulted in a PPARγ dependent reduction of MPP+ induced oxidative stress. We therefore suggest that, in contrast to pioglitazone, Δ9-THC mediates neuroprotection via PPARγ-dependent restoration of mitochondrial content which may be beneficial for PD treatment. PMID:27366949

  16. Molecular Aspects of Exercise-induced Cardiac Remodeling.

    PubMed

    Bernardo, Bianca C; McMullen, Julie R

    2016-11-01

    Exercise-induced cardiac remodeling is typically an adaptive response associated with cardiac myocyte hypertrophy and renewal, increased cardiac myocyte contractility, sarcomeric remodeling, cell survival, metabolic and mitochondrial adaptations, electrical remodeling, and angiogenesis. Initiating stimuli/triggers of cardiac remodeling include increased hemodynamic load, increased sympathetic activity, and the release of hormones and growth factors. Prolonged and strenuous exercise may lead to maladaptive exercise-induced cardiac remodeling including cardiac dysfunction and arrhythmia. In addition, this article describes novel therapeutic approaches for the treatment of heart failure that target mechanisms responsible for adaptive exercise-induced cardiac remodeling, which are being developed and tested in preclinical models.

  17. Why translation counts for mitochondria - retrograde signalling links mitochondrial protein synthesis to mitochondrial biogenesis and cell proliferation.

    PubMed

    Battersby, Brendan J; Richter, Uwe

    2013-10-01

    Organelle biosynthesis is a key requirement for cell growth and division. The regulation of mitochondrial biosynthesis exhibits additional layers of complexity compared with that of other organelles because they contain their own genome and dedicated ribosomes. Maintaining these components requires gene expression to be coordinated between the nucleo-cytoplasmic compartment and mitochondria in order to monitor organelle homeostasis and to integrate the responses to the physiological and developmental demands of the cell. Surprisingly, the parameters that are used to monitor or count mitochondrial abundance are not known, nor are the signalling pathways. Inhibiting the translation on mito-ribosomes genetically or with antibiotics can impair cell proliferation and has been attributed to defects in aerobic energy metabolism, even though proliferating cells rely primarily on glycolysis to fuel their metabolic demands. However, a recent study indicates that mitochondrial translational stress and the rescue mechanisms that relieve this stress cause the defect in cell proliferation and occur before any impairment of oxidative phosphorylation. Therefore, the process of mitochondrial translation in itself appears to be an important checkpoint for the monitoring of mitochondrial homeostasis and might have a role in establishing mitochondrial abundance within a cell. This hypothesis article will explore the evidence supporting a role for mito-ribosomes and translation in a mitochondria-counting mechanism.

  18. Dietary wolfberry up-regulates carotenoid metabolic genes and enhances mitochondrial biogenesis in the retina of db/db diabetic mice

    PubMed Central

    Yu, Huifeng; Wark, Logan; Ji, Hua; Willard, Lloyd; Jaing, Yu; Han, Jing; He, Hui; Ortiz, Edlin; Zhang, Yunong; Medeiros, Denis M; Lin, Dingbo

    2013-01-01

    Scope Our aim was to investigate whether dietary wolfberry altered carotenoid metabolic gene expression and enhanced mitochondrial biogenesis in the retina of diabetic mice. Methods and Results Six-week-old male db/db and wild type mice were fed the control or wolfberry diets for 8 weeks. At study termination, liver and retinal tissues were collected for analysis by transmission electron microscopy, real-time PCR, immunoprecipitation, Western blot, and HPLC. Wolfberry elevated zeaxanthin and lutein levels in the liver and retinal tissues and stimulated expression of retinal scavenger receptor class B type I, glutathione S-transferase Pi 1, and β,β-carotene 9’,10’-oxygenase 2, and induced activation and nuclear enrichment of retinal AMP-activated protein kinase α2 (AMPKα2). Furthermore, wolfberry attenuated hypoxia and mitochondrial stress as demonstrated by declined expression of hypoxia-inducible factor-1α, vascular endothelial growth factor, and heat shock protein 60. Wolfberry enhanced retinal mitochondrial biogenesis in diabetic retinas as demonstrated by reversed mitochondrial dispersion in the retinal pigment epithelium, increased mitochondrial copy number, elevated citrate synthase activity, and up-regulated expression of peroxisome proliferator-activated receptor γ co-activator 1 α, nuclear respiratory factor 1, and mitochondrial transcription factor A. Conclusion Consumption of dietary wolfberry could be beneficial to retinoprotection through reversal of mitochondrial function in diabetic mice. PMID:23505020

  19. Antioxidant supplementation enhances the exercise-induced increase in mitochondrial uncoupling protein 3 and endothelial nitric oxide synthase mRNA content in human skeletal muscle.

    PubMed

    Hellsten, Ylva; Nielsen, Jens J; Lykkesfeldt, Jens; Bruhn, Maria; Silveira, Leonardo; Pilegaard, Henriette; Bangsbo, Jens

    2007-08-01

    The effects of acute exercise on the mRNA content of selected genes were examined during control conditions and after oral intake of antioxidants. In addition, to provide evidence for formation of reactive oxygen species (ROS) in human skeletal muscle during exercise, cytochrome c reduction was measured in microdialysate from the muscle. For the study on the effects of antioxidants on mRNA content, seven healthy, habitually active, male subjects participated in a double-blinded experimental design in which they, on one occasion, received a placebo and, on another, a mixture of antioxidants containing 1500 mg vitamin C, 120 mg coenzyme Q, and 345 mg alpha-tocopherol every day for 7 days before the experiment. On the experimental day the subjects cycled for 90 min and muscle biopsies were taken preexercise and at 1, 3, and 5 h after exercise. Exercise induced an increase in the eNOS, UCP3, PGC-1alpha, VEGF, Hsp72, and HO-1 mRNA content (p < 0.001), whereas there was no change in the Hsc70 mRNA level. Prior antioxidant treatment further enhanced (p < 0.05) the eNOS and UCP3 mRNA content after exercise. Moreover, the overall level of Hsc70 mRNA tended (p = 0.07) to be higher after antioxidant treatment. In another group of healthy male subjects, cytochrome c reduction was determined in microdialysate from the thigh muscle at rest and during knee extensor exercise to determine ROS formation. There was a significant increase in cytochrome c reduction with exercise both at 14 ( approximately 25%) and at 30 W ( approximately 50%). The data show that ROS are formed within skeletal muscle during exercise and that oral intake of antioxidants can enhance the exercise-induced adaptive mRNA responses of eNOS and UCP3.

  20. Mitofusin 2 Deficiency Affects Energy Metabolism and Mitochondrial Biogenesis in MEF Cells.

    PubMed

    Kawalec, Maria; Boratyńska-Jasińska, Anna; Beręsewicz, Małgorzata; Dymkowska, Dorota; Zabłocki, Krzysztof; Zabłocka, Barbara

    2015-01-01

    Mitofusin 2 (Mfn2), mitochondrial outer membrane protein which is involved in rearrangement of these organelles, was first described in pathology of hypertension and diabetes, and more recently much attention is paid to its functions in Charcot-Marie-Tooth type 2A neuropathy (CMT2A). Here, cellular energy metabolism was investigated in mouse embryonic fibroblasts (MEF) differing in the presence of the Mfn2 gene; control (MEFwt) and with Mfn2 gene depleted MEFMfn2-/-. These two cell lines were compared in terms of various parameters characterizing mitochondrial bioenergetics. Here, we have shown that relative rate of proliferation of MEFMfn2-/- cells versus control fibroblasts depend on serum supplementation of the growth media. Moreover, MEFMfn2-/- cells exhibited significantly increased respiration rate in comparison to MEFwt, regardless of serum supplementation of the medium. This effect was correlated with increased level of mitochondrial markers (TOM20 and NAO) as well as mitochondrial transcription factor A (TFAM) and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) protein levels and unchanged total ATP content. Interestingly, mitochondrial DNA content in MEFMfn2-/- cells was not reduced. Fundamentally, these results are in contrast to a commonly accepted belief that mitofusin 2 deficiency inevitably results in debilitation of mitochondrial energy metabolism. However, we suggest a balance between negative metabolic consequences of mitofusin 2 deficiency and adaptive processes exemplified by increased level of PGC-1α and TFAM transcription factor which prevent an excessive depletion of mtDNA and severe impairment of cell metabolism.

  1. trans-Cinnamaldehyde stimulates mitochondrial biogenesis through PGC-1α and PPARβ/δ leading to enhanced GLUT4 expression.

    PubMed

    Gannon, Nicholas P; Schnuck, Jamie K; Mermier, Christine M; Conn, Carole A; Vaughan, Roger A

    2015-12-01

    Type 2 diabetes is characterized by insulin resistance and chronic hyperglycemia, and is increasing in incidence and severity. This work explored the effects of trans-cinnamaldehyde (CA) on carbohydrate metabolism, mitochondrial content, and related metabolic gene and protein expression in cultured myotubes treated with various concentrations of CA for up to 24 h. CA treatment increased myotube myocyte enhancer factor 2 (MEF2) along with glucose transporter 4 (GLUT4) content. CA treatment also significantly increased expression of markers of improved oxidative metabolism including 5' adenosine monophosphate-activated protein kinase (AMPK), peroxisome proliferator-activated receptor γ coactivator 1 α (PGC-1α), cytochrome c (CytC), as well as peroxisome proliferator-activated receptor α (PPARα) and PPARβ/δ. Despite increased expression of proteins associated with improved oxidative metabolism and glucose uptake, CA-treated myotubes exhibited significantly reduced oxidative metabolism compared with controlled cells. Additionally, CA treatment increased markers of glucose-mediated lipid biosynthesis without elevated PPARγ and sterol receptor element binding protein 1c (SREBP-1c) expression. The ability of CA to stimulate mitochondrial biogenesis and GLUT4 expression suggests CA may offer possible benefits for metabolic disease. However, increases in markers of fatty acid synthesis with simultaneously reduced oxidative metabolism suggest CA may have counterproductive effects for metabolic disease, warranting a need for further investigation.

  2. HIV and Cocaine Impact Glial Metabolism: Energy Sensor AMP-activated protein kinase Role in Mitochondrial Biogenesis and Epigenetic Remodeling

    PubMed Central

    Samikkannu, Thangavel; Atluri, Venkata S. R.; Nair, Madhavan P. N.

    2016-01-01

    HIV infection and cocaine use have been identified as risk factors for triggering neuronal dysfunction. In the central nervous system (CNS), energy resource and metabolic function are regulated by astroglia. Glia is the major reservoir of HIV infection and disease progression in CNS. However, the role of cocaine in accelerating HIV associated energy deficit and its impact on neuronal dysfunction has not been elucidated yet. The aim of this study is to elucidate the molecular mechanism of HIV associated neuropathogenesis in cocaine abuse and how it accelerates the energy sensor AMPKs and its subsequent effect on mitochondrial oxidative phosphorylation (OXPHOS), BRSKs, CDC25B/C, MAP/Tau, Wee1 and epigenetics remodeling complex SWI/SNF. Results showed that cocaine exposure during HIV infection significantly increased the level of p24, reactive oxygen species (ROS), ATP-utilization and upregulated energy sensor AMPKs, CDC25B/C, MAP/Tau and Wee1 protein expression. Increased ROS production subsequently inhibits OCR/ECAR ratio and OXPHOS, and eventually upregulate epigenetics remodeling complex SWI/SNF in CHME-5 cells. These results suggest that HIV infection induced energy deficit and metabolic dysfunction is accelerated by cocaine inducing energy sensor AMPKs, mitochondrial biogenesis and chromatin remodeling complex SWI/SNF activation, which may lead to neuroAIDS disease progression. PMID:27535703

  3. Ammonium Chloride Ingestion Attenuates Exercise-Induced mRNA Levels in Human Muscle

    PubMed Central

    Mündel, Toby; Pilegaard, Henriette; Hawke, Emma; Leikis, Murray; Lopez-Villalobos, Nicolas; Oliveira, Rodrigo S. F.; Bishop, David J.

    2015-01-01

    Minimizing the decrease in intracellular pH during high-intensity exercise training promotes greater improvements in mitochondrial respiration. This raises the intriguing hypothesis that pH may affect the exercise-induced transcription of genes that regulate mitochondrial biogenesis. Eight males performed 10x2-min cycle intervals at 80% V˙O2peak intensity on two occasions separated by ~2 weeks. Participants ingested either ammonium chloride (ACID) or calcium carbonate (PLA) the day before and on the day of the exercise trial in a randomized, counterbalanced order, using a crossover design. Biopsies were taken from the vastus lateralis muscle before and after exercise. The mRNA level of peroxisome proliferator-activated receptor co-activator 1α (PGC-1α), citrate synthase, cytochome c and FOXO1 was elevated at rest following ACID (P<0.05). During the PLA condition, the mRNA content of mitochondrial- and glucose-regulating proteins was elevated immediately following exercise (P<0.05). In the early phase (0–2 h) of post-exercise recovery during ACID, PGC-1α, citrate synthase, cytochome C, FOXO1, GLUT4, and HKII mRNA levels were not different from resting levels (P>0.05); the difference in PGC-1α mRNA content 2 h post-exercise between ACID and PLA was not significant (P = 0.08). Thus, metabolic acidosis abolished the early post-exercise increase of PGC-1α mRNA and the mRNA of downstream mitochondrial and glucose-regulating proteins. These findings indicate that metabolic acidosis may affect mitochondrial biogenesis, with divergent responses in resting and post-exercise skeletal muscle. PMID:26656911

  4. MicroRNA-149 inhibits PARP-2 and promotes mitochondrial biogenesis via SIRT-1/PGC-1α network in skeletal muscle.

    PubMed

    Mohamed, Junaith S; Hajira, Ameena; Pardo, Patricia S; Boriek, Aladin M

    2014-05-01

    High-fat diet (HFD) plays a central role in the initiation of mitochondrial dysfunction that significantly contributes to skeletal muscle metabolic disorders in obesity. However, the mechanism by which HFD weakens skeletal muscle metabolism by altering mitochondrial function and biogenesis is unknown. Given the emerging roles of microRNAs (miRNAs) in the regulation of skeletal muscle metabolism, we sought to determine whether activation of a specific miRNA pathway would rescue the HFD-induced mitochondrial dysfunction via the sirtuin-1 (SIRT-1)/ peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) pathway, a pathway that governs genes necessary for mitochondrial function. We here report that miR-149 strongly controls SIRT-1 expression and activity. Interestingly, miR-149 inhibits poly(ADP-ribose) polymerase-2 (PARP-2) and so increased cellular NAD(+) levels and SIRT-1 activity that subsequently increases mitochondrial function and biogenesis via PGC-1α activation. In addition, skeletal muscles from HFD-fed obese mice exhibit low levels of miR-149 and high levels of PARP-2, and they show reduced mitochondrial function and biogenesis due to a decreased activation of the SIRT-1/PGC-1α pathway, suggesting that mitochondrial dysfunction in the skeletal muscle of obese mice may be because of, at least in part, miR-149 dysregulation. Overall, miR-149 may be therapeutically useful for treating HFD-induced skeletal muscle metabolic disorders in such pathophysiological conditions as obesity and type 2 diabetes.

  5. Leucine stimulates PPARβ/δ-dependent mitochondrial biogenesis and oxidative metabolism with enhanced GLUT4 content and glucose uptake in myotubes.

    PubMed

    Schnuck, Jamie K; Sunderland, Kyle L; Gannon, Nicholas P; Kuennen, Matthew R; Vaughan, Roger A

    2016-01-01

    Leucine stimulates anabolic and catabolic processes in skeletal muscle, however little is known about the effects of leucine on peroxisome proliferator-activated receptor (PPAR) activity. This work characterized the effects of 24-h leucine treatment on metabolic parameters and protein expression in cultured myotubes. Leucine significantly increased PPARβ/δ expression as well as markers of mitochondrial biogenesis, leading to significantly increased mitochondrial content and oxidative metabolism in a PPARβ/δ-dependent manner. However, leucine-treated cells did not display significant alterations in uncoupling protein expression or oxygen consumed per relative mitochondrial content suggesting leucine-mediated increases in oxidative metabolism are a function of increased mitochondrial content and not altered mitochondrial efficiency. Leucine treatment also increased GLUT4 content and glucose uptake as well as PPARγ and FAS expression leading to increased total lipid content. Leucine appears to activate PPAR activity leading to increased mitochondrial biogenesis and elevated substrate oxidation, while simultaneously promoting substrate/lipid storage and protein synthesis.

  6. Elevated mitochondrial oxidative stress impairs metabolic adaptations to exercise in skeletal muscle.

    PubMed

    Crane, Justin D; Abadi, Arkan; Hettinga, Bart P; Ogborn, Daniel I; MacNeil, Lauren G; Steinberg, Gregory R; Tarnopolsky, Mark A

    2013-01-01

    Mitochondrial oxidative stress is a complex phenomenon that is inherently tied to energy provision and is implicated in many metabolic disorders. Exercise training increases mitochondrial oxidative capacity in skeletal muscle yet it remains unclear if oxidative stress plays a role in regulating these adaptations. We demonstrate that the chronic elevation in mitochondrial oxidative stress present in Sod2 (+/-) mice impairs the functional and biochemical mitochondrial adaptations to exercise. Following exercise training Sod2 (+/-) mice fail to increase maximal work capacity, mitochondrial enzyme activity and mtDNA copy number, despite a normal augmentation of mitochondrial proteins. Additionally, exercised Sod2 (+/-) mice cannot compensate for their higher amount of basal mitochondrial oxidative damage and exhibit poor electron transport chain complex assembly that accounts for their compromised adaptation. Overall, these results demonstrate that chronic skeletal muscle mitochondrial oxidative stress does not impact exercise induced mitochondrial biogenesis, but impairs the resulting mitochondrial protein function and can limit metabolic plasticity.

  7. Adenosine Monophosphate-Activated Protein Kinase Abates Hyperglycaemia-Induced Neuronal Injury in Experimental Models of Diabetic Neuropathy: Effects on Mitochondrial Biogenesis, Autophagy and Neuroinflammation.

    PubMed

    Yerra, Veera Ganesh; Kumar, Ashutosh

    2017-04-01

    Impaired adenosine monophosphate kinase (AMPK) signalling under hyperglycaemic conditions is known to cause mitochondrial dysfunction in diabetic sensory neurons. Facilitation of AMPK signalling is previously reported to ameliorate inflammation and induce autophagic response in various complications related to diabetes. The present study assesses the role of AMPK activation on mitochondrial biogenesis, autophagy and neuroinflammation in experimental diabetic neuropathy (DN) using an AMPK activator (A769662). A769662 (15 and 30 mg/kg, i.p) was administered to Sprague-Dawley rats (250-270 g) for 2 weeks after 6 weeks of streptozotocin (STZ) injection (55 mg/kg, i.p.). Behavioural parameters (mechanical/thermal hyperalgesia) and functional characteristics (motor/sensory nerve conduction velocities (MNCV and SNCV) and sciatic nerve blood flow (NBF)) were assessed. For in vitro studies, Neuro2a (N2A) cells were incubated with 25 mM glucose to simulate high glucose condition and then studied for mitochondrial dysfunction and protein expression changes. STZ administration resulted in significant hyperglycaemia (>250 mg/dl) in rats. A769662 treatment significantly improved mechanical/thermal hyperalgesia threshold and enhanced MNCV, SNCV and NBF in diabetic animals. A769662 exposure normalised the mitochondrial superoxide production, membrane depolarisation and markedly increased neurite outgrowth of N2A cells. Further, AMPK activation also abolished the NF-κB-mediated neuroinflammation. A769662 treatment increased Thr-172 phosphorylation of AMPK results in stimulated PGC-1α-directed mitochondrial biogenesis and autophagy induction. Our study supports that compromised AMPK signalling in hyperglycaemic conditions causes defective mitochondrial biogenesis ultimately leading to neuronal dysfunction and associated deficits in DN and activation of AMPK can be developed as an attractive therapeutic strategy for the management of DN.

  8. Chronic electrical stimulation drives mitochondrial biogenesis in skeletal muscle of a lizard, Varanus exanthematicus.

    PubMed

    Schaeffer, Paul J; Nichols, Scott D; Lindstedt, Stan L

    2007-10-01

    We investigated the capacity for phenotypic plasticity of skeletal muscle from Varanus exanthematicus, the savannah monitor lizard. Iliofibularis muscle from one leg of each lizard was electrically stimulated for 8 weeks. Both stimulated and contralateral control muscles were collected and processed for electron microscopy. We used stereological analysis of muscle cross-sections to quantify the volume densities of contractile elements, sarcoplasmic reticulum, mitochondria and intracellular lipids. We found that mitochondrial volume density was approximately fourfold higher in the stimulated muscle compared to controls, which were similar to previously reported values. Sarcoplasmic reticulum volume density was reduced by an amount similar to the increase in mitochondrial volume density while the volume density of contractile elements remained unchanged. Intracellular lipid accumulation was visibly apparent in many stimulated muscle sections but the volume density of lipids did not reach a significant difference. Although monitor lizards lack the highly developed aerobic metabolism of mammals, they appear to possess the capacity for muscle plasticity.

  9. Green tea polyphenols stimulate mitochondrial biogenesis and improve renal function after chronic cyclosporin a treatment in rats.

    PubMed

    Rehman, Hasibur; Krishnasamy, Yasodha; Haque, Khujista; Thurman, Ronald G; Lemasters, John J; Schnellmann, Rick G; Zhong, Zhi

    2014-01-01

    Our previous studies showed that an extract from Camellia sinenesis (green tea), which contains several polyphenols, attenuates nephrotoxicity caused by cyclosporine A (CsA). Since polyphenols are stimulators of mitochondrial biogenesis (MB), this study investigated whether stimulation of MB plays a role in green tea polyphenol protection against CsA renal toxicity. Rats were fed a powdered diet containing green tea polyphenolic extract (0.1%) starting 3 days prior to CsA treatment (25 mg/kg, i.g. daily for 3 weeks). CsA alone decreased renal nuclear DNA-encoded oxidative phosphorylation (OXPHOS) protein ATP synthase-β (AS-β) by 42%, mitochondrial DNA (mtDNA)-encoded OXPHOS protein NADH dehydrogenase-3 (ND3) by 87% and their associated mRNAs. Mitochondrial DNA copy number was also decreased by 78% by CsA. Immunohistochemical analysis showed decreased cytochrome c oxidase subunit IV (COX-IV), an OXPHOS protein, in tubular cells. Peroxisome proliferator-activated receptor-γ coactivator (PGC)-1α, the master regulator of MB, and mitochondrial transcription factor-A (Tfam), the transcription factor that regulates mtDNA replication and transcription, were 42% and 90% lower, respectively, in the kidneys of CsA-treated than in untreated rats. These results indicate suppression of MB by chronic CsA treatment. Green tea polyphenols alone and following CsA increased AS-β, ND3, COX-IV, mtDNA copy number, PGC-1α mRNA and protein, decreased acetylated PGC-1α, and increased Tfam mRNA and protein. In association with suppressed MB, CsA increased serum creatinine, caused loss of brush border and dilatation of proximal tubules, tubular atrophy, vacuolization, apoptosis, calcification, and increased neutrophil gelatinase-associated lipocalin expression, leukocyte infiltration, and renal fibrosis. Green tea polyphenols markedly attenuated CsA-induced renal injury and improved renal function. Together, these results demonstrate that green tea polyphenols attenuate Cs

  10. The TDH-GCN5L1-Fbxo15-KBP axis limits mitochondrial biogenesis in mouse embryonic stem cells.

    PubMed

    Donato, Valerio; Bonora, Massimo; Simoneschi, Daniele; Sartini, Davide; Kudo, Yasusei; Saraf, Anita; Florens, Laurence; Washburn, Michael P; Stadtfeld, Matthias; Pinton, Paolo; Pagano, Michele

    2017-03-20

    Self-renewing naive mouse embryonic stem cells (mESCs) contain few mitochondria, which increase in number and volume at the onset of differentiation. KBP (encoded by Kif1bp) is an interactor of the mitochondrial-associated kinesin Kif1Bα. We found that TDH, responsible for mitochondrial production of acetyl-CoA in mESCs, and the acetyltransferase GCN5L1 cooperate to acetylate Lys501 in KBP, allowing its recognition by and degradation via Fbxo15, an F-box protein transcriptionally controlled by the pluripotency core factors and repressed following differentiation. Defects in KBP degradation in mESCs result in an unscheduled increase in mitochondrial biogenesis, enhanced respiration and ROS production, and inhibition of cell proliferation. Silencing of Kif1Bα reverts the aberrant increase in mitochondria induced by KBP stabilization. Notably, following differentiation, Kif1bp(-/-) mESCs display impaired expansion of the mitochondrial mass and form smaller embryoid bodies. Thus, KBP proteolysis limits the accumulation of mitochondria in mESCs to preserve their optimal fitness, whereas KBP accumulation promotes mitochondrial biogenesis in differentiating cells.

  11. The IMMUTANS variegation locus of Arabidopsis defines a mitochondrial alternative oxidase homolog that functions during early chloroplast biogenesis.

    PubMed Central

    Wu, D; Wright, D A; Wetzel, C; Voytas, D F; Rodermel, S

    1999-01-01

    Nuclear gene-induced variegation mutants provide a powerful system to dissect interactions between the genetic systems of the nucleus-cytoplasm, the chloroplast, and the mitochondrion. The immutans (im) variegation mutation of Arabidopsis is nuclear and recessive and results in the production of green- and white-sectored leaves. The green sectors contain cells with normal chloroplasts, whereas the white sectors are heteroplastidic and contain cells with abnormal, pigment-deficient plastids as well as some normal chloroplasts. White sector formation can be promoted by enhanced light intensities, but sectoring becomes irreversible early in leaf development. The white sectors accumulate the carotenoid precursor phytoene. We have positionally cloned IM and found that the gene encodes a 40.5-kD protein with sequence motifs characteristic of alternative oxidase, a mitochondrial protein that functions as a terminal oxidase in the respiratory chains of all plants. However, phylogenetic analyses revealed that the IM protein is only distantly related to these other alternative oxidases, suggesting that IM is a novel member of this protein class. We sequenced three alleles of im, and all are predicted to be null. Our data suggest a model of variegation in which the IM protein functions early in chloroplast biogenesis as a component of a redox chain responsible for phytoene desaturation but that a redundant electron transfer function is capable of compensating for IM activity in some plastids and cells. PMID:9878631

  12. Mitochondrial biogenesis and increased uncoupling protein 1 in brown adipose tissue of mice fed a ketone ester diet.

    PubMed

    Srivastava, Shireesh; Kashiwaya, Yoshihiro; King, M Todd; Baxa, Ulrich; Tam, Joseph; Niu, Gang; Chen, Xiaoyuan; Clarke, Kieran; Veech, Richard L

    2012-06-01

    We measured the effects of a diet in which D-β-hydroxybutyrate-(R)-1,3 butanediol monoester [ketone ester (KE)] replaced equicaloric amounts of carbohydrate on 8-wk-old male C57BL/6J mice. Diets contained equal amounts of fat, protein, and micronutrients. The KE group was fed ad libitum, whereas the control (Ctrl) mice were pair-fed to the KE group. Blood d-β-hydroxybutyrate levels in the KE group were 3-5 times those reported with high-fat ketogenic diets. Voluntary food intake was reduced dose dependently with the KE diet. Feeding the KE diet for up to 1 mo increased the number of mitochondria and doubled the electron transport chain proteins, uncoupling protein 1, and mitochondrial biogenesis-regulating proteins in the interscapular brown adipose tissue (IBAT). [(18)F]-Fluorodeoxyglucose uptake in IBAT of the KE group was twice that in IBAT of the Ctrl group. Plasma leptin levels of the KE group were more than 2-fold those of the Ctrl group and were associated with increased sympathetic nervous system activity to IBAT. The KE group exhibited 14% greater resting energy expenditure, but the total energy expenditure measured over a 24-h period or body weights was not different. The quantitative insulin-sensitivity check index was 73% higher in the KE group. These results identify KE as a potential antiobesity supplement.

  13. Decreased ovarian reserve, dysregulation of mitochondrial biogenesis, and increased lipid peroxidation in female mouse offspring exposed to an obesogenic maternal diet.

    PubMed

    Aiken, Catherine E; Tarry-Adkins, Jane L; Penfold, Naomi C; Dearden, Laura; Ozanne, Susan E

    2016-04-01

    Maternal diet during pregnancy influences the later life reproductive potential of female offspring. We investigate the molecular mechanisms underlying the depletion of ovarian follicular reserve in young adult females following exposure to obesogenic diet in early life. Furthermore, we explore the interaction between adverse maternal diet and postweaning diet in generating reduced ovarian reserve. Female mice were exposed to either maternal obesogenic (high fat/high sugar) or maternal control dietin uteroand during lactation, then weaned onto either obesogenic or control diet. At 12 wk of age, the offspring ovarian reserve was depleted following exposure to maternal obesogenic diet (P< 0.05), but not postweaning obesogenic diet. Maternal obesogenic diet was associated with increased mitochondrial DNA biogenesis (copy numberP< 0.05; transcription factor A, mitochondrial expressionP< 0.05), increased mitochondrial antioxidant defenses [manganese superoxide dismutase (MnSOD)P< 0.05; copper/zinc superoxide dismutaseP< 0.05; glutathione peroxidase 4P< 0.01] and increased lipoxygenase expression (arachidonate 12-lipoxygenaseP< 0.05; arachidonate 15-lipoxygenaseP< 0.05) in the ovary. There was also significantly increased expression of the transcriptional regulator NF-κB (P< 0.05). There was no effect of postweaning diet on any measured ovarian parameters. Maternal diet thus plays a central role in determining follicular reserve in adult female offspring. Our observations suggest that lipid peroxidation and mitochondrial biogenesis are the key intracellular pathways involved in programming of ovarian reserve.-Aiken, C. E., Tarry-Adkins, J. L., Penfold, N. C., Dearden, L., Ozanne, S. E. Decreased ovarian reserve, dysregulation of mitochondrial biogenesis, and increased lipid peroxidation in female mouse offspring exposed to an obesogenic maternal diet.

  14. Quercetin induces mitochondrial biogenesis in experimental traumatic brain injury via the PGC-1α signaling pathway

    PubMed Central

    Li, Xiang; Wang, Handong; Gao, Yongyue; Li, Liwen; Tang, Chao; Wen, Guodao; Yang, Youqing; Zhuang, Zong; Zhou, Mengliang; Mao, Lei; Fan, Youwu

    2016-01-01

    Quercetin, a dietary flavonoid used as a food supplement, has been found to have protective effect against mitochondria damage after traumatic brain injury (TBI) in mice. However, the mechanisms underlying these effects are still not well understood. The aim of the present study was to investigate the effect of quercetin on the potential mechanism mediating these effects in the weight-drop model of TBI in male mice that were treated with quercetin or vehicle via intraperitoneal injection administration 30 min after TBI. Brain samples were collected 24 h later for analysis. Quercetin treatment upregulated the expression of PGC-1α and restored the level of cytochrome c, malondialdehyde (MDA) and superoxide dismutase (SOD). These results demonstrate that quercetin improves mitochondrial function in mice by improving the level of PGC-1α following TBI. PMID:27648146

  15. Quercetin induces mitochondrial biogenesis in experimental traumatic brain injury via the PGC-1α signaling pathway.

    PubMed

    Li, Xiang; Wang, Handong; Gao, Yongyue; Li, Liwen; Tang, Chao; Wen, Guodao; Yang, Youqing; Zhuang, Zong; Zhou, Mengliang; Mao, Lei; Fan, Youwu

    2016-01-01

    Quercetin, a dietary flavonoid used as a food supplement, has been found to have protective effect against mitochondria damage after traumatic brain injury (TBI) in mice. However, the mechanisms underlying these effects are still not well understood. The aim of the present study was to investigate the effect of quercetin on the potential mechanism mediating these effects in the weight-drop model of TBI in male mice that were treated with quercetin or vehicle via intraperitoneal injection administration 30 min after TBI. Brain samples were collected 24 h later for analysis. Quercetin treatment upregulated the expression of PGC-1α and restored the level of cytochrome c, malondialdehyde (MDA) and superoxide dismutase (SOD). These results demonstrate that quercetin improves mitochondrial function in mice by improving the level of PGC-1α following TBI.

  16. [Exercise-induced anaphylaxis].

    PubMed

    Gani, Federica; Selvaggi, Lucia; Roagna, Davide

    2008-01-01

    Exercise-induced anaphylaxis (EIA) was defined for the first time in 1980. EIA is associated with different kind of exercise, although jogging is the most frequently reported. The clinical manifestations progress from itching, erythema and urticaria to some combination of cutaneous angioedema, gastrointestinal and laryngeal symptoms and signs of angioedema and vascular collapse. Mast cell participation in the pathogenesis of this syndrome has been proved by the finding of an elevated serum histamine level during experimentally-induced attacks and by cutaneous degranulation of mast cells with elevated serum tryptase after attacks. As predisposing factors of EIA, a specific or even aspecific sensitivity to food has been reported and such cases are called "food-dependent EIA". Many foods are implicated but particularly wheat, vegetables, crustacean. Another precipitating factor includes drugs intake (non steroidal anti-inflammatory drugs), climate variations and menstrual cycle factors. Treatment of an attack should include all the manoeuvres efficacious in the management of conventional anaphylactic syndrome, including the administration of epinephrine and antihistamines. Prevention of the attacks may be achieved with the interruption of the exercise at the appearance of the first premonitory symptoms. To prevent the onset of EIA it is also suitable to delay the exercise practice after at least 4-6 hours from the swallowing of food.

  17. The role of calcium and calcium/calmodulin-dependent kinases in skeletal muscle plasticity and mitochondrial biogenesis.

    PubMed

    Chin, Eva R

    2004-05-01

    Intracellular Ca(2+) plays an important role in skeletal muscle excitation-contraction coupling and also in excitation-transcription coupling. Activity-dependent alterations in muscle gene expression as a result of increased load (i.e. resistance or endurance training) or decreased activity (i.e. immobilization or injury) are tightly linked to the level of muscle excitation. Differential expression of genes in slow- and fast-twitch fibres is also dependent on fibre activation. Both these biological phenomena are, therefore, tightly linked to the amplitude and duration of the Ca(2+) transient, a signal decoded downstream by Ca(2+)-dependent transcriptional pathways. Evidence is mounting that the calcineurin-nuclear factor of activated T-cells pathway and the Ca(2+)/calmodulin-dependent kinases (CaMK) II and IV play important roles in regulating oxidative enzyme expression, mitochondrial biogenesis and expression of fibre-type specific myofibrillar proteins. CaMKII is known to decode frequency-dependent information and is activated during hypertrophic growth and endurance adaptations. Thus, it was hypothesized that CaMKII, and possibly CaMKIV, are down regulated during muscle atrophy and levels of expression of CaMKII alpha, -II beta, -II gamma and -IV were assessed in skeletal muscles from young, aged and denervated rats. The results indicate that CaMKII gamma, but not CaMKIIalpha or -beta, is up regulated in aged and denervated soleus muscle and that CaMKIV is absent in skeletal but not cardiac muscle. Whether CaMKII gamma up-regulation is part of the pathology of wasting or a result of some adaptational response to atrophy is not known. Future studies will be important in determining whether insights from the adaptational response of muscle to increased loads will provide pharmacological approaches for increasing muscle strength or endurance to counter muscle wasting.

  18. Effects of dietary leucine supplementation on the hepatic mitochondrial biogenesis and energy metabolism in normal birth weight and intrauterine growth-retarded weanling piglets

    PubMed Central

    Su, Weipeng; Xu, Wen; Zhang, Hao; Ying, Zhixiong; Zhou, Le; Zhang, Lili

    2017-01-01

    BACKGROUND/OBJECTIVES The study was conducted to evaluate the effects of dietary leucine supplementation on mitochondrial biogenesis and energy metabolism in the liver of normal birth weight (NBW) and intrauterine growth-retarded (IUGR) weanling piglets. MATERIALS/METHODS A total of sixteen pairs of NBW and IUGR piglets from sixteen sows were selected according to their birth weight. At postnatal day 14, all piglets were weaned and fed either a control diet or a leucine-supplemented diet for 21 d. Thereafter, a 2 × 2 factorial experimental design was used. Each treatment consisted of eight replications with one piglet per replication. RESULTS Compared with NBW piglets, IUGR piglets had a decreased (P < 0.05) hepatic adenosine triphosphate (ATP) content. Also, IUGR piglets exhibited reductions (P < 0.05) in the activities of hepatic mitochondrial pyruvate dehydrogenase (PDH), citrate synthase (CS), α-ketoglutarate dehydrogenase (α-KGDH), malate dehydrogenase (MDH), and complexes I and V, along with decreases (P < 0.05) in the concentration of mitochondrial DNA (mtDNA) and the protein expression of hepatic peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α). Dietary leucine supplementation increased (P < 0.05) the content of ATP, and the activities of CS, α-KGDH, MDH, and complex V in the liver of piglets. Furthermore, compared to those fed a control diet, piglets given a leucine-supplemented diet exhibited increases (P < 0.05) in the mtDNA content and in the mRNA expressions of sirtuin 1, PGC-1α, nuclear respiratory factor 1, mitochondrial transcription factor A, and ATP synthase, H+ transporting, mitochondrial F1 complex, β polypeptide in liver. CONCLUSIONS Dietary leucine supplementation may exert beneficial effects on mitochondrial biogenesis and energy metabolism in NBW and IUGR weanling piglets. PMID:28386385

  19. Low-Dose Methylmercury-Induced Genes Regulate Mitochondrial Biogenesis via miR-25 in Immortalized Human Embryonic Neural Progenitor Cells

    PubMed Central

    Wang, Xinjin; Yan, Mengling; Zhao, Lina; Wu, Qing; Wu, Chunhua; Chang, Xiuli; Zhou, Zhijun

    2016-01-01

    Mitochondria are essential organelles and important targets for environmental pollutants. The detection of mitochondrial biogenesis and generation of reactive oxygen species (ROS) and p53 levels following low-dose methylmercury (MeHg) exposure could expand our understanding of underlying mechanisms. Here, the sensitivity of immortalized human neural progenitor cells (ihNPCs) upon exposure to MeHg was investigated. We found that MeHg altered cell viability and the number of 5-ethynyl-2′-deoxyuridine (EdU)-positive cells. We also observed that low-dose MeHg exposure increased the mRNA expression of cell cycle regulators. We observed that MeHg induced ROS production in a dose-dependent manner. In addition, mRNA levels of peroxisome-proliferator-activated receptor gammacoactivator-1α (PGC-1α), mitochondrial transcription factor A (TFAM) and p53-controlled ribonucleotide reductase (p53R2) were significantly elevated, which were correlated with the increase of mitochondrial DNA (mtDNA) copy number at a concentration as low as 10 nM. Moreover, we examined the expression of microRNAs (miRNAs) known as regulatory miRNAs of p53 (i.e., miR-30d, miR-1285, miR-25). We found that the expression of these miRNAs was significantly downregulated upon MeHg treatment. Furthermore, the overexpression of miR-25 resulted in significantly reducted p53 protein levels and decreased mRNA expression of genes involved in mitochondrial biogenesis regulation. Taken together, these results demonstrated that MeHg could induce developmental neurotoxicity in ihNPCs through altering mitochondrial functions and the expression of miRNA. PMID:27941687

  20. Conjugated linoleic acid (CLA) stimulates mitochondrial biogenesis signaling by the upregulation of PPARγ coactivator 1α (PGC-1α) in C2C12 cells.

    PubMed

    Kim, Yoo; Park, Yeonhwa

    2015-04-01

    Along with its effect on body fat reduction, dietary conjugated linoleic acid (CLA) has been reported to improve physical activity and endurance capacity in mice. It has been suggested these effects may in part be due to physiological changes in skeletal muscle, however, the mode of action is not completely understood. Thus, the purpose of this study was to determine the relevant mechanisms of CLA isomers for mitochondrial biogenesis, one of the most important adaptive responses in skeletal muscle. Both cis-9,trans-11 (c9,t11) and trans-10,cis-12 (t10,c12) CLA isomers increased the expression of peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α), however, only the t10,c12 isomer, but not c9,t11, increased phosphorylation of AMP-activated protein kinase (AMPK) compared to the control. Among downstream biomarkers of PGC-1α, the CLA mixed isomer enhanced the expression of peroxisome proliferator-activated receptor-δ (PPARδ). Both c9,t11 and t10,c12 CLA isomers increased expression of nuclear respiratory factor 1 (NRF-1) and mitochondrial transcription factor A (Tfam), while the c9,t11 increased expression of cytochrome c (Cyt C) and t10,c12 CLA increased expression of voltage-dependent anion channel (VDAC), respectively. Both CLA isomers significantly increased mitochondrial DNA copy number compared to that of control. These findings suggest that the individual CLA isomers potentiate mitochondrial biogenesis via PGC-1α-NRF-1-Tfam signaling cascade, although downstream regulation may be isomer dependent.

  1. Exercise-induced metabolic fluctuations influence AMPK, p38-MAPK and CaMKII phosphorylation in human skeletal muscle

    PubMed Central

    Combes, Adrien; Dekerle, Jeanne; Webborn, Nick; Watt, Peter; Bougault, Valérie; Daussin, Frédéric N

    2015-01-01

    During transition from rest to exercise, metabolic reaction rates increase substantially to sustain intracellular ATP use. These metabolic demands activate several kinases that initiate signal transduction pathways which modulate transcriptional regulation of mitochondrial biogenesis. The purpose of this study was to determine whether metabolic fluctuations per se affect the signaling cascades known to regulate peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α). On two separate occasions, nine men performed a continuous (30-min) and an intermittent exercise (30 × 1-min intervals separated by 1-min of recovery) at 70% of . Skeletal muscle biopsies from the vastus lateralis were taken at rest and at +0 h and +3 h after each exercise. Metabolic fluctuations that correspond to exercise-induced variation in metabolic rates were determined by analysis of VO2 responses. During intermittent exercise metabolic fluctuations were 2.8-fold higher despite identical total work done to continuous exercise (317 ± 41 vs. 312 ± 56 kJ after intermittent and continuous exercise, respectively). Increased phosphorylation of AMP-activated protein kinase (AMPK) (˜2.9-fold, P < 0.01), calcium/calmodulin-dependent protein kinase II (CaMKII) (˜2.7-fold, P < 0.01) and p38-mitogen-activated protein kinase (MAPK) (˜4.2-fold, P < 0.01) occurred immediately in both exercises and to a greater extent after the intermittent exercise (condition x time interaction, P < 0.05). A single bout of intermittent exercise induces a greater activation of these signaling pathways regulating PGC-1α when compared to a single bout of continuous exercise of matched work and intensity. Chronic adaptations to exercise on mitochondria biogenesis are yet to be investigated. PMID:26359238

  2. Adolescents and Exercise Induced Asthma

    ERIC Educational Resources Information Center

    Hansen, Pamela; Bickanse, Shanna; Bogenreif, Mike; VanSickle, Kyle

    2008-01-01

    This article defines asthma and exercise induced asthma, and provides information on the triggers, signs, and symptoms of an attack. It also gives treatments for these conditions, along with prevention guidelines on how to handle an attack in the classroom or on the practice field. (Contains 2 tables and 1 figure.)

  3. Nutrition and Training Influences on the Regulation of Mitochondrial Adenosine Diphosphate Sensitivity and Bioenergetics.

    PubMed

    Holloway, Graham P

    2017-03-01

    Since the seminal finding almost 50 years ago that exercise training increases mitochondrial content in skeletal muscle, a considerable amount of research has been dedicated to elucidate the mechanisms inducing mitochondrial biogenesis. The discovery of peroxisome proliferator-activated receptor γ co-activator 1α as a major regulator of exercise-induced gene transcription was instrumental in beginning to understand the signals regulating this process. However, almost two decades after its discovery, our understanding of the signals inducing mitochondrial biogenesis remain poorly defined, limiting our insights into possible novel training modalities in elite athletes that can increase the oxidative potential of muscle. In particular, the role of mitochondrial reactive oxygen species has received very little attention; however, several lifestyle interventions associated with an increase in mitochondrial reactive oxygen species coincide with the induction of mitochondrial biogenesis. Furthermore, the diminishing returns of exercise training are associated with reductions in exercise-induced, mitochondrial-derived reactive oxygen species. Therefore, research focused on altering redox signaling in elite athletes may prove to be effective at inducing mitochondrial biogenesis and augmenting training regimes. In the context of exercise performance, the biological effect of increasing mitochondrial content is an attenuated rise in free cytosolic adenosine diphosphate (ADP), and subsequently decreased carbohydrate flux at a given power output. Recent evidence has shown that mitochondrial ADP sensitivity is a regulated process influenced by nutritional interventions, acute exercise, and exercise training. This knowledge raises the potential to improve mitochondrial bioenergetics in the absence of changes in mitochondrial content. Elucidating the mechanisms influencing the acute regulation of mitochondrial ADP sensitivity could have performance benefits in athletes

  4. Posttranslational modification of mitochondrial transcription factor A in impaired mitochondria biogenesis: implications in diabetic retinopathy and metabolic memory phenomenon.

    PubMed

    Santos, Julia M; Mishra, Manish; Kowluru, Renu A

    2014-04-01

    Mitochondrial transcription factor A (TFAM) is one of the key regulators of the transcription of mtDNA. In diabetes, despite increase in gene transcripts of TFAM, its protein levels in the mitochondria are decreased and mitochondria copy numbers become subnormal. The aim of this study is to investigate the mechanism(s) responsible for decreased mitochondrial TFAM in diabetes. Using retinal endothelial cells, we have investigated the effect of overexpression of cytosolic chaperone, Hsp70, and TFAM on glucose-induced decrease in mitochondrial TFAM levels, and the transcription of mtDNA-encoded genes, NADH dehydrogenase subunit 6 (ND6) and cytochrome b (Cytb). To investigate the role of posttranslational modifications in subnormal mitochondrial TFAM, ubiquitination of TFAM was assessed, and the results were confirmed in the retina from streptozotocin-induced diabetic rats. While overexpression of Hsp70 failed to prevent glucose-induced decrease in mitochondrial TFAM and transcripts of ND6 and Cytb, overexpression of TFAM ameliorated decrease in its mitochondrial protein levels and transcriptional activity. TFAM was ubiquitinated by high glucose, and PYR-41, an inhibitor of ubiquitination, prevented TFAM ubiquitination and restored the transcriptional activity. Similarly, TFAM was ubiquitinated in the retina from diabetic rats, and it continued to be modified after reinstitution of normal glycemia. Our results clearly imply that the ubiquitination of TFAM impedes its transport to the mitochondria resulting in subnormal mtDNA transcription and mitochondria dysfunction, and inhibition of ubiquitination restores mitochondrial homeostasis. Reversal of hyperglycemia does not provide any benefit to TFAM ubiquitination. Thus, strategies targeting posttranslational modification could provide an avenue to preserve mitochondrial homeostasis, and inhibit the development/progression of diabetic retinopathy.

  5. Impaired mitochondrial biogenesis, defective axonal transport of mitochondria, abnormal mitochondrial dynamics and synaptic degeneration in a mouse model of Alzheimer's disease.

    PubMed

    Calkins, Marcus J; Manczak, Maria; Mao, Peizhong; Shirendeb, Ulziibat; Reddy, P Hemachandra

    2011-12-01

    Increasing evidence suggests that the accumulation of amyloid beta (Aβ) in synapses and synaptic mitochondria causes synaptic mitochondrial failure and synaptic degeneration in Alzheimer's disease (AD). The purpose of this study was to better understand the effects of Aβ in mitochondrial activity and synaptic alterations in neurons from a mouse model of AD. Using primary neurons from a well-characterized Aβ precursor protein transgenic (AβPP) mouse model (Tg2576 mouse line), for the first time, we studied mitochondrial activity, including axonal transport of mitochondria, mitochondrial dynamics, morphology and function. Further, we also studied the nature of Aβ-induced synaptic alterations, and cell death in primary neurons from Tg2576 mice, and we sought to determine whether the mitochondria-targeted antioxidant SS31 could mitigate the effects of oligomeric Aβ. We found significantly decreased anterograde mitochondrial movement, increased mitochondrial fission and decreased fusion, abnormal mitochondrial and synaptic proteins and defective mitochondrial function in primary neurons from AβPP mice compared with wild-type (WT) neurons. Transmission electron microscopy revealed a large number of small mitochondria and structurally damaged mitochondria, with broken cristae in AβPP primary neurons. We also found an increased accumulation of oligomeric Aβ and increased apoptotic neuronal death in the primary neurons from the AβPP mice relative to the WT neurons. Our results revealed an accumulation of intraneuronal oligomeric Aβ, leading to mitochondrial and synaptic deficiencies, and ultimately causing neurodegeneration in AβPP cultures. However, we found that the mitochondria-targeted antioxidant SS31 restored mitochondrial transport and synaptic viability, and decreased the percentage of defective mitochondria, indicating that SS31 protects mitochondria and synapses from Aβ toxicity.

  6. Exercise-induced cardiac remodeling.

    PubMed

    Weiner, Rory B; Baggish, Aaron L

    2012-01-01

    Early investigations in the late 1890s and early 1900s documented cardiac enlargement in athletes with above-normal exercise capacity and no evidence of cardiovascular disease. Such findings have been reported for more than a century and continue to intrigue scientists and clinicians. It is well recognized that repetitive participation in vigorous physical exercise results in significant changes in myocardial structure and function. This process, termed exercise-induced cardiac remodeling (EICR), is characterized by structural cardiac changes including left ventricular hypertrophy with sport-specific geometry (eccentric vs concentric). Associated alterations in both systolic and diastolic functions are emerging as recognized components of EICR. The increasing popularity of recreational exercise and competitive athletics has led to a growing number of individuals exhibiting these findings in routine clinical practice. This review will provide an overview of EICR in athletes.

  7. A practical model of low-volume high-intensity interval training induces mitochondrial biogenesis in human skeletal muscle: potential mechanisms.

    PubMed

    Little, Jonathan P; Safdar, Adeel; Wilkin, Geoffrey P; Tarnopolsky, Mark A; Gibala, Martin J

    2010-03-15

    High-intensity interval training (HIT) induces skeletal muscle metabolic and performance adaptations that resemble traditional endurance training despite a low total exercise volume. Most HIT studies have employed 'all out', variable-load exercise interventions (e.g. repeated Wingate tests) that may not be safe, practical and/or well tolerated by certain individuals. Our purpose was to determine the performance, metabolic and molecular adaptations to a more practical model of low-volume HIT. Seven men (21 + or - 0.4 years, V(O2peak) = 46 + or - 2 ml kg(-1) min(-1)) performed six training sessions over 2 weeks. Each session consisted of 8-12 x 60 s intervals at approximately 100% of peak power output elicited during a ramp V(O2) peak test (355 + or - 10 W) separated by 75 s of recovery. Training increased exercise capacity, as assessed by significant improvements on both 50 kJ and 750 kJ cycling time trials (P < 0.05 for both). Skeletal muscle (vastus lateralis) biopsy samples obtained before and after training revealed increased maximal activity of citrate synthase (CS) and cytochrome c oxidase (COX) as well as total protein content of CS, COX subunits II and IV, and the mitochondrial transcription factor A (Tfam) (P < 0.05 for all). Nuclear abundance of peroxisome proliferator-activated receptor gamma co-activator 1alpha (PGC-1alpha) was approximately 25% higher after training (P < 0.05), but total PGC-1alpha protein content remained unchanged. Total SIRT1 content, a proposed activator of PGC-1alpha and mitochondrial biogenesis, was increased by approximately 56% following training (P < 0.05). Training also increased resting muscle glycogen and total GLUT4 protein content (both P < 0.05). This study demonstrates that a practical model of low volume HIT is a potent stimulus for increasing skeletal muscle mitochondrial capacity and improving exercise performance. The results also suggest that increases in SIRT1, nuclear PGC-1alpha, and Tfam may be involved in

  8. A Novel Iron Chelator-Radical Scavenger Ameliorates Motor Dysfunction and Improves Life Span and Mitochondrial Biogenesis in SOD1(G93A) ALS Mice.

    PubMed

    Golko-Perez, Sagit; Amit, Tamar; Bar-Am, Orit; Youdim, Moussa B H; Weinreb, Orly

    2017-02-01

    The aim of the present study was to evaluate the therapeutic effect of the novel neuroprotective multitarget brain permeable monoamine oxidase inhibitor/iron chelating-radical scavenging drug, VAR10303 (VAR), co-administered with high-calorie/energy-supplemented diet (ced) in SOD1(G93A) transgenic amyotrophic lateral sclerosis (ALS) mice. Administration of VAR-ced was initiated after the appearance of disease symptoms (at day 88), as this regimen is comparable with the earliest time at which drug therapy could start in ALS patients. Using this rescue protocol, we demonstrated in the current study that VAR-ced treatment provided several beneficial effects in SOD1(G93A) mice, including improvement in motor performance, elevation of survival time, and attenuation of iron accumulation and motoneuron loss in the spinal cord. Moreover, VAR-ced treatment attenuated neuromuscular junction denervation and exerted a significant preservation of myofibril regular morphology, associated with a reduction in the expression levels of genes related to denervation and atrophy in the gastrocnemius (GNS) muscle in SOD1(G93A) mice. These effects were accompanied by upregulation of mitochondrial DNA and elevated activities of complexes I and II in the GNS muscle. We have also demonstrated that VAR-ced treatment upregulated the mitochondrial biogenesis master regulator, peroxisome proliferator-activated receptor-γ co-activator 1α (PGC-1α) and increased PGC-1α-targeted metabolic genes and proteins, such as, PPARγ, UCP1/3, NRF1/2, Tfam, and ERRα in GNS muscle. These results provide evidence of therapeutic potential of VAR-ced in SOD1(G93A) mice with underlying molecular mechanisms, further supporting the importance role of multitarget iron chelators in ALS treatment.

  9. The Single Nucleotide Polymorphism Gly482Ser in the PGC-1α Gene Impairs Exercise-Induced Slow-Twitch Muscle Fibre Transformation in Humans

    PubMed Central

    Steinbacher, Peter; Feichtinger, René G.; Kedenko, Lyudmyla; Kedenko, Igor; Reinhardt, Sandra; Schönauer, Anna-Lena; Leitner, Isabella; Sänger, Alexandra M.; Stoiber, Walter; Kofler, Barbara; Förster, Holger; Paulweber, Bernhard; Ring-Dimitriou, Susanne

    2015-01-01

    PGC-1α (peroxisome proliferator-activated receptor γ co-activator 1α) is an important regulator of mitochondrial biogenesis and a master regulator of enzymes involved in oxidative phosphorylation. Recent evidence demonstrated that the Gly482Ser single nucleotide polymorphism (SNP) in the PGC-1α gene affects insulin sensitivity, blood lipid metabolism and binding to myocyte enhancer factor 2 (MEF2). Individuals carrying this SNP were shown to have a reduced cardiorespiratory fitness and a higher risk to develop type 2 diabetes. Here, we investigated the responses of untrained men with the Gly482Ser SNP to a 10 week programme of endurance training (cycling, 3 x 60 min/week, heart rate at 70-90% VO2peak). Quantitative data from analysis of biopsies from vastus lateralis muscle revealed that the SNP group, in contrast to the control group, lacked a training-induced increase in content of slow contracting oxidative fibres. Capillary supply, mitochondrial density, mitochondrial enzyme activities and intramyocellular lipid content increased similarly in both groups. These results indicate that the impaired binding of MEF2 to PGC-1α in humans with this SNP impedes exercise-induced fast-to-slow muscle fibre transformation. PMID:25886402

  10. The single nucleotide polymorphism Gly482Ser in the PGC-1α gene impairs exercise-induced slow-twitch muscle fibre transformation in humans.

    PubMed

    Steinbacher, Peter; Feichtinger, René G; Kedenko, Lyudmyla; Kedenko, Igor; Reinhardt, Sandra; Schönauer, Anna-Lena; Leitner, Isabella; Sänger, Alexandra M; Stoiber, Walter; Kofler, Barbara; Förster, Holger; Paulweber, Bernhard; Ring-Dimitriou, Susanne

    2015-01-01

    PGC-1α (peroxisome proliferator-activated receptor γ co-activator 1α) is an important regulator of mitochondrial biogenesis and a master regulator of enzymes involved in oxidative phosphorylation. Recent evidence demonstrated that the Gly482Ser single nucleotide polymorphism (SNP) in the PGC-1α gene affects insulin sensitivity, blood lipid metabolism and binding to myocyte enhancer factor 2 (MEF2). Individuals carrying this SNP were shown to have a reduced cardiorespiratory fitness and a higher risk to develop type 2 diabetes. Here, we investigated the responses of untrained men with the Gly482Ser SNP to a 10 week programme of endurance training (cycling, 3 x 60 min/week, heart rate at 70-90% VO2peak). Quantitative data from analysis of biopsies from vastus lateralis muscle revealed that the SNP group, in contrast to the control group, lacked a training-induced increase in content of slow contracting oxidative fibres. Capillary supply, mitochondrial density, mitochondrial enzyme activities and intramyocellular lipid content increased similarly in both groups. These results indicate that the impaired binding of MEF2 to PGC-1α in humans with this SNP impedes exercise-induced fast-to-slow muscle fibre transformation.

  11. The evolution of ERMIONE in mitochondrial biogenesis and lipid homeostasis: An evolutionary view from comparative cell biology.

    PubMed

    Wideman, Jeremy G; Muñoz-Gómez, Sergio A

    2016-08-01

    The ER-mitochondria organizing network (ERMIONE) in Saccharomyces cerevisiae is involved in maintaining mitochondrial morphology and lipid homeostasis. ERMES and MICOS are two scaffolding complexes of ERMIONE that contribute to these processes. ERMES is ancient but has been lost in several lineages including animals, plants, and SAR (stramenopiles, alveolates and rhizaria). On the other hand, MICOS is ancient and has remained present in all organisms bearing mitochondrial cristae. The ERMIONE precursor evolved in the α-proteobacterial ancestor of mitochondria which had the central subunit of MICOS, Mic60. The subsequent evolution of ERMIONE and its interactors in eukaryotes reflects the integrative co-evolution of mitochondria and their hosts and the adaptive paths that some lineages have followed in their specialization to certain environments. By approaching the ERMIONE from a perspective of comparative evolutionary cell biology, we hope to shed light on not only its evolutionary history, but also how ERMIONE components may function in organisms other than S. cerevisiae. This article is part of a Special Issue entitled: The cellular lipid landscape edited by Tim P. Levine and Anant K. Menon.

  12. Characterization of the metabolic effect of β-alanine on markers of oxidative metabolism and mitochondrial biogenesis in skeletal muscle

    PubMed Central

    Sunderland, Kyle L.; Kuennen, Matthew R.; Vaughan, Roger A.

    2016-01-01

    [Purpose] β-alanine is a common component of numerous sports supplements purported to improve athletic performance through enhanced carnosine biosynthesis and related intracellular buffering. To date, the effects of β-alanine on oxidative metabolism remain largely unexplored. This work investigated the effects of β-alanine on the expression of proteins which regulate cellular energetics. [Methods] C2C12 myocytes were cultured and differentiated under standard conditions followed by treatment with either β-alanine or isonitrogenous non-metabolizable control D-alanine at 800μM for 24 hours. Metabolic gene and protein expression were quantified by qRT-PCR and immunoblotting, respectively. Glucose uptake and oxygen consumption were measured via fluorescence using commercially available kits. [Results] β-alanine-treated myotubes displayed significantly elevated markers of improved oxidative metabolism including elevated peroxisome proliferator-activated receptor β/δ (PPARβ/δ) and mitochondrial transcription factor a (TFAM) which led to increased mitochondrial content (evidenced by concurrent increases in cytochrome c content). Additionally, β-alanine-treated cells exhibited significantly increased oxygen consumption compared to control in a PPARβ/δ-dependent manner. β-alanine significantly enhanced expression of myocyte enhancer factor 2 (MEF-2) leading to increased glucose transporter 4 (GLUT4) content. [Conclusion] β-alanine appears to increase cellular oxygen consumption as well as the expression of several cellular proteins associated with improved oxidative metabolism, suggesting β-alanine supplementation may provide additional metabolic benefit (although these observations require in vivo experimental verification). PMID:27508152

  13. Cholinergic urticaria and exercise-induced anaphylaxis.

    PubMed

    Montgomery, Stefan L

    2015-01-01

    In this article, we will present the physical manifestations of two similar conditions. The first is cholinergic urticaria. This is chronic urticaria precipitated by an elevated body temperature. The second is exercise-induced anaphylaxis. Anaphylaxis can be idiopathic, a result of a specific allergenic trigger (food, medication, or insect sting), or exercise induced. We will focus on the third subtype. We describe the causes, symptoms, pathophysiology, testing, treatment, and prognosis of these two conditions.

  14. Carbohydrate restricted recovery from long term endurance exercise does not affect gene responses involved in mitochondrial biogenesis in highly trained athletes

    PubMed Central

    Jensen, Line; Gejl, Kasper D; Ørtenblad, Niels; Nielsen, Jakob L; Bech, Rune D; Nygaard, Tobias; Sahlin, Kent; Frandsen, Ulrik

    2015-01-01

    The aim was to determine if the metabolic adaptations, particularly PGC-1α and downstream metabolic genes were affected by restricting CHO following an endurance exercise bout in trained endurance athletes. A second aim was to compare baseline expression level of these genes to untrained. Elite endurance athletes (VO2max 66 ± 2 mL·kg−1·min−1, n = 15) completed 4 h cycling at ∼56% VO2max. During the first 4 h recovery subjects were provided with either CHO or only H2O and thereafter both groups received CHO. Muscle biopsies were collected before, after, and 4 and 24 h after exercise. Also, resting biopsies were collected from untrained subjects (n = 8). Exercise decreased glycogen by 67.7 ± 4.0% (from 699 ± 26.1 to 239 ± 29.5 mmol·kg−1·dw−1) with no difference between groups. Whereas 4 h of recovery with CHO partly replenished glycogen, the H2O group remained at post exercise level; nevertheless, the gene expression was not different between groups. Glycogen and most gene expression levels returned to baseline by 24 h in both CHO and H2O. Baseline mRNA expression of NRF-1, COX-IV, GLUT4 and PPAR-α gene targets were higher in trained compared to untrained. Additionally, the proportion of type I muscle fibers positively correlated with baseline mRNA for PGC-1α, TFAM, NRF-1, COX-IV, PPAR-α, and GLUT4 for both trained and untrained. CHO restriction during recovery from glycogen depleting exercise does not improve the mRNA response of markers of mitochondrial biogenesis. Further, baseline gene expression of key metabolic pathways is higher in trained than untrained. PMID:25677542

  15. Effects of decreased lactate accumulation after dichloroacetate administration on exercise training–induced mitochondrial adaptations in mouse skeletal muscle

    PubMed Central

    Hoshino, Daisuke; Tamura, Yuki; Masuda, Hiroyuki; Matsunaga, Yutaka; Hatta, Hideo

    2015-01-01

    Recent studies suggested that lactate accumulation can be a signal for mitochondrial biogenesis in skeletal muscle. We investigated whether reductions in lactate concentrations in response to dichloroacetate (DCA), an activator of pyruvate dehydrogenase, attenuate mitochondrial adaptations after exercise training in mice. We first confirmed that DCA administration (200 mg/kg BW by i.p. injection) 10 min before exercise decreased muscle and blood lactate concentrations after high-intensity interval exercise (10 bouts of 1 min treadmill running at 40 m/min with a 1 min rest). At the same time, exercise-induced signal cascades did not change by pre-exercise DCA administration. These results suggested that DCA administration affected only lactate concentrations after exercise. We next examined the effects of acute DCA administration on mRNA expressions involved with mitochondrial biogenesis after same high-intensity interval exercise and the effects of chronic DCA administration on mitochondrial adaptations after high-intensity interval training (increasing intensity from 38 to 43 m/min by the end of training period). Acute DCA administration did not change most of the exercise-induced mRNA upregulation. These data suggest that lactate reductions by DCA administration did not affect transcriptional activation after high-intensity interval exercise. However, chronic DCA administration attenuated, in part, mitochondrial adaptations such as training-induced increasing rates of citrate synthase (P = 0.06), β-hydroxyacyl CoA dehydrogenase activity (P < 0.05), cytochrome c oxidase IV (P < 0.05) and a fatty acid transporter, fatty acid translocase/CD36 (P < 0.05), proteins after exercise training. These results suggest that lactate accumulation during high-intensity interval exercise may be associated with mitochondrial adaptations after chronic exercise training. PMID:26416973

  16. Increased 8-hydroxy-2'-deoxyguanosine in plasma and decreased mRNA expression of human 8-oxoguanine DNA glycosylase 1, anti-oxidant enzymes, mitochondrial biogenesis-related proteins and glycolytic enzymes in leucocytes in patients with systemic lupus erythematosus.

    PubMed

    Lee, H-T; Lin, C-S; Lee, C-S; Tsai, C-Y; Wei, Y-H

    2014-04-01

    We measured plasma levels of the oxidative DNA damage marker 8-hydroxy-2'-deoxyguanosine (8-OHdG) and leucocyte mRNA expression levels of the genes encoding the 8-OHdG repair enzyme human 8-oxoguanine DNA glycosylase 1 (hOGG1), the anti-oxidant enzymes copper/zinc superoxide dismutase (Cu/ZnSOD), manganese superoxide dismutase (MnSOD), catalase, glutathione peroxidase-1 (GPx-1), GPx-4, glutathione reductase (GR) and glutathione synthetase (GS), the mitochondrial biogenesis-related proteins mtDNA-encoded ND 1 polypeptide (ND1), ND6, ATPase 6, mitochondrial transcription factor A (Tfam), nuclear respiratory factor 1(NRF-1), pyruvate dehydrogenase E1 component alpha subunit (PDHA1), pyruvate dehydrogenase kinase isoenzyme 1 (PDK-1) and hypoxia inducible factor-1α (HIF-1α) and the glycolytic enzymes hexokinase-II (HK-II), glucose 6-phosphate isomerase (GPI), phosphofructokinase (PFK), glyceraldehyde 3-phosphate dehydrogenase (GAPDH) and lactate dehydrogenase A (LDHa). We analysed their relevance to oxidative damage in 85 systemic lupus erythematosus (SLE) patients, four complicated SLE patients undergoing rituximab treatment and 45 healthy individuals. SLE patients had higher plasma 8-OHdG levels (P < 0·01) but lower leucocyte expression of the genes encoding hOGG1(P < 0·01), anti-oxidant enzymes (P < 0·05), mitochondrial biogenesis-related proteins (P < 0·05) and glycolytic enzymes (P < 0·05) than healthy individuals. The increase in plasma 8-OHdG was correlated positively with the elevation of leucocyte expression of the genes encoding hOGG1 (P < 0·05), anti-oxidant enzymes (P < 0·05), several mitochondrial biogenesis-related proteins (P < 0·05) and glycolytic enzymes (P < 0·05) in lupus patients. The patients, whose leucocyte mtDNA harboured D310 heteroplasmy, exhibited a positive correlation between the mtDNA copy number and expression of ND1, ND6 and ATPase 6 (P < 0·05) and a negative correlation between mt

  17. DEMONSTRATION BULLETIN: BIOGENESIS SOIL WASHING TECHNOLOGY - BIOGENESIS

    EPA Science Inventory

    The BioGenesisSM soil washing technology was developed by BioGenesis Enterprises, Inc. to remove organic compounds from soil. The technology uses a proprietary solution (BioGenesisSM cleaner) to transfer organic compounds from the soil matrix to a liquid phase. BioGenesis claims...

  18. Vitamin E and vitamin C do not reduce insulin sensitivity but inhibit mitochondrial protein expression in exercising obese rats

    PubMed Central

    Picklo, Matthew J.; Thyfault, John P.

    2016-01-01

    Controversy exists as to whether supplementation with the antioxidants vitamin E and vitamin C blocks adaptation to exercise. Exercise is a first-line means to treat obesity and its complications. While diet-induced obesity alters mitochondrial function and induces insulin resistance (IR), no data exist as to whether supplementation with vitamin E and vitamin C modify responses to exercise in pre-existing obesity. We tested the hypothesis that dietary supplementation with vitamin E (0.4 g α-tocopherol acetate/kg) and vitamin C (0.5 g/kg) blocks exercise-induced improvements on IR and mitochondrial content in obese rats maintained on a high-fat (45% fat energy (en)) diet. Diet-induced obese, sedentary rats had a 2-fold higher homeostasis model assessment of insulin resistance and larger insulin area under the curve following glucose tolerances test than rats fed a low-fat (10% fat en) diet. Exercising (12 weeks at 5 times per week in a motorized wheel) of obese rats normalized IR indices, an effect not modified by vitamin E and vitamin C. Vitamin E and vitamin C supplementation with exercise elevated mtDNA content in adipose and skeletal muscle to a greater extent (20%) than exercise alone in a depot-specific manner. On the other hand, vitamin C and vitamin E decreased exercise-induced increases in mitochondrial protein content for complex I (40%) and nicotinamide nucleotide transhydrogenase (35%) in a muscle-dependent manner. These data indicate that vitamin E and vitamin C supplementation in obese rodents does not modify exercise-induced improvements in insulin sensitivity but that changes in mitochondrial biogenesis and mitochondrial protein expression may be modified by antioxidant supplementation. PMID:25761734

  19. Suppression of Mitochondrial Biogenesis through Toll-Like Receptor 4–Dependent Mitogen-Activated Protein Kinase Kinase/Extracellular Signal-Regulated Kinase Signaling in Endotoxin-Induced Acute Kidney Injury

    PubMed Central

    Smith, Joshua A.; Stallons, L. Jay; Collier, Justin B.; Chavin, Kenneth D.

    2015-01-01

    Although disruption of mitochondrial homeostasis and biogenesis (MB) is a widely accepted pathophysiologic feature of sepsis-induced acute kidney injury (AKI), the molecular mechanisms responsible for this phenomenon are unknown. In this study, we examined the signaling pathways responsible for the suppression of MB in a mouse model of lipopolysaccharide (LPS)-induced AKI. Downregulation of peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α), a master regulator of MB, was noted at the mRNA level at 3 hours and protein level at 18 hours in the renal cortex, and was associated with loss of renal function after LPS treatment. LPS-mediated suppression of PGC-1α led to reduced expression of downstream regulators of MB and electron transport chain proteins along with a reduction in renal cortical mitochondrial DNA content. Mechanistically, Toll-like receptor 4 (TLR4) knockout mice were protected from renal injury and disruption of MB after LPS exposure. Immunoblot analysis revealed activation of tumor progression locus 2/mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (TPL-2/MEK/ERK) signaling in the renal cortex by LPS. Pharmacologic inhibition of MEK/ERK signaling attenuated renal dysfunction and loss of PGC-1α, and was associated with a reduction in proinflammatory cytokine (e.g., tumor necrosis factor-α [TNF-α], interleukin-1β) expression at 3 hours after LPS exposure. Neutralization of TNF-α also blocked PGC-1α suppression, but not renal dysfunction, after LPS-induced AKI. Finally, systemic administration of recombinant tumor necrosis factor-α alone was sufficient to produce AKI and disrupt mitochondrial homeostasis. These findings indicate an important role for the TLR4/MEK/ERK pathway in both LPS-induced renal dysfunction and suppression of MB. TLR4/MEK/ERK/TNF-α signaling may represent a novel therapeutic target to prevent mitochondrial dysfunction and AKI produced by sepsis. PMID:25503387

  20. Exercise-induced bronchoconstriction update-2016.

    PubMed

    Weiler, John M; Brannan, John D; Randolph, Christopher C; Hallstrand, Teal S; Parsons, Jonathan; Silvers, William; Storms, William; Zeiger, Joanna; Bernstein, David I; Blessing-Moore, Joann; Greenhawt, Matthew; Khan, David; Lang, David; Nicklas, Richard A; Oppenheimer, John; Portnoy, Jay M; Schuller, Diane E; Tilles, Stephen A; Wallace, Dana

    2016-11-01

    The first practice parameter on exercise-induced bronchoconstriction (EIB) was published in 2010. This updated practice parameter was prepared 5 years later. In the ensuing years, there has been increased understanding of the pathogenesis of EIB and improved diagnosis of this disorder by using objective testing. At the time of this publication, observations included the following: dry powder mannitol for inhalation as a bronchial provocation test is FDA approved however not currently available in the United States; if baseline pulmonary function test results are normal to near normal (before and after bronchodilator) in a person with suspected EIB, then further testing should be performed by using standardized exercise challenge or eucapnic voluntary hyperpnea (EVH); and the efficacy of nonpharmaceutical interventions (omega-3 fatty acids) has been challenged. The workgroup preparing this practice parameter updated contemporary practice guidelines based on a current systematic literature review. The group obtained supplementary literature and consensus expert opinions when the published literature was insufficient. A search of the medical literature on PubMed was conducted, and search terms included pathogenesis, diagnosis, differential diagnosis, and therapy (both pharmaceutical and nonpharmaceutical) of exercise-induced bronchoconstriction or exercise-induced asthma (which is no longer a preferred term); asthma; and exercise and asthma. References assessed as relevant to the topic were evaluated to search for additional relevant references. Published clinical studies were appraised by category of evidence and used to document the strength of the recommendation. The parameter was then evaluated by Joint Task Force reviewers and then by reviewers assigned by the parent organizations, as well as the general membership. Based on this process, the parameter can be characterized as an evidence- and consensus-based document.

  1. Mitochondria modify exercise-induced development of stem cell-derived neurons in the adult brain.

    PubMed

    Steib, Kathrin; Schäffner, Iris; Jagasia, Ravi; Ebert, Birgit; Lie, D Chichung

    2014-05-07

    Neural stem cells in the adult mammalian hippocampus continuously generate new functional neurons, which modify the hippocampal network and significantly contribute to cognitive processes and mood regulation. Here, we show that the development of new neurons from stem cells in adult mice is paralleled by extensive changes to mitochondrial mass, distribution, and shape. Moreover, exercise-a strong modifier of adult hippocampal neurogenesis-accelerates neuronal maturation and induces a profound increase in mitochondrial content and the presence of mitochondria in dendritic segments. Genetic inhibition of the activity of the mitochondrial fission factor dynamin-related protein 1 (Drp1) inhibits neurogenesis under basal and exercise conditions. Conversely, enhanced Drp1 activity furthers exercise-induced acceleration of neuronal maturation. Collectively, these results indicate that adult hippocampal neurogenesis requires adaptation of the mitochondrial compartment and suggest that mitochondria are targets for enhancing neurogenesis-dependent hippocampal plasticity.

  2. Mitochondrial adaptations evoked with exercise are associated with a reduction in age-induced testicular atrophy in Fischer-344 rats

    PubMed Central

    Welter, A.E.; Dominguez, J.M.; Behnke, B.J.; Adhihetty, P.J.

    2015-01-01

    Mitochondrial dysfunction in various tissues has been associated with numerous diseases and conditions including aging. In testes, aging induces atrophy and a decline in male reproductive function but the involvement of mitochondria is not clear. The purpose of this study was to examine whether the mitochondrial profile differed with 1) aging, and 2) 10-weeks of treadmill exercise training, in the testes of young (6 month) and old (24 month) Fischer-344 (F344) animals. Old animals exhibited significant atrophy (30% decline; P<0.05) in testes compared to young animals. However, relative mitochondrial content (cytochrome c oxidase activity and cytochrome c levels) was not altered with age and this was consistent with the lack of change in the mitochondrial biogenesis regulator protein, PGC-1α (peroxisome proliferator-activated receptor gamma coactivator 1-alpha) and its downstream targets NRF-1 (nuclear respiratory factor-1) and Tfam (mitochondrial transcription factor A). No effect was observed in the pro- or anti-apoptotic proteins, Bax and Bcl-2, respectively, but age increased AIF (apoptosis inducing factor; P<0.05) levels. Endurance training induced beneficial mitochondrial adaptations that were more prominent in old animals including greater increases in relative mitochondrial content, biogenesis/remodeling (mitofusin 2; Mfn-2), and antioxidant capacity (MnSOD-mitochondrial superoxide dismutase; P<0.05). Importantly, these exercise-induced changes were associated with an attenuation of testes atrophy in older sedentary animals (P<0.05). Our results indicate that aging-induced atrophy in testes may not be associated with changes in relative mitochondrial content and key regulatory proteins and that exercise started in late-life elicits beneficial changes in mitochondria that may protect against age-induced testicular atrophy. PMID:25108553

  3. Exercise-induced bronchoconstriction update: therapeutic management.

    PubMed

    Spector, Sheldon; Tan, Ricardo

    2012-01-01

    Management of exercise-induced bronchoconstriction (EIB) should include both prevention and treatment directed toward the underlying asthma and bronchial hyperresponsiveness. Both nonpharmacologic and pharmacologic approaches should be followed. Preexercise warm-up, to take advantage of the refractory period that follows EIB, is an important preventive technique. Dietary interventions such as fish oil, vitamin D, and ascorbic acid have shown promising results. Beta 2-agonists are considered the most effective agents for EIB at this time but intermittent use is recommended to avoid tolerance or decreased effectiveness with daily regular use. Leukotriene inhibitors and mast cell stabilizing agents can be useful in EIB but are less effective than beta 2-agonists. Tolerance to beta 2-agonists is not prevented by concomitant use of inhaled corticosteroid but it is not known whether use of leukotriene inhibitors can affect tolerance. EIB in elite athletes with no underlying asthma may have a different pathogenesis.

  4. A Time to Reap, a Time to Sow: Mitophagy and Biogenesis in Cardiac Pathophysiology

    PubMed Central

    Andres, Allen M.; Stotland, Aleksandr; Queliconi, Bruno B.; Gottlieb, Roberta A.

    2014-01-01

    Balancing mitophagy and mitochondrial biogenesis is essential for maintaining a healthy population of mitochondria and cellular homeostasis. Coordinated interplay between these two forces that govern mitochondrial turnover plays an important role as an adaptive response against various cellular stresses that can compromise cell survival. Failure to maintain the critical balance between mitophagy and mitochondrial biogenesis or homeostatic turnover of mitochondria results in a population of dysfunctional mitochondria that contribute to various disease processes. In this review we outline the mechanics and relationships between mitophagy and mitochondrial biogenesis, and discuss the implications of a disrupted balance between these two forces, with an emphasis on cardiac physiology. PMID:25444712

  5. Exercise-induced bronchospasm in clinical practice.

    PubMed

    Pierson, W E

    1988-01-01

    The early recognition and appropriate management of EIB can allow children and adolescents to fully participate in physical activities and sports. The diagnosis by history of chest congestion, coughing, and decreasing performance with exercise is helpful but is aided by a more systematic questionnaire that can detect otherwise "normal" people with EIB. The diagnosis is documented by performance of an exercise challenge test such as a treadmill or cycloergometer to verify bronchospasm induced by exercise. The management can be accomplished by nonpharmacologic means such as an early vigorous warmup, the use of a mask for rebreathing warmed air, and participation in a physical training program to increase anaerobic fitness. Pharmacologic management includes the appropriate use of cromolyn sodium, beta adrenergic agonists, theophylline, ipratroprium bromide, and calcium channel blocking agents. In addition the antihistamine, terfenadine, can also be utilized to effectively block exercise-induced bronchospasm. These pharmacologic agents can be utilized in both national and international competition when approved by the appropriate national governing body and/or the US Olympic Committee and the International Olympic Committee.

  6. Mechanisms of Exercise-Induced Hypoalgesia

    PubMed Central

    Koltyn, Kelli F.; Brellenthin, Angelique G.; Cook, Dane B.; Sehgal, Nalini; Hillard, Cecilia

    2014-01-01

    The purpose of this study was to examine opioid and endocannabinoid mechanisms of exercise-induced hypoalgesia (EIH). Fifty-eight men and women (mean age = 21 yrs) completed three sessions. During the first session, participants were familiarized with the temporal summation of heat pain and pressure pain protocols. In the exercise sessions, following double-blind administration of either an opioid antagonist (50 mg naltrexone) or placebo, participants rated the intensity of heat pulses and indicated their pressure pain thresholds (PPT) and ratings (PPR) before and after 3 minutes of submaximal isometric exercise. Blood was drawn before and after exercise. Results indicated circulating concentrations of two endocannabinoids, N-arachidonylethanolamine (AEA) and 2-arachidonoylglycerol (2-AG) as well as related lipids oleoylethanolamide (OEA), palmitoylethanolamide (PEA), N-docsahexaenoylethanolamine (DHEA), and 2-oleoylglycerol (2-OG) increased significantly (p < 0.05) following exercise. PPT increased significantly (p < 0.05) while PPR decreased significantly (p < 0.05) following exercise. Also, temporal summation ratings were significantly lower (p < 0.05) following exercise. These changes in pain responses did not differ between placebo or naltrexone conditions (p > 0.05). A significant association was found between EIH and DHEA. These results suggest involvement of a non-opioid mechanism in EIH following isometric exercise. PMID:25261342

  7. [Cereal-dependent exercise-induced anaphylaxis].

    PubMed

    Seoane-Rodríguez, Marta; Caralli, María Elisa; Morales-Cabeza, Cristina; Micozzi, Sarah; De Barrio-Fernández, Manuel; Rojas Pérez-Ezquerra, Patricia

    2016-01-01

    Wheat-dependent exercise-induced anaphylaxis (WDEIA) is increasing. In vitro test such as omega-5-gliadin levels are useful in the diagnosis, while oral single blind challenge tests (OCT) with wheat plus exercise continuous being the gold standard diagnostic method. This paper reports the case of a 38-year-old woman, with several episodes of anaphylaxis after eating different foods and doing exercise after ingestion. An allergy study was performed with positive skin prick tests for wheat, barley and rye. Total IgE 238.0KU/L, positive specific IgE (>100KU/L) to wheat, barley and rye, and negative to rTri-a-19 omega-5 gliadin. OCT with bread and exercise was positive. In this case of wheat-dependent exerciseinduced anaphylaxis (WDEIA) with negative serum specific IgE to omega-5-gliadin, negative results with gamma, alpha, bheta y omega-gliadin doesn't exclude the diagnosis of WDEIA.

  8. Exercise-induced respiratory symptoms not due to asthma.

    PubMed

    Pandit, Chetan A; Batterby, Eugenie; Van Asperen, Peter; Cooper, Peter; Selvadurai, Hiran; Fitzgerald, Dominic A

    2014-10-01

    This manuscript describes two interesting patients who had exercise-induced symptoms that unmasked an alternative underlying diagnosis. The first is an 8-year-old boy who was treated for asthma all his life but really had exercise-induced stridor (labelled as wheeze) causing significant exercise limitation, which was due to a double aortic arch with the right arch compressing the trachea. The second case describes the diagnosis of vocal cord dysfunction in a 13-year-old anxious high achiever. He also initially had exercise-induced symptoms treated as exercise-induced wheeze but again had a stridor due to vocal cord dysfunction. Both these cases demonstrate the importance of detailed history including during exercise, which can unmask alternative diagnosis. Another important message is that if there is no response to bronchodilator treatment with absence of typical signs and symptoms of asthma, alternative diagnosis should be considered.

  9. Wheezing or Breezing through Exercise-Induced Asthma.

    ERIC Educational Resources Information Center

    McCarthy, Paul

    1989-01-01

    Several physicians discuss the tests they use to diagnose exercise-induced asthma (EIA), the medications they typically prescribe and why, and the importance of properly educating athletes about EIA. (JD)

  10. Surgical management of a patient with exercise-induced esotropia.

    PubMed

    Abrams, Michael S

    2012-12-01

    Exercise-induced esotropia is a rare form of strabismus characterized by paroxysms of esotropia and diplopia only during exercise. This report describes a 15-year-old boy who presented with a 1-year history of exercise-induced esotropia. He has been asymptomatic after recession of a single medial rectus muscle. It is hypothesized that the esotropia was attributable to a malfunction in the muscle tension-control circuit and that altering the small signal gain with surgery resulted in improvement.

  11. Aspirin may promote mitochondrial biogenesis via the production of hydrogen peroxide and the induction of Sirtuin1/PGC-1α genes

    PubMed Central

    Kamble, Pratibha; Selvarajan, Krithika; Narasimhulu, Chandrakala Aluganti; Nandave, Mukesh; Parthasarathy, Sampath

    2013-01-01

    Based on the rapid hydrolysis of acetyl salicylic acid (ASA, Aspirin) to salicylic acid (SA), the ability of SA to form dihydroxy benzoic acid (DBA), and the latter’s redox reactions to yield hydrogen peroxide (H2O2), we predicted that ASA may have the potential to induce Sirtuin1 (Sirt1) and its downstream effects. We observed that treatment of cultured liver cells with ASA resulted in the induction of Sirt1, peroxisome proliferator-activated receptor-gamma co-activator-1α (PGC-1α), and NAD(P)H quinone oxidoreductase 1 (Nqo1) genes. Paraoxonase 1 (PON1) and Aryl hydrocarbon receptor (AhR) siRNA transfections inhibited the induction of gene expressions by ASA suggesting the need for the acetyl ester hydrolysis and hydroxylation to DHBA. The latter also induced Sirt1, confirming the proposed pathway. As predicted, ASA and SA treatment resulted in the production of H2O2, a known inducer of Sirt1 and confirmed in the current studies. More importantly, ASA treatment resulted in an increase in mitochondria as seen by tracking dyes. We suggest that DHBA, generated from ASA, via its oxidation/reduction reactions mediated by Nqo1 might be involved in the production of O2-. and H2O2. As Sirt1 and PGC-1α profoundly affect mitochondrial metabolism and energy utilization, ASA may have therapeutic potential beyond its ability to inhibit cyclooxygenases. PMID:23228932

  12. Resveratrol attenuates exercise-induced adaptive responses in rats selectively bred for low running performance.

    PubMed

    Hart, Nikolett; Sarga, Linda; Csende, Zsolt; Koch, Lauren G; Britton, Steven L; Davies, Kelvin J A; Radak, Zsolt

    2014-01-01

    Low capacity runner (LCR) rats have been developed by divergent artificial selection for treadmill endurance capacity to explore an aerobic biology-disease connection. The beneficial effects of resveratrol supplementation have been demonstrated in endurance running. In this study it was examined whether 12 weeks of treadmill exercise training and/or resveratrol can retrieve the low running performance of the LCR and impact mitochondrial biogenesis and quality control. Resveratrol regressed running performance in trained LCR (p<0.05). Surprisingly, exercise and resveratrol treatments significantly decreased pAMPK/AMPK, SIRT1, SIRT4, forkhead transcription factor 1 (FOXO1) and mitochondrial transcription factor A (TFAM) levels in these animals (p<0.05). Mitochondrial fusion protein, HSP78 and polynucleotide phosphorylase were significantly induced in LCR-trained, LCR-resveratrol treated, LCR-trained and resveratol treated groups compared to LCR-controls. The data indicate that the AMPK-SIRT1-NAMPT-FOXO1 axis could be important to the limited aerobic endurance capacity of low running capacity rats. Resveratrol supplementation was not beneficial in terms of aerobic endurance performance, mitochondrial biogenesis, or quality control.

  13. Dietary Supplementation with the Microalga Galdieria sulphuraria (Rhodophyta) Reduces Prolonged Exercise-Induced Oxidative Stress in Rat Tissues

    PubMed Central

    Carfagna, Simona; Napolitano, Gaetana; Barone, Daniela; Pinto, Gabriele; Venditti, Paola

    2015-01-01

    We studied the effects of ten-day 1% Galdieria sulphuraria dietary supplementation on oxidative damage and metabolic changes elicited by acute exercise (6-hour swimming) determining oxygen consumption, lipid hydroperoxides, protein bound carbonyls in rat tissue (liver, heart, and muscle) homogenates and mitochondria, tissue glutathione peroxidase and glutathione reductase activities, glutathione content, and rates of H2O2 mitochondrial release. Exercise increased oxidative damage in tissues and mitochondria and decreased tissue content of reduced glutathione. Moreover, it increased State 4 and decreased State 3 respiration in tissues and mitochondria. G. sulphuraria supplementation reduced the above exercise-induced variations. Conversely, alga supplementation was not able to modify the exercise-induced increase in mitochondrial release rate of hydrogen peroxide and in liver and heart antioxidant enzyme activities. The alga capacity to reduce lipid oxidative damage without reducing mitochondrial H2O2 release can be due to its high content of C-phycocyanin and glutathione, which are able to scavenge peroxyl radicals and contribute to phospholipid hydroperoxide metabolism, respectively. In conclusion, G. sulphuraria ability to reduce exercise-linked oxidative damage and mitochondrial dysfunction makes it potentially useful even in other conditions leading to oxidative stress, including hyperthyroidism, chronic inflammation, and ischemia/reperfusion. PMID:25874021

  14. Exercise induces BDNF and synapsin I to specific hippocampal subfields.

    PubMed

    Vaynman, Shoshanna; Ying, Zhe; Gómez-Pinilla, Fernando

    2004-05-01

    To assess the relationship between brain-derived neurotrophic factor (BDNF) and synapsin I in the hippocampus during exercise, we employed a novel microsphere injection method to block the action of BDNF through its tyrosine kinase (Trk) receptor and subsequently measure the mRNA levels of synapsin I, using real-time TaqMan RT-PCR for RNA quantification. After establishing a causal link between BDNF and exercise-induced synapsin I mRNA levels, we studied the exercise-induced distribution of BDNF and synapsin I in the rodent hippocampus. Quantitative immunohistochemical analysis revealed increases of BDNF and synapsin I in CA3 stratum lucidum and dentate gyrus, and synapsin I alone in CA1 stratum radiatum and stratum laconosum moleculare. These results indicate that exercise induces plasticity of select hippocampal transsynaptic circuitry, possibly comprising a spatial restriction on synapsin I regulation by BDNF.

  15. Coping with Exercise-Induced Asthma in Sports.

    ERIC Educational Resources Information Center

    Katz, Roger M.

    1987-01-01

    This article reviews the history of research on exercise-induced asthma (EIA) and the pathophysiology of the condition, including its development and influencing factors. Four groups of drugs that are effective against EIA--theopyhlline, beta-adrenergic agents, cromolyn sodium, and anticholinergics--are discussed. (Author/CB)

  16. EXERCISE-INDUCED PULMONARY HEMORRHAGE AFTER RUNNING A MARATHON

    EPA Science Inventory

    We report on a healthy 26-year-old male who had an exercise-induced pulmonary hemorrhage (EIPH) within 24 hours of running a marathon. There were no symptoms, abnormalities on exam, or radiographic infiltrates. He routinely participated in bronchoscopy research and the EIPH was e...

  17. Exercise-induced asthma. What family physicians should do.

    PubMed Central

    D'Urzo, A.

    1995-01-01

    Exercise-induced asthma is described as a transitory increase in airway resistance during or after vigorous exercise. Nearly 90% of patients with chronic asthma and 40% of allergic nonasthmatic patients have the condition. Family physicians should try to educate patients about their asthma and, barring contraindications, encourage them to participate in regular physical activity. PMID:8563507

  18. Human Cytomegalovirus Infection Upregulates the Mitochondrial Transcription and Translation Machineries

    PubMed Central

    Weekes, M. P.; Antrobus, R.; Rorbach, J.; van Haute, L.; Umrania, Y.; Smith, D. L.; Minczuk, M.; Lehner, P. J.; Sinclair, J. H.

    2016-01-01

    ABSTRACT Infection with human cytomegalovirus (HCMV) profoundly affects cellular metabolism. Like in tumor cells, HCMV infection increases glycolysis, and glucose carbon is shifted from the mitochondrial tricarboxylic acid cycle to the biosynthesis of fatty acids. However, unlike in many tumor cells, where aerobic glycolysis is accompanied by suppression of mitochondrial oxidative phosphorylation, HCMV induces mitochondrial biogenesis and respiration. Here, we affinity purified mitochondria and used quantitative mass spectrometry to determine how the mitochondrial proteome changes upon HCMV infection. We found that the mitochondrial transcription and translation systems are induced early during the viral replication cycle. Specifically, proteins involved in biogenesis of the mitochondrial ribosome were highly upregulated by HCMV infection. Inhibition of mitochondrial translation with chloramphenicol or knockdown of HCMV-induced ribosome biogenesis factor MRM3 abolished the HCMV-mediated increase in mitochondrially encoded proteins and significantly impaired viral growth under bioenergetically restricting conditions. Our findings demonstrate how HCMV manipulates mitochondrial biogenesis to support its replication. PMID:27025248

  19. Acute Endurance Exercise Induces Nuclear p53 Abundance in Human Skeletal Muscle

    PubMed Central

    Tachtsis, Bill; Smiles, William J.; Lane, Steven C.; Hawley, John A.; Camera, Donny M.

    2016-01-01

    Purpose: The tumor suppressor protein p53 may have regulatory roles in exercise response-adaptation processes such as mitochondrial biogenesis and autophagy, although its cellular location largely governs its biological role. We investigated the subcellular localization of p53 and selected signaling targets in human skeletal muscle following a single bout of endurance exercise. Methods: Sixteen, untrained individuals were pair-matched for aerobic capacity (VO2peak) and allocated to either an exercise (EX, n = 8) or control (CON, n = 8) group. After a resting muscle biopsy, EX performed 60 min continuous cycling at ~70% of VO2peak during which time CON subjects rested. A further biopsy was obtained from both groups 3 h post-exercise (EX) or 4 h after the first biopsy (CON). Results: Nuclear p53 increased after 3 h recovery with EX only (~48%, p < 0.05) but was unchanged in the mitochondrial or cytoplasmic fractions in either group. Autophagy protein 5 (Atg-5) decreased in the mitochondrial protein fraction 3 h post-EX (~69%, P < 0.05) but remained unchanged in CON. There was an increase in cytoplasmic levels of the mitophagy marker PINK1 following 3 h of rest in CON only (~23%, P < 0.05). There were no changes in mitochondrial, nuclear, or cytoplasmic levels of PGC-1α post-exercise in either group. Conclusions: The selective increase in nuclear p53 abundance following endurance exercise suggests a potential pro-autophagy response to remove damaged proteins and organelles prior to initiating mitochondrial biogenesis and remodeling responses in untrained individuals. PMID:27199762

  20. Postexercise whole body heat stress additively enhances endurance training-induced mitochondrial adaptations in mouse skeletal muscle.

    PubMed

    Tamura, Yuki; Matsunaga, Yutaka; Masuda, Hiroyuki; Takahashi, Yumiko; Takahashi, Yuki; Terada, Shin; Hoshino, Daisuke; Hatta, Hideo

    2014-10-01

    A recent study demonstrated that heat stress induces mitochondrial biogenesis in C2C12 myotubes, thereby implying that heat stress may be an effective treatment to enhance endurance training-induced mitochondrial adaptations in skeletal muscle. However, whether heat stress actually induces mitochondrial adaptations in skeletal muscle in vivo is unclear. In the present study, we report the novel findings that 1) whole body heat stress produced by exposure of ICR mice to a hot environment (40°C, 30 min/day, 5 days/wk, 3 wk) induced mitochondrial adaptations such as increased mitochondrial enzyme activity (citrate synthase and 3-hydroxyacyl CoA dehydrogenase) and respiratory chain protein content (complexes I-V) in skeletal muscle in vivo and 2) postexercise whole body heat stress additively enhanced endurance training-induced mitochondrial adaptations (treadmill running, 25 m/min, 30 min/day, 5 days/wk, 3 wk). Moreover, to determine the candidate mechanisms underlying mitochondrial adaptations, we investigated the acute effects of postexercise whole body heat stress on the phosphorylation status of cellular signaling cascades that subsequently induce mitochondrial gene transcription. We found that whole body heat stress boosted the endurance exercise-induced phosphorylation of p38 MAPK, increased the phosphorylation status of p70S6K, a biomarker of mammalian target of rapamycin complex 1 activity, and unexpectedly dephosphorylated AMP-activated protein kinase and its downstream target acetyl-CoA carboxylase in skeletal muscle. Our present observations suggest that heat stress can act as an effective postexercise treatment. Heat stress treatment appeared to be clinically beneficial for people who have difficulty participating in sufficient exercise training, such as the elderly, injured athletes, and patients.

  1. Human Mitochondrial Protein Database

    National Institute of Standards and Technology Data Gateway

    SRD 131 Human Mitochondrial Protein Database (Web, free access)   The Human Mitochondrial Protein Database (HMPDb) provides comprehensive data on mitochondrial and human nuclear encoded proteins involved in mitochondrial biogenesis and function. This database consolidates information from SwissProt, LocusLink, Protein Data Bank (PDB), GenBank, Genome Database (GDB), Online Mendelian Inheritance in Man (OMIM), Human Mitochondrial Genome Database (mtDB), MITOMAP, Neuromuscular Disease Center and Human 2-D PAGE Databases. This database is intended as a tool not only to aid in studying the mitochondrion but in studying the associated diseases.

  2. Extreme sports: extreme physiology. Exercise-induced pulmonary oedema.

    PubMed

    Ma, Joyce Lok Gee; Dutch, Martin John

    2013-08-01

    We report five patients who presented to an on-site medical team with concurrent haemoptysis and shortness of breath at a recent triathlon event. After initial management in the field, three of the five patients were transported to hospital via ambulance for further management, resulting in patients with haemoptysis and dyspnoea being 17 times more likely to require hospital transport. It is important to consider the differential diagnoses for this presentation, particularly exercise-induced pulmonary oedema.

  3. Eucapnic voluntary hyperpnoea and exercise-induced vocal cord dysfunction

    PubMed Central

    Turmel, Julie; Gagnon, Simon; Bernier, Mélanie; Boulet, Louis-Philippe

    2015-01-01

    Introduction Exercise-induced bronchoconstriction (EIB) is a common condition in endurance athletes. Exercise-induced vocal cord dysfunction (EIVCD) is a frequent confounder of EIB. The diagnosis of EIVCD may be challenging and can be missed as the problem is often intermittent and may only occur during intense exercise. Eucapnic voluntary hyperventilation (EVH) is the best test to detect EIB. This pilot study aimed to assess if EVH could be helpful in the diagnosis of EIVCD associated or not to EIB in athletes. Methods A nasolaryngoscopy was performed during a 6 min EVH test, in 13 female athletes suspected to have VCD, aged 21±7 years. Image analysis was conducted by two Ear Nose and Throat surgeons in random order. Results During the EVH, three athletes showed incomplete paradoxical vocal cords movement, without inspiratory stridor. However, 12 athletes showed marked supraglottic movement without inspiratory stridor. In two athletes, this supraglottic movement was severe, one showing a marked collapse of the epiglottis with an almost complete obstruction of the larynx by the arytenoid cartilage mucosa. In 3 of the 12 athletes with supraglottic movement, severe vibration of the mucosa covering the arytenoid cartilages was also observed. Conclusions EVH challenge in athletes can provide information on various types of glottic and supraglottic obstruction in reproducing laryngeal movements during hyperventilation. Our findings make us suggest that exercise induced upper airway obstructions should be named: Exercise-induced laryngeal obstruction (EILO). Then, EILO should be divided in three categories: supraglottic, glottic (EIVCD) and mixed (glottic and supraglottic) obstruction. PMID:27900141

  4. Airway smooth muscle in exercise-induced bronchospasm: some speculations.

    PubMed

    Middleton, E

    1975-11-01

    Some possible neurophysiological, biochemical, and pharmacological pathways affecting the state of contractility if airway smooth muscle in exercise-induced bronchospasm (EIB) are described. No unifying hypothesis can be set forth at this time. Indeed, it is likely that the heterogeneous nature of EIB is a reflection of the numerous biochemical loci in smooth muscle cells that could be affected by the various metabolic changes accompanying heavy exertion.

  5. Overloaded training increases exercise-induced oxidative stress and damage.

    PubMed

    Palazzetti, Stephane; Richard, Marie-Jeanne; Favier, Alain; Margaritis, Irene

    2003-08-01

    We hypothesized that overloaded training (OT) in triathlon would induce oxidative stress and damage on muscle and DNA. Nine male triathletes and 6 male sedentary subjects participated in this study. Before and after a 4-week OT, triathletes exercised for a duathlon. Blood ratio of reduced vs. oxidized glutathione (GSH/GSSG), plasma thiobarbituric acid reactive substances (TBARS), leukocyte DNA damage, creatine kinase (CK), and CK-MB mass in plasma, erythrocyte superoxide dismutase (SOD) activity, erythrocyte and plasma glutathione peroxidase (GSH-Px) activities, and plasma total antioxidant status (TAS) were measured before and after OT in pre- and postexercise situations. Triathletes were overloaded in response to OT. In rest conditions, OT induced plasma GSH-Px activity increase and plasma TAS decrease (both p < 0.05). In exercise conditions, OT resulted in higher exercise-induced variations of blood GSH/GSSG ratio, TBARS level (both p < 0.05), and CK-MB mass (p < 0.01) in plasma; and decreased TAS response (p < 0.05). OT could compromise the antioxidant defense mechanism with respect to exercise-induced response. The resulting increased exercise-induced oxidative stress and further cellular susceptibility to damage needs more study.

  6. Exercise induces autophagy in peripheral tissues and in the brain.

    PubMed

    He, Congcong; Sumpter, Rhea; Levine, Beth

    2012-10-01

    We recently identified physical exercise as a newly defined inducer of autophagy in vivo. Exercise induced autophagy in multiple organs involved in metabolic regulation, such as muscle, liver, pancreas and adipose tissue. To study the physiological role of exercise-induced autophagy, we generated mice with a knock-in nonphosphorylatable mutation in BCL2 (Thr69Ala, Ser70Ala and Ser84Ala) (BCL2 AAA) that are defective in exercise- and starvation-induced autophagy but not in basal autophagy. We found that BCL2 AAA mice could not run on a treadmill as long as wild-type mice, and did not undergo exercise-mediated increases in skeletal glucose muscle uptake. Unlike wild-type mice, the BCL2 AAA mice failed to reverse high-fat diet-induced glucose intolerance after 8 weeks of exercise training, possibly due to defects in signaling pathways that regulate muscle glucose uptake and metabolism during exercise. Together, these findings suggested a hitherto unknown important role of autophagy in mediating exercise-induced metabolic benefits. In the present addendum, we show that treadmill exercise also induces autophagy in the cerebral cortex of adult mice. This observation raises the intriguing question of whether autophagy may in part mediate the beneficial effects of exercise in neurodegeneration, adult neurogenesis and improved cognitive function.

  7. Peroxisome Biogenesis and Function

    PubMed Central

    Kaur, Navneet; Reumann, Sigrun; Hu, Jianping

    2009-01-01

    Peroxisomes are small and single membrane-delimited organelles that execute numerous metabolic reactions and have pivotal roles in plant growth and development. In recent years, forward and reverse genetic studies along with biochemical and cell biological analyses in Arabidopsis have enabled researchers to identify many peroxisome proteins and elucidate their functions. This review focuses on the advances in our understanding of peroxisome biogenesis and metabolism, and further explores the contribution of large-scale analysis, such as in sillco predictions and proteomics, in augmenting our knowledge of peroxisome function In Arabidopsis. PMID:22303249

  8. Curli Biogenesis and Function

    PubMed Central

    Barnhart, Michelle M.; Chapman, Matthew R.

    2010-01-01

    Curli are the major proteinaceous component of a complex extra-cellular matrix produced by many Enterobacteriaceae. Curli were first discovered in the late 1980s on Escherichia coli strains that caused bovine mastitis, and have since been implicated in many physiological and pathogenic processes of E. coli and Salmonella spp. Curli fibers are involved in adhesion to surfaces, cell aggregation, and biofilm formation. Curli also mediate host cell adhesion and invasion, and they are potent inducers of the host inflammatory response. The structure and biogenesis of curli are unique among bacterial fibers that have been described to date. Structurally and biochemically, curli belong to a growing class of fibers known as amyloids. Amyloid fiber formation is responsible for several human diseases including Alzheimer's, Huntington's, and prion diseases, although the process of in vivo amyloid formation is not well understood. Curli provide a unique system to study macromolecular assembly in bacteria and in vivo amyloid fiber formation. Here, we review curli biogenesis, regulation, role in biofilm formation, and role in pathogenesis. PMID:16704339

  9. Molecular Genetics of Mitochondrial Disorders

    ERIC Educational Resources Information Center

    Wong, Lee-Jun C.

    2010-01-01

    Mitochondrial respiratory chain (RC) disorders (RCDs) are a group of genetically and clinically heterogeneous diseases because of the fact that protein components of the RC are encoded by both mitochondrial and nuclear genomes and are essential in all cells. In addition, the biogenesis, structure, and function of mitochondria, including DNA…

  10. Regulation and quantification of cellular mitochondrial morphology and content.

    PubMed

    Tronstad, Karl J; Nooteboom, Marco; Nilsson, Linn I H; Nikolaisen, Julie; Sokolewicz, Maciek; Grefte, Sander; Pettersen, Ina K N; Dyrstad, Sissel; Hoel, Fredrik; Willems, Peter H G M; Koopman, Werner J H

    2014-01-01

    Mitochondria play a key role in signal transduction, redox homeostasis and cell survival, which extends far beyond their classical functioning in ATP production and energy metabolism. In living cells, mitochondrial content ("mitochondrial mass") depends on the cell-controlled balance between mitochondrial biogenesis and degradation. These processes are intricately linked to changes in net mitochondrial morphology and spatiotemporal positioning ("mitochondrial dynamics"), which are governed by mitochondrial fusion, fission and motility. It is becoming increasingly clear that mitochondrial mass and dynamics, as well as its ultrastructure and volume, are mechanistically linked to mitochondrial function and the cell. This means that proper quantification of mitochondrial morphology and content is of prime importance in understanding mitochondrial and cellular physiology in health and disease. This review first presents how cellular mitochondrial content is regulated at the level of mitochondrial biogenesis, degradation and dynamics. Next we discuss how mitochondrial dynamics and content can be analyzed with a special emphasis on quantitative live-cell microscopy strategies.

  11. Exercise-Induced Oxidative Stress Responses in the Pediatric Population

    PubMed Central

    Avloniti, Alexandra; Chatzinikolaou, Athanasios; Deli, Chariklia K.; Vlachopoulos, Dimitris; Gracia-Marco, Luis; Leontsini, Diamanda; Draganidis, Dimitrios; Jamurtas, Athanasios Z.; Mastorakos, George; Fatouros, Ioannis G.

    2017-01-01

    Adults demonstrate an upregulation of their pro- and anti-oxidant mechanisms in response to acute exercise while systematic exercise training enhances their antioxidant capacity, thereby leading to a reduced generation of free radicals both at rest and in response to exercise stress. However, less information exists regarding oxidative stress responses and the underlying mechanisms in the pediatric population. Evidence suggests that exercise-induced redox perturbations may be valuable in order to monitor exercise-induced inflammatory responses and as such training overload in children and adolescents as well as monitor optimal growth and development. The purpose of this review was to provide an update on oxidative stress responses to acute and chronic exercise in youth. It has been documented that acute exercise induces age-specific transient alterations in both oxidant and antioxidant markers in children and adolescents. However, these responses seem to be affected by factors such as training phase, training load, fitness level, mode of exercise etc. In relation to chronic adaptation, the role of training on oxidative stress adaptation has not been adequately investigated. The two studies performed so far indicate that children and adolescents exhibit positive adaptations of their antioxidant system, as adults do. More studies are needed in order to shed light on oxidative stress and antioxidant responses, following acute exercise and training adaptations in youth. Available evidence suggests that small amounts of oxidative stress may be necessary for growth whereas the transition to adolescence from childhood may promote maturation of pro- and anti-oxidant mechanisms. Available evidence also suggests that obesity may negatively affect basal and exercise-related antioxidant responses in the peripubertal period during pre- and early-puberty. PMID:28106721

  12. Exercise-Induced Oxidative Stress Responses in the Pediatric Population.

    PubMed

    Avloniti, Alexandra; Chatzinikolaou, Athanasios; Deli, Chariklia K; Vlachopoulos, Dimitris; Gracia-Marco, Luis; Leontsini, Diamanda; Draganidis, Dimitrios; Jamurtas, Athanasios Z; Mastorakos, George; Fatouros, Ioannis G

    2017-01-17

    Adults demonstrate an upregulation of their pro- and anti-oxidant mechanisms in response to acute exercise while systematic exercise training enhances their antioxidant capacity, thereby leading to a reduced generation of free radicals both at rest and in response to exercise stress. However, less information exists regarding oxidative stress responses and the underlying mechanisms in the pediatric population. Evidence suggests that exercise-induced redox perturbations may be valuable in order to monitor exercise-induced inflammatory responses and as such training overload in children and adolescents as well as monitor optimal growth and development. The purpose of this review was to provide an update on oxidative stress responses to acute and chronic exercise in youth. It has been documented that acute exercise induces age-specific transient alterations in both oxidant and antioxidant markers in children and adolescents. However, these responses seem to be affected by factors such as training phase, training load, fitness level, mode of exercise etc. In relation to chronic adaptation, the role of training on oxidative stress adaptation has not been adequately investigated. The two studies performed so far indicate that children and adolescents exhibit positive adaptations of their antioxidant system, as adults do. More studies are needed in order to shed light on oxidative stress and antioxidant responses, following acute exercise and training adaptations in youth. Available evidence suggests that small amounts of oxidative stress may be necessary for growth whereas the transition to adolescence from childhood may promote maturation of pro- and anti-oxidant mechanisms. Available evidence also suggests that obesity may negatively affect basal and exercise-related antioxidant responses in the peripubertal period during pre- and early-puberty.

  13. Poxvirus membrane biogenesis.

    PubMed

    Moss, Bernard

    2015-05-01

    Poxviruses differ from most DNA viruses by replicating entirely within the cytoplasm. The first discernible viral structures are crescents and spherical immature virions containing a single lipoprotein membrane bilayer with an external honeycomb lattice. Because this viral membrane displays no obvious continuity with a cellular organelle, a de novo origin was suggested. Nevertheless, transient connections between viral and cellular membranes could be difficult to resolve. Despite the absence of direct evidence, the intermediate compartment (ERGIC) between the endoplasmic reticulum (ER) and Golgi apparatus and the ER itself were considered possible sources of crescent membranes. A break-through in understanding poxvirus membrane biogenesis has come from recent studies of the abortive replication of several vaccinia virus null mutants. Novel images showing continuity between viral crescents and the ER and the accumulation of immature virions in the expanded ER lumen provide the first direct evidence for a cellular origin of this poxvirus membrane.

  14. Exercise-Induced growth hormone during acute sleep deprivation.

    PubMed

    Ritsche, Kevin; Nindl, Bradly C; Wideman, Laurie

    2014-10-01

    The effect of acute (24-h) sleep deprivation on exercise-induced growth hormone (GH) and insulin-like growth factor-1 (IGF-1) was examined. Ten men (20.6 ± 1.4 years) completed two randomized 24-h sessions including a brief, high-intensity exercise bout following either a night of sleep (SLEEP) or (24-h) sleep deprivation (SLD). Anaerobic performance (mean power [MP], peak power [PP], minimum power [MinP], time to peak power [TTPP], fatigue index, [FI]) and total work per sprint [TWPS]) was determined from four maximal 30-sec Wingate sprints on a cycle ergometer. Self-reported sleep 7 days prior to each session was similar between SLEEP and SLD sessions (7.92 ± 0.33 vs. 7.98 ± 0.39 h, P = 0.656, respectively) and during the actual SLEEP session in the lab, the total amount of sleep was similar to the 7 days leading up to the lab session (7.72 ± 0.14 h vs. 7.92 ± 0.33 h, respectively) (P = 0.166). No differences existed in MP, PP, MinP, TTPP, FI, TWPS, resting GH concentrations, time to reach exercise-induced peak GH concentration (TTP), or free IGF-1 between sessions. GH area under the curve (AUC) (825.0 ± 199.8 vs. 2212.9 ± 441.9 μg/L*min, P < 0.01), exercise-induced peak GH concentration (17.8 ± 3.7 vs. 39.6 ± 7.1 μg/L, P < 0.01) and ΔGH (peak GH - resting GH) (17.2 ± 3.7 vs. 38.2 ± 7.3 μg/L, P < 0.01) were significantly lower during the SLEEP versus SLD session. Our results indicate that the exercise-induced GH response was significantly augmented in sleep-deprived individuals.

  15. Sinusitis and chronic progressive exercise-induced cough and dyspnea.

    PubMed

    Williams, Adam N; Simon, Ronald A; Woessner, Katharine M

    2008-01-01

    We present the case of a 47-year-old man with exercise-induced dyspnea, cough, chest tightness, and recalcitrant chronic rhinosinusitis. Evaluation revealed IgE sensitization to grass, tree, and weed pollen, no evidence of obstruction on spirometry, and a negative methacholine challenge. Diagnostic considerations included allergic and nonallergic rhinitis, asthma, aspirin-exacerbated respiratory disease, vocal cord dysfunction, extra-esophageal manifestations of acid reflux, and vasculitits. Further evaluation with sinus imaging, laryngoscopy, ambulatory pharyngeal pH testing, upper endoscopy, and bronchoscopy led to a diagnosis. Key issues surrounding the diagnostic and therapeutic approaches to this patient's condition are reviewed.

  16. Exercise-induced endocannabinoid signaling is modulated by intensity.

    PubMed

    Raichlen, David A; Foster, Adam D; Seillier, Alexandre; Giuffrida, Andrea; Gerdeman, Gregory L

    2013-04-01

    Endocannabinoids (eCB) are endogenous ligands for cannabinoid receptors that are densely expressed in brain networks responsible for reward. Recent work shows that exercise activates the eCB system in humans and other mammals, suggesting eCBs are partly responsible for the reported improvements in mood and affect following aerobic exercise in humans. However, exercise-induced psychological changes reported by runners are known to be dependent on exercise intensity, suggesting that any underlying molecular mechanism should also change with varying levels of exercise intensity. Here, we examine circulating levels of eCBs following aerobic exercise (treadmill running) in recreationally fit human runners at four different intensities. We show that eCB signaling is indeed intensity dependent, with significant changes in circulating eCBs observed following moderate intensities only (very high and very low intensity exercises do not significantly alter circulating eCB levels). Our results are consistent with intensity-dependent psychological state changes with exercise and therefore support the hypothesis that eCB activity is related to neurobiological effects of exercise. Thus, future studies examining the role of exercise-induced eCB signaling on neurobiology or physiology must take exercise intensity into account.

  17. The influence of exercise-induced fatigue on cognitive function.

    PubMed

    Moore, Robert D; Romine, Mathew W; O'connor, Patrick J; Tomporowski, Phillip D

    2012-05-01

    Although anecdotal reports suggest that information processing and decision making is impaired immediately following prolonged periods of physical activity, results obtained from laboratory studies of exercise-induced fatigue have been inconsistent. Fatigue effects may be task specific and related to the time of post-exercise testing. The present study examined the effects on adults' performance of two cognitive tasks that differed in processing demands over an 80-min period of fatigue. Thirty young adult men and women were randomly assigned to either an exercise group and completed a 60-min bout of cycle ergometry at 90% ventilatory threshold or a control group and rested for 60 min. Following interventions, each participant completed a simple and complex version of a visual perceptual discrimination test, a 40-min memory-based vigilance test and a repetition of the visual perceptual discrimination tests. Those who exercised evidenced significant decrements in performance on complex perceptual-discrimination tasks compared to participants who rested. The response time of exercisers during a memory-demanding vigilance test were significantly slower than those of participants who rested; however, detection performance did not differ between groups neither was there a decrease in target detection across the vigil. The effects of exercise-induced fatigue may be task specific, with greater effects on perceptual tasks, which involve relatively automatic processing, compared to effortful memory-based tasks.

  18. Exercise-induced bronchoconstriction and atopy in Tunisian athletes

    PubMed Central

    Sallaoui, Ridha; Chamari, Karim; Mossa, Abbas; Tabka, Zouhair; Chtara, Moktar; Feki, Youssef; Amri, Mohamed

    2009-01-01

    Background This study is a cross sectional analysis, aiming to evaluate if atopy is as a risk factor for exercise induced bronchoconstriction (EIB) among Tunisian athletes. Methods Atopy was defined by a skin prick test result and EIB was defined as a decrease of at least 15% in forced expiratory volume in one second (FEV1) after 8-min running at 80–85% HRmaxTheo. The study population was composed of 326 athletes (age: 20.8 ± 2.7 yrs – mean ± SD; 138 women and 188 men) of whom 107 were elite athletes. Results Atopy was found in 26.9% (88/326) of the athletes. Post exercise spirometry revealed the presence of EIB in 9.8% of the athletes including 13% of the elite athletes. Frequency of atopy in athletes with EIB was significantly higher than in athletes without EIB [62.5% vs 23.1%, respectively]. Conclusion This study showed that atopic Tunisian athletes presented a higher risk of developing exercise induced bronchoconstriction than non-atopic athletes. PMID:19196480

  19. Effect of simulated weightlessness on exercise-induced anaerobic threshold

    NASA Technical Reports Server (NTRS)

    Convertino, V. A.; Karst, G. M.; Kirby, C. R.; Goldwater, D. J.

    1986-01-01

    The effect of simulated weightlessness, induced by ten days of continuous bedrest (BR) in the -6 deg head-down position, on the exercise-induced anaerobic threshold (AT) was determined by comparing specific ventilatory and gas-exchange measurements during an incremental ergometer test performed before and after BR. The primary index for determining the exercise-induced AT values of each subject was visual identification of the workrate or oxygen uptake (VO2) at which the ratio of the expired minute ventilation volume (VE) to VO2 exhibited a systematic increase without a concomitant increase in the VE/VCO2 value. Following BR, the mean VO2max of the subjects decreased by 7.0 percent, and the AT decreased from a mean of 1.26 L/min VO2 before BR to 0.95 L/min VO2 after BR. The decrease in AT was manifested by a decrease in both absolute and relative workrates. The change in AT correlated significantly with the change in plasma volume but not with the change in VO2max. The results suggest that the reduction in AT cannot be completely explained by the reduction in VO2, and that the AT decrease is associated with the reduction in intravascular fluid volume.

  20. Acute exercise-induced bilateral thigh compartment syndrome.

    PubMed

    Boland, Michael R; Heck, Chris

    2009-03-01

    Acute compartment syndrome of the thigh is rare due to the space's ability to accommodate large volumes of fluid and, with the exception of the lateral septum, its thin compliant linings. This article describes a case of bilateral exercise-induced severe compartment syndrome treated with anterior and posterior fasciotomies. A 29-year-old man was admitted to intensive care with myoglobinuria. His left thigh was evaluated 18 hours later for compartment syndrome. The patient reported that 14 hours prior to initial presentation, he had participated in a 1-hour session of vigorous basketball. He gradually developed bilateral moderately severe thigh pain and tea-colored urine. Physical examination revealed pain secondary to passive stretch of both knees at 20 degrees flexion, plus firm anterior and posterior compartments to palpation. A handheld pressure monitor revealed the following compartment pressures: left anterior 80 mm Hg; left posterior 75 mm Hg; right anterior 45 mm Hg; and right posterior 50 mm Hg. Bilateral emergent anterior and posterior compartment fasciotomies were performed. The patient developed a significant severe distal motor and sensory neurological deficit on the left side, which recovered to 3/5 motor strength and protective sensation. At 6-month follow-up, he ambulated with the assistance of a left ankle foot orthosis. Acute severe compartment syndrome can occur following vigorous exercise. We recommend fasciotomies after exercise-induced acute compartment syndrome rather than initial observation because of the severity of morbidity associated with undertreated compartment syndrome.

  1. Exploring the Relationship between Exercise-Induced Arousal and Cognition Using Fractionated Response Time

    ERIC Educational Resources Information Center

    Chang, Yu-Kai; Etnier, Jennifer L.; Barella, Lisa A.

    2009-01-01

    Although a generally positive effect of acute exercise on cognitive performance has been demonstrated, the specific nature of the relationship between exercise-induced arousal and cognitive performance remains unclear. This study was designed to identify the relationship between exercise-induced arousal and cognitive performance for the central…

  2. Effects of nedocromil sodium, cromolyn sodium, and a placebo in exercise-induced asthma.

    PubMed

    Morton, A R; Ogle, S L; Fitch, K D

    1992-02-01

    The incidence and severity of exercise-induced asthma were determined in nineteen asthmatic patients who performed eight minutes of exercise following four treatments administered in a random order. The treatments were nedocromil sodium, cromolyn sodium, placebo, and no treatment. It was concluded that nedocromil sodium (8 mg) and cromolyn sodium (4 mg) provide equal protection against exercise-induced asthma.

  3. Familial Paroxysmal Exercise-Induced Dystonia: Atypical Presentation of Autosomal Dominant GTP-Cyclohydrolase 1 Deficiency

    ERIC Educational Resources Information Center

    Dale, Russell C.; Melchers, Anna; Fung, Victor S. C.; Grattan-Smith, Padraic; Houlden, Henry; Earl, John

    2010-01-01

    Paroxysmal exercise-induced dystonia (PED) is one of the rarer forms of paroxysmal dyskinesia, and can occur in sporadic or familial forms. We report a family (male index case, mother and maternal grandfather) with autosomal dominant inheritance of paroxysmal exercise-induced dystonia. The dystonia began in childhood and was only ever induced…

  4. Suspected exercise-induced seizures in a young dog.

    PubMed

    Motta, L; Dutton, E

    2013-04-01

    A 12-month-old female neutered crossbreed was referred for investigation of seizure-like episodes occurring only at intense exercise. Thorough medical, neurological and cardiac investigations were performed and excluded the most commonly known causes of seizure-like activity. The dog was fitted with an ambulatory electrocardiography device and underwent another exercise-induced seizure. The electrocardiogram during the episode revealed a sinus tachycardia at approximately 300 beats/minute. A video recording of the episode revealed generalised tonic clonic limb activity with jaw chomping and frothing at the mouth typical of seizure activity. Antiepileptic medications were not prescribed and the owner was advised not to exercise the dog intensely. The dog responded well and did not seizure after 12 months of mild-moderate off-lead exercise. As all the seizures in this case were triggered by intense physical activity, it is suggested that this may be a new form of reflex seizure activity.

  5. Dietary strategies to recover from exercise-induced muscle damage.

    PubMed

    Sousa, Mónica; Teixeira, Vítor H; Soares, José

    2014-03-01

    Exhaustive or unaccustomed intense exercise can cause exercise-induced muscle damage (EIMD) and its undesirable consequences may decrease the ability to exercise and to adhere to a training programme. This review briefly summarises the muscle damage process, focusing predominantly on oxidative stress and inflammation as contributing factors, and describes how nutrition may be positively used to recover from EIMD. The combined intake of carbohydrates and proteins and the use of antioxidants and/or anti-inflammatory nutrients within physiological ranges are interventions that may assist the recovery process. Although the works studying food instead of nutritional supplements are very scarce, their results seem to indicate that food might be a favourable option as a recovery strategy. To date, the only tested foods were milk, cherries, blueberries and pomegranate with promising results. Other potential solutions are foods rich in protein, carbohydrates, antioxidants and/or anti-inflammatory nutrients.

  6. Oral biomarkers in exercise-induced neuroplasticity in Parkinson's disease.

    PubMed

    Mougeot, J-Lc; Hirsch, M A; Stevens, C B; Mougeot, Fkb

    2016-11-01

    In this article, we review candidate biomarkers for Parkinson's disease (PD) in oral cavity, potential of oral biomarkers as markers of neuroplasticity, and literature on the effects of exercise on oral cavity biomarkers in PD. We first describe how pathophysiological pathways of PD may be transduced from brain stem and ganglia to oral cavity through the autonomic nervous system or transduced by a reverse path. Next we describe the effects of exercise in PD and potential impact on oral cavity. We propose that biomarkers in oral cavity may be useful targets for describing exercise-induced brain neuroplasticity in PD. Nevertheless, much research remains to be carried out before applying these biomarkers for the determination of disease state and therapeutic response to develop strategies to mitigate motor or non-motor symptoms in PD.

  7. The inflammatory basis of exercise-induced bronchoconstriction.

    PubMed

    Brannan, John D; Turton, James A

    2010-12-01

    Exercise-induced bronchoconstriction (EIB) is common in individuals with asthma, and may be observed even in the absence of a clinical diagnosis of asthma. Exercise-induced bronchoconstriction can be diagnosed via standardized exercise protocols, and anti-inflammatory therapy with inhaled corticosteroids (ICS) is often warranted. Exercise-related symptoms are commonly reported in primary care; however, access to standardized exercise protocols to assess EIB are often restricted because of the need for specialized equipment, as well as time constraints. Symptoms and lung function remain the most accessible indicators of EIB, yet these are poor predictors of its presence and severity. Evidence suggests that exercise causes the airways to narrow as a result of the osmotic and thermal consequences of respiratory water loss. The increase in airway osmolarity leads to the release of bronchoconstricting mediators (eg, histamine, prostaglandins, leukotrienes) from inflammatory cells (eg, mast cells and eosinophils). The objective assessment of EIB suggests the presence of airway inflammation, which is sensitive to ICS in association with a responsive airway smooth muscle. Surrogate tests for EIB, such as eucapnic voluntary hyperpnea or the osmotic challenge tests, cause airway narrowing via a similar mechanism, and a response indicates likely benefit from ICS therapy. The complete inhibition of EIB with ICS therapy in individuals with asthma may be a useful marker of control of airway pathology. Furthermore, inhibition of EIB provides additional, useful information regarding the identification of clinical control based on symptoms and lung function. This article explores the inflammatory basis of EIB in asthma as well as the effect of ICS on the pathophysiology of EIB.

  8. Exercise-induced muscle cramp. Proposed mechanisms and management.

    PubMed

    Bentley, S

    1996-06-01

    Muscle cramp is a common, painful, physiological disturbance of skeletal muscle. Many athletes are regularly frustrated by exercise-induced muscle cramp yet the pathogenesis remains speculative with little scientific research on the subject. This has resulted in a perpetuation of myths as to the cause and treatment of it. There is a need for scientifically based protocols for the management of athletes who suffer exercise-related muscle cramp. This article reviews the literature and neurophysiology of muscle cramp occurring during exercise. Disturbances at various levels of the central and peripheral nervous system and skeletal muscle are likely to be involved in the mechanism of cramp and may explain the diverse range of conditions in which cramp occurs. The activity of the motor neuron is subject to a multitude of influences including peripheral receptor sensory input, spinal reflexes, inhibitory interneurons in the spinal cord, synaptic and neurotransmitter modulation and descending CNS input. The muscle spindle and golgi tendon organ proprioceptors are fundamental to the control of muscle length and tone and the maintenance of posture. Disturbance in the activity of these receptors may occur through faulty posture, shortened muscle length, intense exercise and exercise to fatigue, resulting in increased motor neuron activity and motor unit recruitment. The relaxation phase of muscle contraction is prolonged in a fatigued muscle, raising the likelihood of fused summation of action potentials if motor neuron activity delivers a sustained high firing frequency. Treatment of cramp is directed at reducing muscle spindle and motor neuron activity by reflex inhibition and afferent stimulation. There are no proven strategies for the prevention of exercise-induced muscle cramp but regular muscle stretching using post-isometric relaxation techniques, correction of muscle balance and posture, adequate conditioning for the activity, mental preparation for competition and

  9. The role of muscle mass in exercise-induced hyperemia.

    PubMed

    Garten, Ryan S; Groot, H Jonathan; Rossman, Matthew J; Gifford, Jayson R; Richardson, Russell S

    2014-05-01

    Exercise-induced hyperemia is often normalized for muscle mass, and this value is sometimes evaluated at relative exercise intensities to take muscle recruitment into account. Therefore, this study sought to better understand the impact of muscle mass on leg blood flow (LBF) during exercise. LBF was assessed by Doppler ultrasound in 27 young healthy male subjects performing knee-extensor (KE) exercise at three absolute (5, 15, and 25 W) and three relative [20, 40, and 60% of maximum KE (KEmax)] workloads. Thigh muscle mass (5.2-8.1 kg) and LBF were significantly correlated at rest (r = 0.54; P = 0.004). Exercise-induced hyperemia was linearly related to absolute workload, but revealed substantial between-subject variability, documented by the coefficient of variation (5 W: 17%; 15 W: 16%; 25 W: 16%). Quadriceps muscle mass (1.5-2.7 kg) and LBF were not correlated at 5, 15, or 25 W (r = 0.09-0.01; P = 0.7-0.9). Normalizing blood flow for quadriceps muscle mass did not improve the coefficient of variation at each absolute workload (5 W: 21%; 15 W: 21%; 25 W: 22%), while the additional evaluation at relative exercise intensities resulted in even greater variance (20% KEmax: 29%; 40% KEmax: 29%; 60% KEmax: 27%). Similar findings were documented when subjects were parsed into high and low aerobic capacity. Thus, in contrast to rest, blood flow during exercise is unrelated to muscle mass, and simply normalizing for muscle mass or comparing normalized blood flow at a given relative exercise intensity has no effect on the inherent blood flow variability. Therefore, during exercise, muscle mass does not appear to be a determinant of the hyperemic response.

  10. Cellulose biogenesis in Dictyostelium discoideum

    SciTech Connect

    Blanton, R.L.

    1993-12-31

    Organisms that synthesize cellulose can be found amongst the bacteria, protistans, fungi, and animals, but it is in plants that the importance of cellulose in function (as the major structural constituent of plant cell walls) and economic use (as wood and fiber) can be best appreciated. The structure of cellulose and its biosynthesis have been the subjects of intense investigation. One of the most important insights gained from these studies is that the synthesis of cellulose by living organisms involves much more than simply the polymerization of glucose into a (1{r_arrow}4)-{beta}-linked polymer. The number of glucoses in a polymer (the degree of polymerization), the crystalline form assumed by the glucan chains when they crystallize to form a microfibril, and the dimensions and orientation of the microfibrils are all subject to cellular control. Instead of cellulose biosynthesis, a more appropriate term might be cellulose biogenesis, to emphasize the involvement of cellular structures and mechanisms in controlling polymerization and directing crystallization and deposition. Dictyostelium discoideum is uniquely suitable for the study of cellulose biogenesis because of its amenability to experimental study and manipulation and the extent of our knowledge of its basic cellular mechanisms (as will be evident from the rest of this volume). In this chapter, I will summarize what is known about cellulose biogenesis in D. discoideum, emphasizing its potential to illuminate our understanding both of D. discoideum development and plant cellulose biogenesis.

  11. Exercise-Induced Pulmonary Edema in a Triathlon

    PubMed Central

    Yamanashi, Hirotomo; Koyamatsu, Jun; Nobuyoshi, Masaharu; Murase, Kunihiko; Maeda, Takahiro

    2015-01-01

    Introduction. Family physicians have more opportunities to attend athletic competitions as medical staff at first-aid centers because of the increasing popularity of endurance sports. Case. A 38-year-old man who participated in a triathlon race experienced difficulty in breathing after swimming and was moved to a first-aid center. His initial oxygen saturation was 82% and a thoracic computed tomography scan showed bilateral ground glass opacity in the peripheral lungs. His diagnosis was noncardiogenic pulmonary edema associated with exercise or swimming: exercise-induced pulmonary edema (EIPE) or swimming-induced pulmonary edema (SIPE). Treatment with furosemide and corticosteroid relieved his symptoms of pulmonary edema. Discussion. Noncardiogenic pulmonary edema associated with endurance sports is not common, but knowledge about EIPE/SIPE or neurogenic pulmonary edema associated with hyponatremia, which is called Ayus-Arieff syndrome, is crucial. Knowledge and caution for possible risk factors, such as exposure to cold water or overhydration, are essential for both medical staff and endurance athletes. Conclusion. To determine the presence of pulmonary edema associated with strenuous exercise, oxygen saturation should be used as a screening tool at a first-aid center. To avoid risks for EIPE/SIPE, knowledge about these diseases is essential for medical staff and for athletes who perform extreme exercise. PMID:26229538

  12. Resistance to exercise-induced weight loss: compensatory behavioral adaptations.

    PubMed

    Melanson, Edward L; Keadle, Sarah Kozey; Donnelly, Joseph E; Braun, Barry; King, Neil A

    2013-08-01

    In many interventions that are based on an exercise program intended to induce weight loss, the mean weight loss observed is modest and sometimes far less than what the individual expected. The individual responses are also widely variable, with some individuals losing a substantial amount of weight, others maintaining weight, and a few actually gaining weight. The media have focused on the subpopulation that loses little weight, contributing to a public perception that exercise has limited utility to cause weight loss. The purpose of the symposium was to present recent, novel data that help explain how compensatory behaviors contribute to a wide discrepancy in exercise-induced weight loss. The presentations provide evidence that some individuals adopt compensatory behaviors, that is, increased energy intake and/or reduced activity, that offset the exercise energy expenditure and limit weight loss. The challenge for both scientists and clinicians is to develop effective tools to identify which individuals are susceptible to such behaviors and to develop strategies to minimize their effect.

  13. Lycium barbarum Polysaccharides Reduce Exercise-Induced Oxidative Stress

    PubMed Central

    Shan, Xiaozhong; Zhou, Junlai; Ma, Tao; Chai, Qiongxia

    2011-01-01

    The purpose of the present study was to investigate the effects of Lycium barbarum polysaccharides (LBP) on exercise-induced oxidative stress in rats. Rats were divided into four groups, i.e., one control group and three LBP treated groups. The animals received an oral administration of physiological saline or LBP (100, 200 and 400 mg/kg body weight) for 28 days. On the day of the exercise test, rats were required to run to exhaustion on the treadmill. Body weight, endurance time, malondialdehyde (MDA), super oxide dismutase (SOD) and glutathione peroxidase (GPX) level of rats were measured. The results showed that the body weight of rats in LBP treated groups were not significantly different from that in the normal control group before and after the experiment (P > 0.05). After exhaustive exercise, the mean endurance time of treadmill running to exhaustion of rats in LBP treated groups were significantly prolonged compared with that in the normal control group. MDA levels of rats in LBP treated groups were significantly decreased compared with that in the normal control group (P < 0.05). SOD and GPX levels of rats in LBP treated groups were significantly increased compared with that in the normal control group (P < 0.05). Together, these results indicate that LBP was effective in preventing oxidative stress after exhaustive exercise. PMID:21541044

  14. Exercise-Induced Muscle Damage and Running Economy in Humans

    PubMed Central

    Assumpção, Cláudio de Oliveira; Lima, Leonardo Coelho Rabello; Oliveira, Felipe Bruno Dias; Greco, Camila Coelho; Denadai, Benedito Sérgio

    2013-01-01

    Running economy (RE), defined as the energy demand for a given velocity of submaximal running, has been identified as a critical factor of overall distance running performance. Plyometric and resistance trainings, performed during a relatively short period of time (~15–30 days), have been successfully used to improve RE in trained athletes. However, these exercise types, particularly when they are unaccustomed activities for the individuals, may cause delayed onset muscle soreness, swelling, and reduced muscle strength. Some studies have demonstrated that exercise-induced muscle damage has a negative impact on endurance running performance. Specifically, the muscular damage induced by an acute bout of downhill running has been shown to reduce RE during subsequent moderate and high-intensity exercise (>65% VO2max). However, strength exercise (i.e., jumps, isoinertial and isokinetic eccentric exercises) seems to impair RE only for subsequent high-intensity exercise (~90% VO2max). Finally, a single session of resistance exercise or downhill running (i.e., repeated bout effect) attenuates changes in indirect markers of muscle damage and blunts changes in RE. PMID:23431253

  15. Exercise-Induced Vasculitis: A Review with Illustrated Cases.

    PubMed

    Espitia, Olivier; Dréno, Brigitte; Cassagnau, Elisabeth; Didier, Quentin; Quillard, Thibaut; Nicol, Christelle; Le Bouch, Yann; Planchon, Bernard; Pistorius, Marc-Antoine

    2016-12-01

    Although exercise-induced vasculitis (EIV) is usually misdiagnosed, it is not uncommon. Occurring mostly after prolonged exercise, especially in hot weather, EIV is an isolated cutaneous vasculitis with stereotypical presentation. This article reviews the clinical characteristics, treatments, and outcomes of EIV based on the published literature. We report 99 patients who developed EIV after walking, dancing, swimming, or hiking especially during hot weather, including the records of 16 patients with EIV treated at our hospital from 2007 to 2015. Erythematous or purpuric plaques arise on the lower legs, without the involvement of compression socks or stockings. Symptoms include itch, pain, and a burning sensation. EIV is an isolated cutaneous vasculitis. Lesions resolve spontaneously after 10 days. When triggering conditions persist, relapses are frequent (77.5 %). Histopathology demonstrates leukocytoclastic vasculitis in 95 % of cases with C3 or immunoglobulin M deposits in 88 and 46 % of cases, respectively. Blood investigations are negative. EIV appears to be a consequence of venous stasis induced by an acute failure of the muscle pump of the calf and thermoregulation decompensation. Both appear after prolonged and unusual exercise in hot weather. Treatment is not codified; topical corticosteroids may reduce symptoms and wearing light clothes might limit lesion occurrence.

  16. Provocation by eucapnic voluntary hyperpnoea to identify exercise induced bronchoconstriction

    PubMed Central

    Anderson, S; Argyros, G; Magnussen, H; Holzer, K

    2001-01-01

    The International Olympic Committee Medical Commission (IOC-MC) requires notification for use of a ß2 agonist at the Winter Olympic Games in Salt Lake City. This notification will be required seven days before the event and must be accompanied by objective evidence that justifies the need to use one. The IOC-MC has expressed the viewpoint that, at present, eucapnic voluntary hyperpnoea (EVH) is the optimal laboratory challenge to confirm that an athlete has exercise induced bronchoconstriction (EIB). The EVH test recommended was specifically designed to identify EIB. EVH has been performed in thousands of subjects in both the laboratory and the field. The test requires the subject to hyperventilate dry air containing 5% carbon dioxide at room temperature for six minutes at a target ventilation of 30 times the subject's forced expiratory volume in one second (FEV1). The test conditions can be modified to simulate the conditions that give the athlete their symptoms with exercise. A reduction in FEV1 of 10% or more of the value before the test is considered positive. Key Words: hyperpnoea; bronchial provocation; exercise PMID:11579071

  17. [Exercise-induced urticaria and angioedema - case report].

    PubMed

    Stelmach, Iwona; Sztafińska, Anna; Lechańka, Joanna; Balcerak, Joanna; Jerzyńska, Joanna

    2014-01-01

    Urticaria is a heterogeneous group of disorders, with various clinical manifestations and intensity of symptoms. Urticaria can be induced with a wide variety of environmental stimuli, such as cold, pressure, vibration, sunlight, exercise, temperature changes, heat, and water. In a select group of patients, exercise can induce a spectrum of urticaria symptoms, ranging from cutaneous pruritus and warmth, generalised urticaria, angioedema, and the appearance of such additional manifestations as collapse, upper respiratory distress, and anaphylaxis. Specific provocation tests should be carried out on an individual basis to investigate the suspected cause and proper diagnosis. Modification of activities and behaviour is the mainstay of treatment in patients with physical urticaria. The aim of this study was to emphasise that primary care paediatricians should be able to recognise physical urticaria, supply a patient with rescue medications, and refer him/her to a specialist. In the article, the authors present a 13-year-old girl with typical urticaria lesions and angioedema after exercise. According to the history, physical examination, and provocation test, exercise-induced urticaria and angioedema were diagnosed.

  18. Knee proprioception after exercise-induced muscle damage.

    PubMed

    Torres, R; Vasques, J; Duarte, J A; Cabri, J M H

    2010-06-01

    The purpose of the present study was to investigate whether exercise-induced quadriceps muscle damage affects knee proprioception such as joint position sense (JPS), force sense and the threshold to detect passive movement (TTDPM). Fourteen young men performed sets of eccentric quadriceps contractions at a target of 60% of the maximal concentric peak torque until exhaustion; the exercise was interrupted whenever the subject could not complete two sets. Muscle soreness, JPS, the TTDPM and force sense were examined before the exercise as well as one, 24, 48, 72 and 96 h after exercise. The results were compared using one-way repeated-measure ANOVA. Plasma CK activity, collected at the same times, was analyzed by the Friedman's test to discriminate differences between baseline values and each of the other assessment moments (p<0.05). Relative to the proprioception assessment, JPS at 30 and 70 degrees of knee flexion and force sense were significantly decreased up to 48 h, whereas TTDPM decreased significantly at only one hour and 24 h after exercise, at 30 and 70 degrees of the knee flexion, respectively. The results allow the conclusion that eccentric exercise leading to muscle damage alters joint proprioception, suggesting that there might be impairment in the intrafusal fibres of spindle muscles and in the tendon organs.

  19. Regulation of skeletal muscle mitochondrial function by nuclear receptors: implications for health and disease.

    PubMed

    Perez-Schindler, Joaquin; Philp, Andrew

    2015-10-01

    Skeletal muscle metabolism is highly dependent on mitochondrial function, with impaired mitochondrial biogenesis associated with the development of metabolic diseases such as insulin resistance and type 2 diabetes. Mitochondria display substantial plasticity in skeletal muscle, and are highly sensitive to levels of physical activity. It is thought that physical activity promotes mitochondrial biogenesis in skeletal muscle through increased expression of genes encoded in both the nuclear and the mitochondrial genome; however, how this process is co-ordinated at the cellular level is poorly understood. Nuclear receptors (NRs) are key signalling proteins capable of integrating environmental factors and mitochondrial function, thereby providing a potential link between exercise and mitochondrial biogenesis. The aim of this review is to highlight the function of NRs in skeletal muscle mitochondrial biogenesis and discuss the therapeutic potential of NRs for the management and treatment of chronic metabolic disease.

  20. Modulation of mitochondrial biomarkers by intermittent hypobaric hypoxia and aerobic exercise after eccentric exercise in trained rats.

    PubMed

    Rizo-Roca, David; Ríos-Kristjánsson, Juan Gabriel; Núñez-Espinosa, Cristian; Santos-Alves, Estela; Magalhães, José; Ascensão, António; Pagès, Teresa; Viscor, Ginés; Torrella, Joan Ramon

    2017-02-02

    Unaccustomed eccentric contractions induce muscle damage, calcium homeostasis disruption and mitochondrial alterations. Since exercise and hypoxia are known to modulate mitochondrial function, we aimed to analyze the effects on eccentric exercise-induced muscle damage (EEIMD), in trained rats, of two recovery protocols based on: 1) intermittent hypobaric hypoxia (IHH) and 2) IHH followed by exercise. The expression of biomarkers related to mitochondrial biogenesis, dynamics, oxidative stress and bioenergetics was evaluated. Soleus muscles were excised before (CTRL) and 1, 3, 7 and 14 days after an EEIMD protocol. The following treatments were applied one day after the EEIMD: passive normobaric recovery (PNR), four-hour daily exposure to passive IHH at 4000m (PHR) or IHH exposure followed by aerobic exercise (AHR). Citrate synthase activity had reduced 7 and 14 days after application of the EEIMD protocol. However, this reduction was attenuated in AHR rats at day 14. PGC-1α and Sirt3 and TOM20 levels had decreased after 1 and 3 days, but the AHR group exhibited increased expression of these proteins, as well as of Tfam, by the end of the protocol. Mfn2 greatly reduced during the first 72 h, but returned to basal levels passively. At day 14, AHR rats had higher levels of Mfn2, OPA1 and Drp1 than PNR animals. Both groups exposed to IHH showed a lower p66shc(ser36)/p66shc ratio than PNR animals, as well as higher complex IV subunit I and ANT levels. These results suggest that IHH positively modulates key mitochondrial aspects after EEIMD, especially when combined with aerobic exercise.

  1. mCSF1, a nucleus-encoded CRM protein required for the processing of many mitochondrial introns, is involved in the biogenesis of respiratory complexes I and IV in Arabidopsis.

    PubMed

    Zmudjak, Michal; Colas des Francs-Small, Catherine; Keren, Ido; Shaya, Felix; Belausov, Eduard; Small, Ian; Ostersetzer-Biran, Oren

    2013-07-01

    The coding regions of many mitochondrial genes in plants are interrupted by intervening sequences that are classified as group II introns. Their splicing is essential for the expression of the genes they interrupt and hence for respiratory function, and is facilitated by various protein cofactors. Despite the importance of these cofactors, only a few of them have been characterized. CRS1-YhbY domain (CRM) is a recently recognized RNA-binding domain that is present in several characterized splicing factors in plant chloroplasts. The Arabidopsis genome encodes 16 CRM proteins, but these are largely uncharacterized. Here, we analyzed the intracellular location of one of these hypothetical proteins in Arabidopsis, mitochondrial CAF-like splicing factor 1 (mCSF1; At4 g31010), and analyzed the growth phenotypes and organellar activities associated with mcsf1 mutants in plants. Our data indicated that mCSF1 resides within mitochondria and its functions are essential during embryogenesis. Mutant plants with reduced mCSF1 displayed inhibited germination and retarded growth phenotypes that were tightly associated with reduced complex I and IV activities. Analogously to the functions of plastid-localized CRM proteins, analysis of the RNA profiles in wildtype and mcsf1 plants showed that mCSF1 acts in the splicing of many of the group II intron RNAs in Arabidopsis mitochondria.

  2. Exercise-induced silent myocardial ischemia in patients with vasospastic angina

    SciTech Connect

    Aoki, M.; Koyanagi, S.; Sakai, K.; Irie, T.; Takeshita, A.; Nakamura, M.; Nakagaki, O. )

    1990-03-01

    To clarify the incidence and clinical characteristics of exercise-induced myocardial ischemia in patients with vasospastic angina, we performed exercise thallium computed tomography in 25 patients who had no significant coronary artery stenosis greater than 70%. Coronary artery spasm was documented by coronary angiography in all patients. Eleven patients (44%) developed exercise-induced perfusion defects, but only four of them had anginal pain (36%). Diltiazem (90 mg, administered orally) prevented the development of exercise-induced perfusion defects in all patients. Multivessel coronary spasm was documented by coronary angiography in 11 patients, and nine of them (82%) showed exercise-induced perfusion defects (p less than 0.05). From this study it can be concluded: (1) Exercise-induced myocardial ischemia was demonstrated in 44% of patients who had vasospastic angina without fixed coronary stenosis, and 64% of them were asymptomatic. (2) Patients with multivessel spasm had a greater prevalence of exercise-induced myocardial ischemia than those with single-vessel spasm.

  3. Sodium cromoglycate and ipratropium bromide in exercise-induced asthma.

    PubMed Central

    Thomson, N C; Patel, K R; Kerr, J W

    1978-01-01

    In thirteen patients with extrinsic asthma the effects of placebo, sodium cromoglycate, ipratropium bromide, and ipratropium bromide plus sodium cromoglycate were studied in a random double-blind fashion to assess their inhibitory action in exercise-induced asthma (EIA). Exercise testing consisted of steady state running on an inclined treadmill for up to eight minutes. In eight of the 13 patients studied the baseline ratio of expiratory flow at 50% vital capacity (VC) breathing helium-oxygen (V50He) to V50air was over 1.20 and they were called responders; the remaining five patients were called non-responders. There was a significantly lower baseline maximum mid-expiratory flow rate (MMEF) in non-responders (P less than 0.02) as compared to responders but no difference in forced expiratory volume in one second (FEV1) or forced vital capacity (FVC). Sodium cromoglycate (P less than 0.02), ipratropium bromide (P less than 0.01), and ipratropium bromide plus spdium cromoglycate (P less than 0.01) all significantly inhibited the percentage fall in FEV1 after exercise in the responders. Ipratropium bromide had no preventive action on non-responders, unlike sodium cromoglycate (P less than 0.05) and ipratropium bromide plus sodium cromoglycate (P less than 0.02). It is postulated that mediator release is an important factor in development of EIA in most extrinsic asthmatics, whereas cholinergic mechanisms are relevant only in those patients in whom the main site of airflow obstruction is in the large central airways. PMID:154747

  4. Modulating exercise-induced hormesis: Does less equal more?

    PubMed

    Peake, Jonathan M; Markworth, James F; Nosaka, Kazunori; Raastad, Truls; Wadley, Glenn D; Coffey, Vernon G

    2015-08-01

    Hormesis encompasses the notion that low levels of stress stimulate or upregulate existing cellular and molecular pathways that improve the capacity of cells and organisms to withstand greater stress. This notion underlies much of what we know about how exercise conditions the body and induces long-term adaptations. During exercise, the body is exposed to various forms of stress, including thermal, metabolic, hypoxic, oxidative, and mechanical stress. These stressors activate biochemical messengers, which in turn activate various signaling pathways that regulate gene expression and adaptive responses. Historically, antioxidant supplements, nonsteroidal anti-inflammatory drugs, and cryotherapy have been favored to attenuate or counteract exercise-induced oxidative stress and inflammation. However, reactive oxygen species and inflammatory mediators are key signaling molecules in muscle, and such strategies may mitigate adaptations to exercise. Conversely, withholding dietary carbohydrate and restricting muscle blood flow during exercise may augment adaptations to exercise. In this review article, we combine, integrate, and apply knowledge about the fundamental mechanisms of exercise adaptation. We also critically evaluate the rationale for using interventions that target these mechanisms under the overarching concept of hormesis. There is currently insufficient evidence to establish whether these treatments exert dose-dependent effects on muscle adaptation. However, there appears to be some dissociation between the biochemical/molecular effects and functional/performance outcomes of some of these treatments. Although several of these treatments influence common kinases, transcription factors, and proteins, it remains to be determined if these interventions complement or negate each other, and whether such effects are strong enough to influence adaptations to exercise.

  5. Diagnosis of exercise-induced anaphylaxis: current insights

    PubMed Central

    Pravettoni, Valerio; Incorvaia, Cristoforo

    2016-01-01

    Exercise-induced anaphylaxis (EIAn) is defined as the occurrence of anaphylactic symptoms (skin, respiratory, gastrointestinal, and cardiovascular symptoms) after physical activity. In about a third of cases, cofactors, such as food intake, temperature (warm or cold), and drugs (especially nonsteroidal anti-inflammatory drugs) can be identified. When the associated cofactor is food ingestion, the correct diagnosis is food-dependent EIAn (FDEIAn). The literature describes numerous reports of FDEIAn after intake of very different foods, from vegetables and nuts to meats and seafood. One of the best-characterized types of FDEIAn is that due to ω5-gliadin of wheat, though cases of FDEIAn after wheat ingestion by sensitization to wheat lipid transfer protien (LTP) are described. Some pathophysiological mechanisms underlying EIAn have been hypothesized, such as increase/alteration in gastrointestinal permeability, alteration of tissue transglutaminase promoting IgE cross-linking, enhanced expression of cytokines, redistribution of blood during physical exercise leading to altered mast-cell degranulation, and also changes in the acid–base balance. Nevertheless, until now, none of these hypotheses has been validated. The diagnosis of EIAn and FDEIAn is achieved by means of a challenge, with physical exercise alone for EIAn, and with the assumption of the suspected food followed by physical exercise for FDEIAn; in cases of doubtful results, a double-blind placebo-controlled combined food–exercise challenge should be performed. The prevention of this particular kind of anaphylaxis is the avoidance of the specific trigger, ie, physical exercise for EIAn, the assumption of the culprit food before exercise for FDEIAn, and in general the avoidance of the recognized cofactors. Patients must be supplied with an epinephrine autoinjector, as epinephrine has been clearly recognized as the first-line intervention for anaphylaxis. PMID:27822074

  6. Beta2-agonists and exercise-induced asthma.

    PubMed

    Anderson, Sandra D; Caillaud, Corinne; Brannan, John D

    2006-01-01

    Beta2-agonists taken immediately before exercise provide significant protection against exercise- induced asthma (EIA) in most patients. However, when they are taken daily, there are some negative aspects regarding severity, control, and recovery from EIA. First, there is a significant minority (15-20%) of asthmatics whose EIA is not prevented by beta2-agonists, even when inhaled corticosteroids are used concomitantly. Second, with daily use, there is a decline in duration of the protective effect of long-acting beta2-agonists. Third, if breakthrough EIA occurs, recovery of lung function is slower in response to a beta2-agonist, and additional doses are often required to achieve pre-exercise values. If a person who takes a beta2-agonist daily experiences problems with exercise, then the physician should consider changing the treatment regimen to achieve better control of EIA. These problems likely result from desensitization of the beta2-receptor on the mast cell, which enhances mediator release, and on the bronchial smooth muscle, which enhances the bronchoconstrictor response and delays recovery from EIA. These effects are reversed within 72 h after cessation of a beta2-agonists. The important clinical question is: Are we actually compromising the beneficial effects of beta2-agonists on the prevention and recovery from EIA by prescribing them daily? Patients with EIA need to ensure that their doses of inhaled corticosteroid or other anti-inflammatory therapy are optimized so that, if necessary, a beta2-agonist can be used intermittently as prophylactic medication with greater confidence in the outcome.

  7. Exercise-induced oxidative stress and hypoxic exercise recovery.

    PubMed

    Ballmann, Christopher; McGinnis, Graham; Peters, Bridget; Slivka, Dustin; Cuddy, John; Hailes, Walter; Dumke, Charles; Ruby, Brent; Quindry, John

    2014-04-01

    Hypoxia due to altitude diminishes performance and alters exercise oxidative stress responses. While oxidative stress and exercise are well studied, the independent impact of hypoxia on exercise recovery remains unknown. Accordingly, we investigated hypoxic recovery effects on post-exercise oxidative stress. Physically active males (n = 12) performed normoxic cycle ergometer exercise consisting of ten high:low intensity intervals, 20 min at moderate intensity, and 6 h recovery at 975 m (normoxic) or simulated 5,000 m (hypoxic chamber) in a randomized counter-balanced cross-over design. Oxygen saturation was monitored via finger pulse oximetry. Blood plasma obtained pre- (Pre), post- (Post), 2 h post- (2Hr), 4 h post- (4Hr), and 6 h (6Hr) post-exercise was assayed for Ferric Reducing Ability of Plasma (FRAP), Trolox Equivalent Antioxidant Capacity (TEAC), Lipid Hydroperoxides (LOOH), and Protein Carbonyls (PC). Biopsies from the vastus lateralis obtained Pre and 6Hr were analyzed by real-time PCR quantify expression of Heme oxygenase 1 (HMOX1), Superoxide Dismutase 2 (SOD2), and Nuclear factor (euthyroid-derived2)-like factor (NFE2L2). PCs were not altered between trials, but a time effect (13 % Post-2Hr increase, p = 0.044) indicated exercise-induced blood oxidative stress. Plasma LOOH revealed only a time effect (p = 0.041), including a 120 % Post-4Hr increase. TEAC values were elevated in normoxic recovery versus hypoxic recovery. FRAP values were higher 6Hr (p = 0.045) in normoxic versus hypoxic recovery. Exercise elevated gene expression of NFE2L2 (20 % increase, p = 0.001) and SOD2 (42 % increase, p = 0.003), but hypoxic recovery abolished this response. Data indicate that recovery in a hypoxic environment, independent of exercise, may alter exercise adaptations to oxidative stress and metabolism.

  8. Exercise-induced bronchospasm, asthma control, and obesity.

    PubMed

    Ostrom, Nancy K; Parsons, Jonathan P; Eid, Nemr S; Craig, Timothy J; Stoloff, Stuart; Hayden, Mary Lou; Colice, Gene L

    2013-01-01

    Exercise-induced bronchospasm (EIB) commonly affects patients with asthma. However, the relationship between EIB and asthma control remains unclear. Exercise limitation due to asthma might lead to reduced physical activity, but little information is available regarding obesity and EIB in asthma. A recent survey evaluated the frequency of EIB and exercise-related respiratory symptoms in a large number of patients with asthma. The survey results were reanalyzed to address any relationship between EIB and asthma control and obesity. A nationwide random sample of children aged 4-12 years (n = 250), adolescents aged 13-17 years (n = 266), and adults aged ≥18 years (n = 1001) with asthma were interviewed by telephone. Questions in the survey addressed asthma symptoms in general, medication use, and height and weight. Asthma control was categorized using established methods in the Expert Panel Report 3. Body mass index (BMI) was calculated using standard nomograms and obesity was defined as a BMI ≥ 30 kg/m(2). Most children (77.6%), adolescents (71.1%), and adults (83.1%) had either "not well" or "very poorly" controlled asthma. Children with "not well" controlled asthma reported a history of EIB significantly more often than those with "well" controlled" asthma. Asthma patients of all ages who had "not well" and "very poorly" controlled asthma described multiple (four or more) exercise-related respiratory symptoms significantly more often than those with "well-controlled" asthma. Obesity was significantly more common in adolescents with "not well" and "very poorly" controlled asthma and adults with "very poorly" controlled asthma. Children, adolescents, and adults with asthma infrequently have well-controlled disease. A history of EIB and exercise-related respiratory symptoms occur more commonly in patients with not well and very poorly controlled asthma. Obesity was found more often in adolescents and adults, but not children, with asthma, which was not well and

  9. Effects of ipratropium on exercise-induced bronchospasm.

    PubMed

    Boaventura, L C; Araujo, A C; Martinez, J B; Vianna, E O

    2010-07-01

    Exercise-induced bronchospasm (EIB) is the transient narrowing of the airways that follows vigorous exercise. Ipratropium bromide may be used to prevent EIB, but its effect varies among individuals. We hypothesized that time of administration of ipratropium interferes with its action. This was a prospective, double-blind, cross-over study carried out to evaluate the bronchoprotective and bronchodilatory effect of ipratropium at different times of day. The study consisted of 4 exercise challenge tests (2 at 7 am and 2 at 6 pm). In the morning, one of the tests was performed after placebo administration and the other one after ipratropium (80 microg) and the two tests (placebo and ipratropium) were repeated in the evening. Twenty-one patients with severe or moderate asthma and previous confirmation of EIB were enrolled in this prospective trial. The bronchodilatory effect of ipratropium was 0.25+/-0.21 L or 13.11+/-10.99% (p=0.001 compared to baseline values) in the morning, and 0.14+/-0.25 L or 7.25+/-11.37% (p>0.05) in the evening. In the morning, EIB was 0.58+/-0.29 L on the placebo day and 0.38+/-0.22 L on the treatment day (p=0.01). In the evening, EIB was 0.62+/-0.28 L on the placebo day and 0.51+/-0.35 L on the treatment day (p>0.05). We suggest that the use of ipratropium for the treatment of asthma and EIB should take into consideration the time of administration.

  10. Exercise-induced bronchospasm in the elite athlete.

    PubMed

    Rundell, Kenneth W; Jenkinson, David M

    2002-01-01

    The term exercise-induced bronchospasm (EIB) describes the acute transient airway narrowing that occurs during and most often after exercise in 10 to 50% of elite athletes, depending upon the sport examined. Although multiple factors are unquestionably involved in the EIB response, airway drying caused by a high exercise-ventilation rate is primary in most cases. The severity of this reaction reflects the allergic predisposition of the athlete, the water content of the inspired air, the type and concentration of air pollutants inspired, and the intensity (or ventilation rate) of the exercise. The highest prevalence of EIB is seen in winter-sport populations, where athletes are chronically exposed to cold dry air and/or environmental pollutants found in indoor ice arenas. When airway surface liquid lost during the natural warming and humidification process of respiration is not replenished at a rate equal to the loss, the ensuing osmolarity change stimulates the release of inflammatory mediators and results in bronchospasm; this cascade of events is exacerbated by airway inflammation and airway remodelling. The acute EIB response is characterised by airway smooth muscle contraction, membrane swelling, and/or mucus plug formation. Evidence suggests that histamine, leukotrienes and prostanoids are likely mediators for this response. Although the presence of symptoms and a basic physical examination are marginally effective, objective measures of lung function should be used for accurate and reliable diagnosis of EIB. Diagnosis should include baseline spirometry, followed by an appropriate bronchial provocation test. To date, the best test to confirm EIB may simply be standard pulmonary function testing before and after high-intensity dry air exercise. A 10% post-challenge fall in forced expiratory volume in 1 second is used as diagnostic criteria. The goal of medical intervention is to limit EIB exacerbation and allow the athlete to train and compete symptom free

  11. Short and longer-term effects of creatine supplementation on exercise induced muscle damage.

    PubMed

    Rosene, John; Matthews, Tracey; Ryan, Christine; Belmore, Keith; Bergsten, Alisa; Blaisdell, Jill; Gaylord, James; Love, Rebecca; Marrone, Michael; Ward, Kristine; Wilson, Eric

    2009-01-01

    The purpose of this investigation was to determine if creatine supplementation assisted with reducing the amount of exercise induced muscle damage and if creatine supplementation aided in recovery from exercise induced muscle damage. Two groups of subjects (group 1 = creatine; group 2 = placebo) participated in an eccentric exercise protocol following 7 and 30 days of creatine or placebo supplementation (20 g.d(-1) for 7 d followed by 6g.d(-1) for 23 d = 30 d). Prior to the supplementation period, measurements were obtained for maximal dynamic strength, maximal isometric force, knee range of motion, muscle soreness, and serum levels of creatine kinase (CK) and lactate dehydrogenase (LDH). Following 7 days of creatine supplementation, on day 8, subjects began consuming 6 g.d(-1) of creatine for 23 days. Additionally on days 8 and 31, subjects performed an eccentric exercise protocol using the knee extensors to induce muscle damage. Indirect markers of muscle damage, including maximal isometric force, knee range of motion, muscle soreness, and serum levels of CK and LDH, were collected at 12, 24, and 48 hours following each exercise bout. The results indicated that acute bouts of creatine have no effect on indirect markers of muscle damage for the acute (7 days) bout. However, maximal isometric force was greater for the creatine group versus placebo for the chronic (30 days) bout. This suggests that the ergogenic effect of creatine following 30 days of supplementation may have a positive impact on exercise induced muscle damage. Key pointsEccentric muscle actions highly associated with exercise induced muscle damage.Creatine supplementation has ergogenic effect to increase protein synthesis.Creatine supplementation does not attenuate exercise induced muscle damage with short term supplementation (7 days).Increased maximal isometric force seen with creatine supplementation after 30 days following exercise induced muscle damage.Ergogenic effect of creatine

  12. Short and longer-term effects of creatine supplementation on exercise induced muscle damage

    PubMed Central

    Rosene, John; Matthews, Tracey; Ryan, Christine; Belmore, Keith; Bergsten, Alisa; Blaisdell, Jill; Gaylord, James; Love, Rebecca; Marrone, Michael; Ward, Kristine; Wilson, Eric

    2009-01-01

    The purpose of this investigation was to determine if creatine supplementation assisted with reducing the amount of exercise induced muscle damage and if creatine supplementation aided in recovery from exercise induced muscle damage. Two groups of subjects (group 1 = creatine; group 2 = placebo) participated in an eccentric exercise protocol following 7 and 30 days of creatine or placebo supplementation (20 g.d-1 for 7 d followed by 6g.d-1 for 23 d = 30 d). Prior to the supplementation period, measurements were obtained for maximal dynamic strength, maximal isometric force, knee range of motion, muscle soreness, and serum levels of creatine kinase (CK) and lactate dehydrogenase (LDH). Following 7 days of creatine supplementation, on day 8, subjects began consuming 6 g.d-1 of creatine for 23 days. Additionally on days 8 and 31, subjects performed an eccentric exercise protocol using the knee extensors to induce muscle damage. Indirect markers of muscle damage, including maximal isometric force, knee range of motion, muscle soreness, and serum levels of CK and LDH, were collected at 12, 24, and 48 hours following each exercise bout. The results indicated that acute bouts of creatine have no effect on indirect markers of muscle damage for the acute (7 days) bout. However, maximal isometric force was greater for the creatine group versus placebo for the chronic (30 days) bout. This suggests that the ergogenic effect of creatine following 30 days of supplementation may have a positive impact on exercise induced muscle damage. Key points Eccentric muscle actions highly associated with exercise induced muscle damage. Creatine supplementation has ergogenic effect to increase protein synthesis. Creatine supplementation does not attenuate exercise induced muscle damage with short term supplementation (7 days). Increased maximal isometric force seen with creatine supplementation after 30 days following exercise induced muscle damage. Ergogenic effect of creatine

  13. Cigarette smoke inhibits brain mitochondrial adaptations of exercised mice.

    PubMed

    Speck, Ana Elisa; Fraga, Daiane; Soares, Priscila; Scheffer, Débora L; Silva, Luciano A; Aguiar, Aderbal S; Estreck, Emílio L; Pinho, Ricardo A

    2011-06-01

    Physical exercise and smoking are environmental factors that generally cause opposite health-promoting adaptations. Both physical exercise and smoking converge on mitochondrial adaptations in various tissues, including the pro-oxidant nervous system. Here, we analyzed the impact of cigarette smoking on exercise-induced brain mitochondrial adaptations in the hippocampus and pre-frontal cortex of adult mice. The animals were exposed to chronic cigarette smoke followed by 8 weeks of moderate-intensity physical exercise that increased mitochondrial activity in the hippocampus and pre-frontal cortex in the non-smoker mice. However, mice previously exposed to cigarette smoke did not present these exercise-induced mitochondrial adaptations. Our results suggest that smoking can inhibit some brain health-promoting changes induced by physical exercise.

  14. Rescue of Heart Failure by Mitochondrial Recovery.

    PubMed

    Marquez, Jubert; Lee, Sung Ryul; Kim, Nari; Han, Jin

    2016-03-01

    Heart failure (HF) is a multifactorial disease brought about by numerous, and oftentimes complex, etiological mechanisms. Although well studied, HF continues to affect millions of people worldwide and current treatments can only prevent further progression of HF. Mitochondria undoubtedly play an important role in the progression of HF, and numerous studies have highlighted mitochondrial components that contribute to HF. This review presents an overview of the role of mitochondrial biogenesis, mitochondrial oxidative stress, and mitochondrial permeability transition pore in HF, discusses ongoing studies that attempt to address the disease through mitochondrial targeting, and provides an insight on how these studies can affect future research on HF treatment.

  15. Upregulation of Mitochondrial Content in Cytochrome c Oxidase Deficient Fibroblasts.

    PubMed

    Kogot-Levin, Aviram; Saada, Ann; Leibowitz, Gil; Soiferman, Devorah; Douiev, Liza; Raz, Itamar; Weksler-Zangen, Sarah

    2016-01-01

    Cytochrome-c-oxidase (COX) deficiency is a frequent cause of mitochondrial disease and is associated with a wide spectrum of clinical phenotypes. We studied mitochondrial function and biogenesis in fibroblasts derived from the Cohen (CDs) rat, an animal model of COX deficiency. COX activity in CDs-fibroblasts was 50% reduced compared to control rat fibroblasts (P<0.01). ROS-production in CDs fibroblasts increased, along with marked mitochondrial fragmentation and decreased mitochondrial membrane-potential, indicating mitochondrial dysfunction. Surprisingly, cellular ATP content, oxygen consumption rate (OCR) and the extracellular acidification rate (ECAR) were unchanged. To clarify the discrepancy between mitochondrial dysfunction and ATP production, we studied mitochondrial biogenesis and turnover. The content of mitochondria was higher in CDs-fibroblasts. Consistently, AMPK activity and the expression of NRF1-target genes, NRF2 and PGC1-α that mediate mitochondrial biogenesis were increased (P<0.01 vs control fibroblast). In CDs-fibrobalsts, the number of autophagosomes (LC3+ puncta) containing mitochondria in CDs fibroblasts was similar to that in control fibroblasts, suggesting that mitophagy was intact. Altogether, our findings demonstrate that mitochondrial dysfunction and oxidative stress are associated with an increase in mitochondrial biogenesis, resulting in preservation of ATP generation.

  16. Bioinformatics Analysis Reveals MicroRNAs Regulating Biological Pathways in Exercise-Induced Cardiac Physiological Hypertrophy

    PubMed Central

    Xu, Jiahong; Liu, Yang; Xie, Yuan

    2017-01-01

    Exercise-induced physiological cardiac hypertrophy is generally considered to be a type of adaptive change after exercise training and is beneficial for cardiovascular diseases. This study aims at investigating exercise-regulated microRNAs (miRNAs) and their potential biological pathways. Here, we collected 23 miRNAs from 8 published studies. MirPath v.3 from the DIANA tools website was used to execute the analysis, and TargetScan was used to predict the target genes. Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) analyses were performed to identify potential pathways and functional annotations associated with exercise-induced physiological cardiac hypertrophy. Various miRNA targets and molecular pathways, such as Fatty acid elongation, Arrhythmogenic right ventricular cardiomyopathy (ARVC), and ECM-receptor interaction, were identified. This study could prompt the understanding of the regulatory mechanisms underlying exercise-induced physiological cardiac hypertrophy. PMID:28286759

  17. Bioinformatics Analysis Reveals MicroRNAs Regulating Biological Pathways in Exercise-Induced Cardiac Physiological Hypertrophy.

    PubMed

    Xu, Jiahong; Liu, Yang; Xie, Yuan; Zhao, Cuimei; Wang, Hongbao

    2017-01-01

    Exercise-induced physiological cardiac hypertrophy is generally considered to be a type of adaptive change after exercise training and is beneficial for cardiovascular diseases. This study aims at investigating exercise-regulated microRNAs (miRNAs) and their potential biological pathways. Here, we collected 23 miRNAs from 8 published studies. MirPath v.3 from the DIANA tools website was used to execute the analysis, and TargetScan was used to predict the target genes. Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) analyses were performed to identify potential pathways and functional annotations associated with exercise-induced physiological cardiac hypertrophy. Various miRNA targets and molecular pathways, such as Fatty acid elongation, Arrhythmogenic right ventricular cardiomyopathy (ARVC), and ECM-receptor interaction, were identified. This study could prompt the understanding of the regulatory mechanisms underlying exercise-induced physiological cardiac hypertrophy.

  18. EVALUATION OF THE BIOGENESIS SOIL WASHING TECHNOLOGY

    EPA Science Inventory

    The BioGenesis Enterprises, Inc. (BioGenesis) soil washing technology was demonstrated as part of the US Environmental Protection Agency's (EPA) Superfund Innovative Technology Evaluation (SITE) program in November 1992. The demonstration was conducted over three days at a petrol...

  19. Green Tea Catechin Consumption Enhances Exercise-Induced Abdominal Fat Loss

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Aim: This study evaluated the influence of a green tea catechin beverage on body composition and fat distribution in overweight and obese adults during exercised-induced weight loss. Methods: Participants (N=132) were randomly assigned to receive a 500 mL beverage containing approximately 625 mg of...

  20. Update on Exercise-Induced Asthma. A Report of the Olympic Exercise Asthma Summit Conference.

    ERIC Educational Resources Information Center

    Storms, William W.; Joyner, David M.

    1997-01-01

    Summarizes results from the Olympic Exercise Asthma Summit Conference, offering the latest on identifying and managing exercise-induced asthma (EIA). Concludes that effective pharmacologic and nonpharmacologic treatment is available, but EIA is underrecognized and underdiagnosed. Physicians should look for it in all patients, including school…

  1. Exercise-induced haemoptysis as a rare presentation of a rare lung disease.

    PubMed

    Mihalek, Andrew D; Haney, Carissa; Merino, Maria; Roy-Chowdhuri, Sinchita; Moss, Joel; Olivier, Kenneth N

    2016-09-01

    Amyloid primarily affecting the lungs is a seldom seen clinical entity. This case discusses the work-up of a patient presenting with exercise-induced haemoptysis and diffuse cystic lung disease on radiographic imaging. The common clinical and radiographic findings of diffuse cystic lung diseases as well as a brief overview of pulmonary amyloid are presented.

  2. The Effects of Creatine Supplementation on Exercise-Induced Muscle Damage.

    ERIC Educational Resources Information Center

    Rawson, Eric S.; Gunn, Bridget; Clarkson, Priscilla M.

    2001-01-01

    Investigated the effects of oral creatine (Cr) supplementation on markers of exercise-induced muscle damage following high-force eccentric exercise in men randomly administered Cr or placebo. Results indicated that 5 days of Cr supplementation did not reduce indirect makers of muscle damage or enhance recovery from high-force eccentric exercise.…

  3. Influence of artistic gymnastics on iron nutritional status and exercise-induced hemolysis in female athletes.

    PubMed

    Sureira, Thaiz Mattos; Amancio, Olga Silverio; Pellegrini Braga, Josefina Aparecida

    2012-08-01

    This study evaluates the relationship between body iron losses and gains in artistic gymnastics female athletes. It shows that despite the low iron intake and exercise-induced hemolysis, iron deficiency or iron-deficiency anemia does not occur, but partial changes in the hematological profile do. The hypothesis that gymnasts' nutritional behavior contributes to anemia, which may be aggravated by exercise-induced hemolysis, led to this cross-sectional study, conducted with 43 female artistic gymnasts 6-16 yr old. The control group was formed by 40 nontraining girls, paired by age. Hemogram, serum iron, ferritin, soluble transferrin receptor, haptoglobin, total and fractional bilirubin, Type I urine, and parasitologic and occult fecal blood tests were evaluated. The athletes presented mean hematimetric and serum iron values (p = .020) higher than those of the control group. The bilirubin result discarded any hemolytic alteration in both groups. The haptoglobin results were lower in the athlete group (p = .002), confirming the incidence of exercise-induced hemolysis. Both groups presented low iron intake. The results suggest that artistic gymnastics practice leads to exercise-induced hemolysis and partially changes the hematological profile, although not causing iron deficiency or iron-deficiency anemia, even in the presence of low iron intake.

  4. Thyroid Hormone and Estrogen Regulate Exercise-Induced Growth Hormone Release

    PubMed Central

    Ignacio, Daniele Leão; da S. Silvestre, Diego H.; Cavalcanti-de-Albuquerque, João Paulo Albuquerque; Louzada, Ruy Andrade

    2015-01-01

    Growth hormone (GH) regulates whole body metabolism, and physical exercise is the most potent stimulus to induce its secretion in humans. The mechanisms underlying GH secretion after exercise remain to be defined. The aim of this study was to elucidate the role of estrogen and pituitary type 1 deiodinase (D1) activation on exercise-induced GH secretion. Ten days after bilateral ovariectomy, animals were submitted to 20 min of treadmill exercise at 75% of maximum aerobic capacity and tissues were harvested immediately or 30 min after exercise. Non-exercised animals were used as controls. A significant increase in D1 activity occurred immediately after exercise (~60%) in sham-operated animals and GH was higher (~6-fold) 30 min after exercise. Estrogen deficient rats exhibited basal levels of GH and D1 activity comparable to those found in control rats. However, after exercise both D1 activity and serum GH levels were blunted compared to sedentary rats. To understand the potential cause-effect of D1 activation in exercise-induced GH release, we pharmacologically blocked D1 activity by propylthiouracil (PTU) injection into intact rats and submitted them to the acute exercise session. D1 inhibition blocked exercise-induced GH secretion, although basal levels were unaltered. In conclusion, estrogen deficiency impairs the induction of thyroid hormone activating enzyme D1 in the pituitary, and GH release by acute exercise. Also, acute D1 activation is essential for exercise-induced GH response. PMID:25874614

  5. [Impaired exercise-induced blood pressure control in patients with Parkinson's disease and related disorders].

    PubMed

    Deguchi, Kazushi

    2013-01-01

    An almost directly proportional increase in blood pressure (BP) and heart rate with exercise intensity has been reported in healthy subjects. In contrast, patients with multiple system atrophy (MSA) and pure autonomic failure (PAF) characterized by autonomic failure exhibit exercise-induced hypotension (EIH), prolonged hypotension following the cessation of exercise and exaggerated orthostatic hypotension after exercise. EIH, which can be the earliest symptom of PAF, provides a clue to the diagnosis of autonomic failure. Exercise-induced hypertension, which may be due to adrenergic receptor supersensitivity, may also be observed. BP during and after exercise was significantly lower in patients with Parkinson's disease (PD) than in healthy subjects. Some PD patients exhibited symptoms related to EIH. PD patients who did not achieve 85% of target HR with treadmill testing lacked BP elevations during sub-maximal and peak exercise. On the other hand, no significant difference was observed in exercise-induced BP elevations between PD patients with and without cardiac sympathetic denervation. Since BP control during exercise in PD was not affected by dosing with levodopa, exercise-related BP abnormalities in PD appear to manifest with the disease. These findings suggest that PD has impaired exercise-induced BP control, but not to the extent of MSA and PAF.

  6. Exercise Challenge for Exercise-Induced Bronchospasm. Confirming Presence, Evaluating Control.

    ERIC Educational Resources Information Center

    Kaplan, Ted A.

    1995-01-01

    Exercise-induced bronchospasm commonly strikes young people, keeping many away from activity. The exercise challenge test (a powerful tool in diagnosing the condition, fine-tuning treatment, and improving patient compliance) can help get patients back in action. Knowing how to interpret and use test results helps physicians expedite effective…

  7. All-trans retinoic acid induces oxidative phosphorylation and mitochondria biogenesis in adipocytes[S

    PubMed Central

    Tourniaire, Franck; Musinovic, Hana; Gouranton, Erwan; Astier, Julien; Marcotorchino, Julie; Arreguin, Andrea; Bernot, Denis; Palou, Andreu; Bonet, M. Luisa; Ribot, Joan; Landrier, Jean-François

    2015-01-01

    A positive effect of all-trans retinoic acid (ATRA) on white adipose tissue (WAT) oxidative and thermogenic capacity has been described and linked to an in vivo fat-lowering effect of ATRA in mice. However, little is known about the effects of ATRA on mitochondria in white fat. Our objective has been to characterize the effect of ATRA on mitochondria biogenesis and oxidative phosphorylation (OXPHOS) capacity in mature white adipocytes. Transcriptome analysis, oxygraphy, analysis of mitochondrial DNA (mtDNA), and flow cytometry-based analysis of mitochondria density were performed in mature 3T3-L1 adipocytes after 24 h incubation with ATRA (2 µM) or vehicle. Selected genes linked to mitochondria biogenesis and function and mitochondria immunostaining were analyzed in WAT tissues of ATRA-treated as compared with vehicle-treated mice. ATRA upregulated the expression of a large set of genes linked to mtDNA replication and transcription, mitochondrial biogenesis, and OXPHOS in adipocytes, as indicated by transcriptome analysis. Oxygen consumption rate, mtDNA content, and staining of mitochondria were increased in the ATRA-treated adipocytes. Similar results were obtained in WAT depots of ATRA-treated mice. We conclude that ATRA impacts mitochondria in adipocytes, leading to increased OXPHOS capacity and mitochondrial content in these cells. PMID:25914170

  8. All-trans retinoic acid induces oxidative phosphorylation and mitochondria biogenesis in adipocytes.

    PubMed

    Tourniaire, Franck; Musinovic, Hana; Gouranton, Erwan; Astier, Julien; Marcotorchino, Julie; Arreguin, Andrea; Bernot, Denis; Palou, Andreu; Bonet, M Luisa; Ribot, Joan; Landrier, Jean-François

    2015-06-01

    A positive effect of all-trans retinoic acid (ATRA) on white adipose tissue (WAT) oxidative and thermogenic capacity has been described and linked to an in vivo fat-lowering effect of ATRA in mice. However, little is known about the effects of ATRA on mitochondria in white fat. Our objective has been to characterize the effect of ATRA on mitochondria biogenesis and oxidative phosphorylation (OXPHOS) capacity in mature white adipocytes. Transcriptome analysis, oxygraphy, analysis of mitochondrial DNA (mtDNA), and flow cytometry-based analysis of mitochondria density were performed in mature 3T3-L1 adipocytes after 24 h incubation with ATRA (2 µM) or vehicle. Selected genes linked to mitochondria biogenesis and function and mitochondria immunostaining were analyzed in WAT tissues of ATRA-treated as compared with vehicle-treated mice. ATRA upregulated the expression of a large set of genes linked to mtDNA replication and transcription, mitochondrial biogenesis, and OXPHOS in adipocytes, as indicated by transcriptome analysis. Oxygen consumption rate, mtDNA content, and staining of mitochondria were increased in the ATRA-treated adipocytes. Similar results were obtained in WAT depots of ATRA-treated mice. We conclude that ATRA impacts mitochondria in adipocytes, leading to increased OXPHOS capacity and mitochondrial content in these cells.

  9. Exercise-induced cardioprotection: a role for eNOS uncoupling and NO metabolites.

    PubMed

    Farah, C; Kleindienst, A; Bolea, G; Meyer, G; Gayrard, S; Geny, B; Obert, P; Cazorla, O; Tanguy, S; Reboul, Cyril

    2013-11-01

    Exercise is an efficient strategy for myocardial protection against ischemia-reperfusion (IR) injury. Although endothelial nitric oxide synthase (eNOS) is phosphorylated and activated during exercise, its role in exercise-induced cardioprotection remains unknown. This study investigated whether modulation of eNOS activation during IR could participate in the exercise-induced cardioprotection against IR injury. Hearts isolated from sedentary or exercised rats (5 weeks training) were perfused with a Langendorff apparatus and IR performed in the presence or absence of NOS inhibitors [N-nitro-L-arginine methyl ester, L-NAME or N5-(1-iminoethyl)-L-ornithine, L-NIO] or tetrahydrobiopterin (BH₄). Exercise training protected hearts against IR injury and this effect was abolished by L-NAME or by L-NIO treatment, indicating that exercise-induced cardioprotection is eNOS dependent. However, a strong reduction of eNOS phosphorylation at Ser1177 (eNOS-PSer1177) and of eNOS coupling during early reperfusion was observed in hearts from exercised rats (which showed higher eNOS-PSer1177 and eNOS dimerization at baseline) in comparison to sedentary rats. Despite eNOS uncoupling, exercised hearts had more S-nitrosylated proteins after early reperfusion and also less nitro-oxidative stress, indexed by lower malondialdehyde content and protein nitrotyrosination compared to sedentary hearts. Moreover, in exercised hearts, stabilization of eNOS dimers by BH4 treatment increased nitro-oxidative stress and then abolished the exercise-induced cardioprotection, indicating that eNOS uncoupling during IR is required for exercise-induced myocardial cardioprotection. Based on these results, we hypothesize that in the hearts of exercised animals, eNOS uncoupling associated with the improved myocardial antioxidant capacity prevents excessive NO synthesis and limits the reaction between NO and O₂·- to form peroxynitrite (ONOO⁻), which is cytotoxic.

  10. Eukaryotic ribosome biogenesis at a glance.

    PubMed

    Thomson, Emma; Ferreira-Cerca, Sébastien; Hurt, Ed

    2013-11-01

    Ribosomes play a pivotal role in the molecular life of every cell. Moreover, synthesis of ribosomes is one of the most energetically demanding of all cellular processes. In eukaryotic cells, ribosome biogenesis requires the coordinated activity of all three RNA polymerases and the orchestrated work of many (>200) transiently associated ribosome assembly factors. The biogenesis of ribosomes is a tightly regulated activity and it is inextricably linked to other fundamental cellular processes, including growth and cell division. Furthermore, recent studies have demonstrated that defects in ribosome biogenesis are associated with several hereditary diseases. In this Cell Science at a Glance article and the accompanying poster, we summarise the current knowledge on eukaryotic ribosome biogenesis, with an emphasis on the yeast model system.

  11. Reductive stress impairs myoblasts mitochondrial function and triggers mitochondrial hormesis.

    PubMed

    Singh, François; Charles, Anne-Laure; Schlagowski, Anna-Isabel; Bouitbir, Jamal; Bonifacio, Annalisa; Piquard, François; Krähenbühl, Stephan; Geny, Bernard; Zoll, Joffrey

    2015-07-01

    Even though oxidative stress damage from excessive production of ROS is a well known phenomenon, the impact of reductive stress remains poorly understood. This study tested the hypothesis that cellular reductive stress could lead to mitochondrial malfunction, triggering a mitochondrial hormesis (mitohormesis) phenomenon able to protect mitochondria from the deleterious effects of statins. We performed several in vitro experiments on L6 myoblasts and studied the effects of N-acetylcysteine (NAC) at different exposure times. Direct NAC exposure (1mM) led to reductive stress, impairing mitochondrial function by decreasing maximal mitochondrial respiration and increasing H₂O₂production. After 24h of incubation, the reactive oxygen species (ROS) production was increased. The resulting mitochondrial oxidation activated mitochondrial biogenesis pathways at the mRNA level. After one week of exposure, mitochondria were well-adapted as shown by the decrease of cellular ROS, the increase of mitochondrial content, as well as of the antioxidant capacities. Atorvastatin (ATO) exposure (100μM) for 24h increased ROS levels, reduced the percentage of live cells, and increased the total percentage of apoptotic cells. NAC exposure during 3days failed to protect cells from the deleterious effects of statins. On the other hand, NAC pretreatment during one week triggered mitochondrial hormesis and reduced the deleterious effect of statins. These results contribute to a better understanding of the redox-dependant pathways linked to mitochondria, showing that reductive stress could trigger mitochondrial hormesis phenomenon.

  12. Synergistic effect of cAMP and palmitate in promoting altered mitochondrial function and cell death in HepG2 cells

    PubMed Central

    Zhang, Linxia; Seitz, Linsey C.; Abramczyk, Amy M.; Chan, Christina

    2009-01-01

    Saturated free fatty acids (FFAs), e.g. palmitate, have long been shown to induce toxicity and cell death in various types of cells. In this study, we demonstrate that cAMP synergistically amplifies the effect of palmitate on the induction of cell death in human hepatocellular carcinoma cell line, HepG2 cells. Elevation of cAMP level in palmitate treated cells led to enhanced mitochondrial fragmentation, mitochondrial reactive oxygen species (ROS) generation and mitochondrial biogenesis. Mitochondrial fragmentation precedes mitochondrial ROS generation and mitochondrial biogenesis, and may contribute to mitochondrial ROS overproduction and subsequent mitochondrial biogenesis. Fragmentation of mitochondria also facilitated the release of cytotoxic mitochondrial proteins, such as Smac, from the mitochondria and subsequent activation of caspases. However, cell death induced by palmitate and cAMP was caspase-independent and mainly necrotic. PMID:20026039

  13. AMP-activated protein kinase is required for exercise-induced peroxisome proliferator-activated receptor co-activator 1 translocation to subsarcolemmal mitochondria in skeletal muscle.

    PubMed

    Smith, Brennan K; Mukai, Kazutaka; Lally, James S; Maher, Amy C; Gurd, Brendon J; Heigenhauser, George J F; Spriet, Lawrence L; Holloway, Graham P

    2013-03-15

    In skeletal muscle, mitochondria exist as two subcellular populations known as subsarcolemmal (SS) and intermyofibrillar (IMF) mitochondria. SS mitochondria preferentially respond to exercise training, suggesting divergent transcriptional control of the mitochondrial genomes. The transcriptional co-activator peroxisome proliferator-activated receptor γ co-activator 1α (PGC-1α) and mitochondrial transcription factor A (Tfam) have been implicated in the direct regulation of the mitochondrial genome in mice, although SS and IMF differences may exist, and the potential signalling events regulating the mitochondrial content of these proteins have not been elucidated. Therefore, we examined the potential for PGC-1α and Tfam to translocate to SS and IMF mitochondria in human subjects, and performed experiments in rodents to identify signalling mechanisms regulating these translocation events. Acute exercise in humans and rats increased PGC-1α content in SS but not IMF mitochondria. Acute exposure to 5-aminoimidazole-4-carboxamide-1-β-ribofuranoside in rats recapitulated the exercise effect of increased PGC-1α protein within SS mitochondria only, suggesting that AMP-activated protein kinase (AMPK) signalling is involved. In addition, rendering AMPK inactive (AMPK kinase dead mice) prevented exercise-induced PGC-1α translocation to SS mitochondria, further suggesting that AMPK plays an integral role in these translocation events. In contrast to the conserved PGC-1α translocation to SS mitochondria across species (humans, rats and mice), acute exercise only increased mitochondrial Tfam in rats. Nevertheless, in rat resting muscle PGC-1α and Tfam co-immunoprecipate with α-tubulin, suggesting a common cytosolic localization. These data suggest that exercise causes translocation of PGC-1α preferentially to SS mitochondria in an AMPK-dependent manner.

  14. NAD(+)-dependent activation of Sirt1 corrects the phenotype in a mouse model of mitochondrial disease.

    PubMed

    Cerutti, Raffaele; Pirinen, Eija; Lamperti, Costanza; Marchet, Silvia; Sauve, Anthony A; Li, Wei; Leoni, Valerio; Schon, Eric A; Dantzer, Françoise; Auwerx, Johan; Viscomi, Carlo; Zeviani, Massimo

    2014-06-03

    Mitochondrial disorders are highly heterogeneous conditions characterized by defects of the mitochondrial respiratory chain. Pharmacological activation of mitochondrial biogenesis has been proposed as an effective means to correct the biochemical defects and ameliorate the clinical phenotype in these severely disabling, often fatal, disorders. Pathways related to mitochondrial biogenesis are targets of Sirtuin1, a NAD(+)-dependent protein deacetylase. As NAD(+) boosts the activity of Sirtuin1 and other sirtuins, intracellular levels of NAD(+) play a key role in the homeostatic control of mitochondrial function by the metabolic status of the cell. We show here that supplementation with nicotinamide riboside, a natural NAD(+) precursor, or reduction of NAD(+) consumption by inhibiting the poly(ADP-ribose) polymerases, leads to marked improvement of the respiratory chain defect and exercise intolerance of the Sco2 knockout/knockin mouse, a mitochondrial disease model characterized by impaired cytochrome c oxidase biogenesis. This strategy is potentially translatable into therapy of mitochondrial disorders in humans.

  15. Social isolation prevents exercise-induced proliferation of hippocampal progenitor cells in female rats.

    PubMed

    Leasure, J Leigh; Decker, Linda

    2009-10-01

    Social isolation negatively affects the behavior and health of laboratory rats. Recently, it has been found that social isolation retards exercise-induced neurogenesis in the hippocampal dentate gyrus (DG) of male rats (Stranahan et al. (2006) Nat Neurosci 9:526-533). Since male and female rats react differently to housing changes and exercise opportunities, we investigated whether social isolation would also suppress the exercise-dependent increase in proliferation of dentate gyrus progenitor cells in females. Accordingly, female rats were housed either alone (isolated) or in groups (social) with (exercise) or without (sedentary) the opportunity to run in an exercise wheel. Proliferating progenitor cells were labeled with bromodeoxyuridine (BrdU). As expected, exercise increased the number of BrdU+ cells in socially housed animals. However, isolation prevented this running-induced increase. Our results expand upon previous findings by showing that the female brain is also susceptible to the suppressive effect of social isolation on exercise-induced neurogenesis.

  16. Polyphenols in exercise performance and prevention of exercise-induced muscle damage.

    PubMed

    Malaguti, Marco; Angeloni, Cristina; Hrelia, Silvana

    2013-01-01

    Although moderate physical exercise is considered an essential component of a healthy lifestyle that leads the organism to adapt itself to different stresses, exercise, especially when exhaustive, is also known to induce oxidative stress, inflammation, and muscle damage. Many efforts have been carried out to identify dietary strategies or micronutrients able to prevent or at least attenuate the exercise-induced muscle damage and stress. Unfortunately most studies have failed to show protection, and at the present time data supporting the protective effect of micronutrients, as antioxidant vitamins, are weak and trivial. This review focuses on those polyphenols, present in the plant kingdom, that have been recently suggested to exert some positive effects on exercise-induced muscle damage and oxidative stress. In the last decade flavonoids as quercetin, catechins, and other polyphenols as resveratrol have caught the scientists attention. However, at the present time drawing a clear and definitive conclusion seems to be untimely.

  17. Polyphenols in Exercise Performance and Prevention of Exercise-Induced Muscle Damage

    PubMed Central

    Hrelia, Silvana

    2013-01-01

    Although moderate physical exercise is considered an essential component of a healthy lifestyle that leads the organism to adapt itself to different stresses, exercise, especially when exhaustive, is also known to induce oxidative stress, inflammation, and muscle damage. Many efforts have been carried out to identify dietary strategies or micronutrients able to prevent or at least attenuate the exercise-induced muscle damage and stress. Unfortunately most studies have failed to show protection, and at the present time data supporting the protective effect of micronutrients, as antioxidant vitamins, are weak and trivial. This review focuses on those polyphenols, present in the plant kingdom, that have been recently suggested to exert some positive effects on exercise-induced muscle damage and oxidative stress. In the last decade flavonoids as quercetin, catechins, and other polyphenols as resveratrol have caught the scientists attention. However, at the present time drawing a clear and definitive conclusion seems to be untimely. PMID:23983900

  18. Exercise-induced neuroprotective effects on neurodegenerative diseases: the key role of trophic factors.

    PubMed

    Campos, Carlos; Rocha, Nuno Barbosa F; Lattari, Eduardo; Paes, Flávia; Nardi, António E; Machado, Sérgio

    2016-06-01

    Age-related neurodegenerative disorders, like Alzheimer's or Parkinson's disease, are becoming a major issue to public health care. Currently, there is no effective pharmacological treatment to address cognitive impairment in these patients. Here, we aim to explore the role of exercise-induced trophic factor enhancement in the prevention or delay of cognitive decline in patients with neurodegenerative diseases. There is a significant amount of evidence from animal and human studies that links neurodegenerative related cognitive deficits with changes on brain and peripheral trophic factor levels. Several trials with elderly individuals and patients with neurodegenerative diseases report exercise induced cognitive improvements and changes on trophic factor levels including BDNF, IGF-I, among others. Further studies with healthy aging and clinical populations are needed to understand how diverse exercise interventions produce different variations in trophic factor signaling. Genetic profiles and potential confounders regarding trophic factors should also be addressed in future trials.

  19. Suppression of exercise-induced angina by magnesium sulfate in patients with variant angina

    SciTech Connect

    Kugiyama, K.; Yasue, H.; Okumura, K.; Goto, K.; Minoda, K.; Miyagi, H.; Matsuyama, K.; Kojima, A.; Koga, Y.; Takahashi, M.

    1988-11-01

    The effects of intravenous magnesium on exercise-induced angina were examined in 15 patients with variant angina and in 13 patients with stable effort angina and were compared with those of placebo. Symptom-limited bicycle exercise and thallium-201 myocardial scintigraphy were performed after intravenous administration of 0.27 mmol/kg body weight of magnesium sulfate and after placebo on different days. In all patients, serum magnesium levels after administration of magnesium sulfate were about twofold higher than levels after placebo. Exercise-induced angina associated with transient ST segment elevation occurred in 11 patients with variant angina receiving placebo and in only 2 of these patients receiving magnesium (p less than 0.005). On the other hand, exercise-induced angina was not suppressed by magnesium in any patient with stable effort angina. In these patients there was no significant difference in exercise duration after administration of placebo versus after administration of magnesium. The size of the perfusion defect as measured by thallium-201 scintigraphy was significantly less in patients with variant angina receiving magnesium than that in those receiving placebo (p less than 0.001), whereas it was not significantly different in patients with stable effort angina receiving placebo versus magnesium. In conclusion, exercise-induced angina is suppressed by intravenous magnesium in patients with variant angina but not in patients with stable effort angina. This beneficial effect of magnesium in patients with variant angina is most likely due to improvement of regional myocardial blood flow by suppression of coronary artery spasm.

  20. Effect of N-2-mercaptopropionyl glycine on exercise-induced cardiac adaptations.

    PubMed

    Nelson, Matthew J; Harris, M Brennan; Boluyt, Marvin O; Hwang, Hyun Seok; Starnes, Joseph W

    2011-04-01

    The purpose of this study was to test the hypothesis that exercise-induced cardiac adaptations would be attenuated by the free radical scavenger N-2-mercaptopropionyl glycine (MPG). Male Sprague-Dawley rats were divided into four groups (n = 9-13 per group) for 3-4 wk: sedentary (S), S+MPG (100 mg/kg ip daily), exercised on a treadmill (E) (60 min/day, 5 days/wk, at a speed of 20 m/min up a 6° grade in a 6°C room), or E+MPG given 10 min prior to exercise. Additional rats (n = 55) were used to determine acute exercise effects on myocardial redox state [nonprotein nonglutathione sulfhydryls (NPNGSH)] and PI3K/Akt signaling pathway activation. Compared with S, NPNGSH levels were 48% lower in E (P < 0.05) and unchanged in E+MPG (P > 0.05). MPG also attenuated exercise-induced activation of the signaling proteins Akt and S6. Hearts from the 4-wk groups were weighed, and cardiac function was evaluated using an isolated perfused working heart preparation. Similar increases (P < 0.05) in both exercised groups were observed for heart weight and heart weight-to-body weight ratio. Cardiac function improved in E vs. S, as indicated by greater (P < 0.05) external work performed (cardiac output × systolic pressure) and efficiency of external work (work/Vo(2)). MPG prevented these exercise-induced functional improvements. Skeletal muscle mitochondria content increased to similar levels in E and E+MPG. This study provides evidence that free radicals do not play an essential role in the development of exercise-induced cardiac hypertrophy; however, they appear to be involved in functional cardiac adaptations, which may be mediated through the PI3K/Akt pathway.

  1. Leg Immersion in Warm Water, Stretch-Shortening Exercise, and Exercise-Induced Muscle Damage

    PubMed Central

    Skurvydas, Albertas; Kamandulis, Sigitas; Stanislovaitis, Aleksas; Streckis, Vytautas; Mamkus, Gediminas; Drazdauskas, Adomas

    2008-01-01

    Context: Whether muscle warming protects against exercise-induced muscle damage is unknown. Objective: To determine the effect of leg immersion in warm water before stretch-shortening exercise on the time course of indirect markers of exercise-induced muscle damage. Design: Crossover trial. Setting: Human kinetics laboratory. Patients or Other Participants: Eleven healthy, untrained men (age  =  21.5 ± 1.7 years). Intervention(s): Participants' legs were immersed in a water bath at 44 ± 1°C for 45 minutes. Main Outcome Measure(s): Creatine kinase changes in the blood, muscle soreness, prolonged (within 72 hours) impairment in maximal voluntary contraction force and height of drop jump, and electrically evoked muscle force at low and high stimulation frequencies at short and long muscle lengths. Results: Leg immersion in warm water before stretch-shortening exercise reduced most of the indirect markers of exercise-induced muscle damage, including creatine kinase activity in the blood, muscle soreness, maximal voluntary contraction force, and jump height. The values for maximal voluntary contraction force and jump height, however, were higher during prewarming than for the control condition at 48 hours after stretch-shortening exercise, but this difference was only minor at other time points. Muscle prewarming did not bring about any changes in the dynamics of low-frequency fatigue, registered at either short or long muscle length, within 72 hours of stretch-shortening exercise. Conclusions: Leg immersion in warm water before stretch-shortening exercise reduced most of the indirect markers of exercise-induced muscle damage. However, the clinical application of muscle prewarming may be limited, because decreasing muscle damage did not necessarily lead to improved voluntary performance. PMID:19030137

  2. Efficacy of omeprazole for the prevention of exercise-induced gastritis in racing Alaskan sled dogs.

    PubMed

    Davis, M S; Willard, M D; Nelson, S L; McCullough, S M; Mandsager, R E; Roberts, J; Payton, M E

    2003-01-01

    Exercise-induced gastritis and gastric ulcers are common in humans and horses, and recently have been described in racing sled dogs. The cause of exercise-induced gastric disease is not completely understood in any species, but pharmacologic suppression of acid secretion is an effective treatment in humans and horses. Thus, we tested the hypothesis that omeprazole, a proton-pump inhibitor shown to reduce gastric acid secretion in dogs, would reduce the severity of exercise-induced gastric disease. Three teams of 16 dogs each competing in the 2002 Iditarod Sled Dog Race were recruited for participation. Within each team, dogs were randomly assigned to either treatment (20 mg omeprazole PO q24h) or placebo. Treatments were administered until either completion of the race or withdrawal of an individual dog from competition. Gastric endoscopy was performed in all dogs 24 hours after completion or withdrawal, and the gastric mucosa was scored by using a subjective severity score (0 = normal, 3 = numerous bleeding ulcers). Treatment with omeprazole significantly reduced mean gastricseverity score compared to placebo (omeprazole: 0.65 +/- 0.17, placebo: 1.09 +/- 0.18; P = .028), but also was associated with increased frequency of diarrhea during the race (omeprazole 54%, placebo 21%; P = .017). Examination of our data suggests that omeprazole may be an effective treatment for exercise-induced gastric disease in racing sled dogs. However, further investigation regarding the cause and clinical relevance of diarrhea associated with omeprazole treatment must be conducted before omeprazole can be recommended for routine prophylactic treatment in these athletes.

  3. Clinical significance of plasminogen activator inhibitor activity in patients with exercise-induced ischemia

    SciTech Connect

    Sakata, K.; Kurata, C.; Taguchi, T.; Suzuki, S.; Kobayashi, A.; Yamazaki, N.; Rydzewski, A.; Takada, Y.; Takada, A. )

    1990-10-01

    To assess the fibrinolytic system in patients with exercise-induced ischemia and its relation to ischemia and severity of coronary artery disease (CAD), 47 patients with CAD confirmed by results of coronary angiography underwent symptom-limited multistage exercise thallium-201 emission computed tomography. All patients with CAD had exercise-induced ischemia as assessed from thallium-201 images. Pre- and peak exercise blood samples from each patient and preexercise blood samples from control subjects were assayed for several fibrinolytic components and were also assayed for plasma adrenaline. The extent of ischemia was defined as delta visual uptake score (total visual uptake score in delayed images minus total visual uptake score in initial images) and the severity of CAD as the number of diseased vessels. In the basal condition, plasminogen activator inhibitor (PAI) activity was significantly higher in patients with exercise-induced ischemia as compared to control subjects (p less than 0.01), although there were no significant differences in other fibrinolytic variables between the two groups. Moreover, PAI activity in the basal condition displayed a significantly positive correlation with the extent of ischemia (r = 0.47, p less than 0.01). Patients with exercise-induced ischemia were divided into two groups (24 with single-vessel disease and 23 with multivessel disease). There were no significant differences in coronary risk factors, hemodynamics, or plasma adrenaline levels during exercise between single-vessel and multivessel disease except that delta visual uptake score was significantly higher in multivessel disease (p less than 0.01).

  4. Exercise excess pressure and exercise-induced albuminuria in patients with type 2 diabetes mellitus.

    PubMed

    Climie, Rachel E D; Srikanth, Velandai; Keith, Laura J; Davies, Justin E; Sharman, James E

    2015-05-01

    Exercise-induced albuminuria is common in patients with type 2 diabetes mellitus (T2DM) in response to maximal exercise, but the response to light-moderate exercise is unclear. Patients with T2DM have abnormal central hemodynamics and greater propensity for exercise hypertension. This study sought to determine the relationship between light-moderate exercise central hemodynamics (including aortic reservoir and excess pressure) and exercise-induced albuminuria. Thirty-nine T2DM (62 ± 9 yr; 49% male) and 39 nondiabetic controls (53 ± 9 yr; 51% male) were examined at rest and during 20 min of light-moderate cycle exercise (30 W; 50 revolutions/min). Albuminuria was assessed by the albumin-creatinine ratio (ACR) at rest and 30 min postexercise. Hemodynamics recorded included brachial and central blood pressure (BP), aortic stiffness, augmented pressure (AP), aortic reservoir pressure, and excess pressure integral (Pexcess). There was no difference in ACR between groups before exercise (P > 0.05). Exercise induced a significant rise in ACR in T2DM but not controls (1.73 ± 1.43 vs. 0.53 ± 1.0 mg/mol, P = 0.002). All central hemodynamic variables were significantly higher during exercise in T2DM (i.e., Pexcess, systolic BP and AP; P < 0.01 all). In T2DM (but not controls), exercise Pexcess was associated with postexercise ACR (r = 0.51, P = 0.002), and this relationship was independent of age, sex, body mass index, heart rate, aortic stiffness, antihypertensive medication, and ambulatory daytime systolic BP (β = 0.003, P = 0.003). Light-moderate exercise induced a significant rise in ACR in T2DM, and this was independently associated with Pexcess, a potential marker of vascular dysfunction. These novel findings suggest that Pexcess could be important for appropriate renal function in T2DM.

  5. The Role of Exercise-Induced Cardiovascular Adaptation in Brain Health.

    PubMed

    Tarumi, Takashi; Zhang, Rong

    2015-10-01

    Regular aerobic exercise improves brain health; however, a potential dose-response relationship and the underling physiological mechanisms remain unclear. Existing data support the following hypotheses: 1) exercise-induced cardiovascular adaptation plays an important role in improving brain perfusion, structure, and function, and 2) a hormetic relation seems to exist between the intensity of exercise and brain health, which needs to be further elucidated.

  6. Tdrkh is essential for spermatogenesis and participates in primary piRNA biogenesis in the germline

    PubMed Central

    Saxe, Jonathan P; Chen, Mengjie; Zhao, Hongyu; Lin, Haifan

    2013-01-01

    Piwi proteins and Piwi-interacting RNAs (piRNAs) repress transposition, regulate translation, and guide epigenetic programming in the germline. Here, we show that an evolutionarily conserved Tudor and KH domain-containing protein, Tdrkh (a.k.a. Tdrd2), is required for spermatogenesis and involved in piRNA biogenesis. Tdrkh partners with Miwi and Miwi2 via symmetrically dimethylated arginine residues in Miwi and Miwi2. Tdrkh is a mitochondrial protein often juxtaposed to pi-bodies and piP-bodies and is required for Tdrd1 cytoplasmic localization and Miwi2 nuclear localization. Tdrkh mutants display meiotic arrest at the zygotene stage, attenuate methylation of Line1 DNA, and upregulate Line1 RNA and protein, without inducing apoptosis. Furthermore, Tdrkh mutants have severely reduced levels of mature piRNAs but accumulate a distinct population of 1′U-containing, 2′O-methylated 31–37 nt RNAs that largely complement the missing mature piRNAs. Our results demonstrate that the primary piRNA biogenesis pathway involves 3′→5′ processing of 31–37 nt intermediates and that Tdrkh promotes this final step of piRNA biogenesis but not the ping-pong cycle. These results shed light on mechanisms underlying primary piRNA biogenesis, an area in which information is conspicuously absent. PMID:23714778

  7. Protective and biogenesis effects of sodium hydrosulfide on brain mitochondria after cardiac arrest and resuscitation.

    PubMed

    Pan, Hao; Xie, Xuemeng; Chen, Di; Zhang, Jincheng; Zhou, Yaguang; Yang, Guangtian

    2014-10-15

    Mitochondrial dysfunction plays a critical role in brain injury after cardiac arrest and cardiopulmonary resuscitation (CPR). Recent studies demonstrated that hydrogen sulfide (H2S) donor compounds preserve mitochondrial morphology and function during ischemia-reperfusion injury. In this study, we sought to explore the effects of sodium hydrosulfide (NaHS) on brain mitochondria 24h after cardiac arrest and resuscitation. Male Sprague-Dawley rats were subjected to 6min cardiac arrest and then resuscitated successfully. Rats received NaHS (0.5mg/kg) or vehicle (0.9% NaCl, 1.67ml/kg) 1min before the start of CPR intravenously, followed by a continuous infusion of NaHS (1.5mg/kg/h) or vehicle (5ml/kg/h) for 3h. Neurological deficit was evaluated 24h after resuscitation and then cortex was collected for assessments. As a result, we found that rats treated with NaHS revealed an improved neurological outcome and cortex mitochondrial morphology 24h after resuscitation. We also observed that NaHS therapy reduced intracellular reactive oxygen species generation and calcium overload, inhibited mitochondrial permeability transition pores, preserved mitochondrial membrane potential, elevated ATP level and ameliorated the cytochrome c abnormal distribution. Further studies indicated that NaHS administration increased mitochondrial biogenesis in cortex at the same time. Our findings suggested that administration of NaHS 1min prior CPR and followed by a continuous infusion ameliorated neurological dysfunction 24h after resuscitation, possibly through mitochondria preservation as well as by promoting mitochondrial biogenesis.

  8. Dose-response effect of sodium cromoglycate pressurised aerosol in exercise induced asthma.

    PubMed Central

    Tullett, W M; Tan, K M; Wall, R T; Patel, K R

    1985-01-01

    The effects of 2, 10, and 20 mg of sodium cromoglycate delivered by aerosol were compared with those of placebo in a double blind study in 11 patients with extrinsic and exercise induced asthma. The effect of nebulised sodium cromoglycate delivered through a Wright nebuliser (estimated dose 12 mg) was also studied. Patients exercised on a treadmill for six to eight minutes at submaximal work loads on five days, 30 minutes after inhaling placebo or sodium cromoglycate. The FEV1 was recorded before treatment, before exercise, and up to 30 minutes after exercise. Mean baseline values of FEV1 before and after placebo or sodium cromoglycate did not differ significantly on the five days. After exercise the mean (SEM) maximal percentage fall in FEV1 after placebo; 12 mg sodium cromoglycate nebuliser solution; and 2, 10, and 20 mg sodium cromoglycate aerosol were 31.1 (3.8); 9.4 (2.1); and 19.4 (4.6), 13.7 (3.5), and 9.4 (1.9). Sodium cromoglycate inhibited exercise induced asthma at all doses used; the protective effect of the aerosol increased from 2 to 20 mg. The protective effect of 20 mg sodium cromoglycate aerosol was similar to that seen with 12 mg nebulised solution. Our results suggest that the effect of sodium cromoglycate aerosol in exercise induced asthma is dose related. PMID:3918356

  9. Ultra-endurance exercise induces stress and inflammation and affects circulating hematopoietic progenitor cell function.

    PubMed

    Stelzer, I; Kröpfl, J M; Fuchs, R; Pekovits, K; Mangge, H; Raggam, R B; Gruber, H-J; Prüller, F; Hofmann, P; Truschnig-Wilders, M; Obermayer-Pietsch, B; Haushofer, A C; Kessler, H H; Mächler, P

    2015-10-01

    Although amateur sports have become increasingly competitive within recent decades, there are as yet few studies on the possible health risks for athletes. This study aims to determine the impact of ultra-endurance exercise-induced stress on the number and function of circulating hematopoietic progenitor cells (CPCs) and hematological, inflammatory, clinical, metabolic, and stress parameters in moderately trained amateur athletes. Following ultra-endurance exercise, there were significant increases in leukocytes, platelets, interleukin-6, fibrinogen, tissue enzymes, blood lactate, serum cortisol, and matrix metalloproteinase-9. Ultra-endurance exercise did not influence the number of CPCs but resulted in a highly significant decline of CPC functionality after the competition. Furthermore, Epstein-Barr virus was seen to be reactivated in one of seven athletes. The link between exercise-induced stress and decline of CPC functionality is supported by a negative correlation between cortisol and CPC function. We conclude that ultra-endurance exercise induces metabolic stress and an inflammatory response that affects not only mature hematopoietic cells but also the function of the immature hematopoietic stem and progenitor cell fraction, which make up the immune system and provide for regeneration.

  10. Arterial baroreflex buffering of sympathetic activation during exercise-induced elevations in arterial pressure.

    PubMed Central

    Scherrer, U; Pryor, S L; Bertocci, L A; Victor, R G

    1990-01-01

    Static muscle contraction activates metabolically sensitive muscle afferents that reflexively increase sympathetic nerve activity and arterial pressure. To determine if this contraction-induced reflex is modulated by the sinoaortic baroreflex, we performed microelectrode recordings of sympathetic nerve activity to resting leg muscle during static handgrip in humans while attempting to clamp the level of baroreflex stimulation by controlling the exercise-induced rise in blood pressure with pharmacologic agents. The principal new finding is that partial pharmacologic suppression of the rise in blood pressure during static handgrip (nitroprusside infusion) augmented the exercise-induced increases in heart rate and sympathetic activity by greater than 300%. Pharmacologic accentuation of the exercise-induced rise in blood pressure (phenylephrine infusion) attenuated these reflex increases by greater than 50%. In contrast, these pharmacologic manipulations in arterial pressure had little or no effect on: (a) forearm muscle cell pH, an index of the metabolic stimulus to skeletal muscle afferents; or (b) central venous pressure, an index of the mechanical stimulus to cardiopulmonary afferents. We conclude that in humans the sinoaortic baroreflex is much more effective than previously thought in buffering the reflex sympathetic activation caused by static muscle contraction. PMID:2254449

  11. Massage and ultrasound as therapeutic modalities in exercise-induced muscle damage.

    PubMed

    Tiidus, P M

    1999-06-01

    Although both massage and ultrasound treatment are used in clinical settings to enhance muscle functional recovery following exercise-induced muscle damage, there is a paucity of experimental evidence for their efficacy. Theoretically both massage and ultrasound could affect some physiological factors associated with enhancement of postexercise muscle recovery. However, the actual physiological mechanisms by which massage or ultrasound could influence postexercise muscle damage and repair are unknown. Most experimental evidence suggests that massage has little influence on muscle blood flow, clearance of "noxious" substances, recovery of postexercise muscle strength, or delayed soreness sensation. However, more data is needed before conclusions can be drawn as to the ability of massage to influence postexercise inflammatory response or various other physiological changes that characterize exercise-induced muscle damage and repair. There is even less information on the ability of ultrasound to influence physiological or functional factors associated with postexercise muscle damage. The few experiments that have been done tend to be contradictory and have yet to consider the range of ultrasound treatment parameters for therapeutic effectiveness in treating postexercise damage and influencing repair processes. Much more research is needed to determine whether either treatment modality can have any therapeutic effect on exercise-induced muscle damage and recovery of postexercise muscle function.

  12. Determinants of exercise-induced fat oxidation in obese women and men.

    PubMed

    Haufe, S; Engeli, S; Budziarek, P; Utz, W; Schulz-Menger, J; Hermsdorf, M; Wiesner, S; Otto, C; Fuhrmann, J C; Luft, F C; Boschmann, M; Jordan, J

    2010-03-01

    Endurance training at an intensity eliciting maximal fat oxidation may have a beneficial effect on body weight and glucose metabolism in obese patients. However, the exercise intensity at which maximal fat oxidation occurs and the factors limiting fat oxidation are not well studied in this population. Obese, otherwise healthy men (n=38) and women (n=91) performed an incremental exercise test up to exhaustion on a cycle ergometer. Substrate oxidation was estimated using indirect calorimetry. Magnetic resonance tomography and spectroscopy were conducted to assess body fat distribution and intramyocellular fat content. We determined the exercise intensity at which maximal body fat oxidation occurs and assessed whether body composition, body fat distribution, intramyocellular fat content, or oxidative capacity predict exercise-induced fat oxidation. Maximal exercise-induced fat oxidation was 0.30+/-0.02 g/min in men and 0.23+/-0.01 g/min in women (p<0.05). Exercise intensity at the maximum fat oxidation was 42+/-2.2% VO (2 max) in men and 43+/-1.7% VO (2 max) in women. With multivariate analysis, exercise-induced fat oxidation was related to fat-free mass, percent fat mass, and oxidative capacity, but not to absolute fat mass, visceral fat, or intramyocellular fat content. We conclude that in obese subjects the capacity to oxidize fat during exercise appears to be limited by skeletal muscle mass and oxidative capacity rather than the availability of visceral or intramyocellular fat.

  13. Familial hypercholesterolemia impairs exercise-induced systemic vasodilation due to reduced NO bioavailability.

    PubMed

    de Beer, Vincent J; Merkus, Daphne; Bender, Shawn B; Tharp, Darla L; Bowles, Douglas K; Duncker, Dirk J; Laughlin, M Harold

    2013-12-01

    Hypercholesterolemia impairs endothelial function [e.g., the nitric oxide (NO)-cyclic GMP-phosphodiesterase 5 (PDE5) pathway], limits shear stress-induced vasodilation, and is therefore expected to reduce exercise-induced vasodilation. To assess the actual effects of hypercholesterolemia on endothelial function and exercise-induced vasodilation, we compared the effects of endothelial NO synthase (eNOS) and PDE5 inhibition in chronically instrumented Yucatan (Control) and Rapacz familial hypercholesterolemic (FH) swine, at rest and during treadmill exercise. The increases in systemic vascular conductance produced by ATP (relative to nitroprusside) and exercise were blunted in FH compared with Control swine. The vasoconstrictor response to eNOS inhibition, with nitro-l-arginine (NLA), was attenuated in FH compared with Control swine, both at rest and during exercise. Furthermore, whereas the vasodilator response to nitroprusside was enhanced slightly, the vasodilator response to PDE5 inhibition, with EMD360527, was reduced in FH compared with Control swine. Finally, in the pulmonary circulation, FH resulted in attenuated vasodilator responses to ATP, while maintaining the responses to both NLA and EMD360527. In conclusion, hypercholesterolemia reduces exercise-induced vasodilation in the systemic but not the pulmonary circulation. This reduction appears to be the principal result of a decrease in NO bioavailability, which is mitigated by a lower PDE5 activity.

  14. Contribution of endothelium-derived hyperpolarizing factor to exercise-induced vasodilation in health and hypercholesterolemia.

    PubMed

    Ozkor, Muhiddin A; Hayek, Salim S; Rahman, Ayaz M; Murrow, Jonathan R; Kavtaradze, Nino; Lin, Ji; Manatunga, Amita; Quyyumi, Arshed A

    2015-02-01

    The role of endothelium-derived hyperpolarizing factor (EDHF) in either the healthy circulation or in those with hypercholesterolemia is unknown. In healthy and hypercholesterolemic subjects, we measured forearm blood flow (FBF) using strain-gauge plethysmography at rest, during graded handgrip exercise, and after sodium nitroprusside infusion. Measurements were repeated after l-NMMA, tetraethylammonium (TEA), and combined infusions. At rest, l-NMMA infusion reduced FBF in healthy but not hypercholesterolemic subjects. At peak exercise, vasodilation was lower in hypercholesterolemic compared to healthy subjects (274% vs 438% increase in FBF, p=0.017). TEA infusion reduced exercise-induced vasodilation in both healthy and hypercholesterolemic subjects (27%, p<0.0001 and -20%, p<0.0001, respectively). The addition of l-NMMA to TEA further reduced FBF in healthy (-14%, p=0.012) but not in hypercholesterolemic subjects, indicating a reduced nitric oxide and greater EDHF-mediated contribution to exercise-induced vasodilation in hypercholesterolemia. In conclusion, exercise-induced vasodilation is impaired and predominantly mediated by EDHF in hypercholesterolemic subjects. CLINICAL TRIAL REGISTRATION IDENTIFIER NCT00166166:

  15. The basic chemistry of exercise-induced DNA oxidation: oxidative damage, redox signaling, and their interplay.

    PubMed

    Cobley, James N; Margaritelis, Nikos V; Morton, James P; Close, Graeme L; Nikolaidis, Michalis G; Malone, John K

    2015-01-01

    Acute exercise increases reactive oxygen and nitrogen species generation. This phenomenon is associated with two major outcomes: (1) redox signaling and (2) macromolecule damage. Mechanistic knowledge of how exercise-induced redox signaling and macromolecule damage are interlinked is limited. This review focuses on the interplay between exercise-induced redox signaling and DNA damage, using hydroxyl radical ((·)OH) and hydrogen peroxide (H2O2) as exemplars. It is postulated that the biological fate of H2O2 links the two processes and thus represents a bifurcation point between redox signaling and damage. Indeed, H2O2 can participate in two electron signaling reactions but its diffusion and chemical properties permit DNA oxidation following reaction with transition metals and (·)OH generation. It is also considered that the sensing of DNA oxidation by repair proteins constitutes a non-canonical redox signaling mechanism. Further layers of interaction are provided by the redox regulation of DNA repair proteins and their capacity to modulate intracellular H2O2 levels. Overall, exercise-induced redox signaling and DNA damage may be interlinked to a greater extent than was previously thought but this requires further investigation.

  16. Evidence of a Redox-Dependent Regulation of Immune Responses to Exercise-Induced Inflammation

    PubMed Central

    Sakelliou, Alexandra; Athanailidis, Ioannis; Tsoukas, Dimitrios; Chatzinikolaou, Athanasios; Draganidis, Dimitris; Jamurtas, Athanasios Z.; Liacos, Christina; Mandalidis, Dimitrios; Stamatelopoulos, Kimon; Dimopoulos, Meletios A.; Mitrakou, Asimina

    2016-01-01

    We used thiol-based antioxidant supplementation (n-acetylcysteine, NAC) to determine whether immune mobilisation following skeletal muscle microtrauma induced by exercise is redox-sensitive in healthy humans. According to a two-trial, double-blind, crossover, repeated measures design, 10 young men received either placebo or NAC (20 mg/kg/day) immediately after a muscle-damaging exercise protocol (300 eccentric contractions) and for eight consecutive days. Blood sampling and performance assessments were performed before exercise, after exercise, and daily throughout recovery. NAC reduced the decline of reduced glutathione in erythrocytes and the increase of plasma protein carbonyls, serum TAC and erythrocyte oxidized glutathione, and TBARS and catalase activity during recovery thereby altering postexercise redox status. The rise of muscle damage and inflammatory markers (muscle strength, creatine kinase activity, CRP, proinflammatory cytokines, and adhesion molecules) was less pronounced in NAC during the first phase of recovery. The rise of leukocyte and neutrophil count was decreased by NAC after exercise. Results on immune cell subpopulations obtained by flow cytometry indicated that NAC ingestion reduced the exercise-induced rise of total macrophages, HLA+ macrophages, and 11B+ macrophages and abolished the exercise-induced upregulation of B lymphocytes. Natural killer cells declined only in PLA immediately after exercise. These results indicate that thiol-based antioxidant supplementation blunts immune cell mobilisation in response to exercise-induced inflammation suggesting that leukocyte mobilization may be under redox-dependent regulation. PMID:27974950

  17. Acute exercise induces biphasic increase in respiratory mRNA in skeletal muscle

    SciTech Connect

    Ikeda, Shin-ichi; Kizaki, Takako; Haga, Shukoh; Ohno, Hideki; Takemasa, Tohru

    2008-04-04

    Peroxisome proliferator-activated receptor {gamma} coactivator-1{alpha} (PGC-1{alpha}) promotes the expression of oxidative enzymes in skeletal muscle. We hypothesized that activation of the p38 MAPK (mitogen-activated protein kinase) in response to exercise was associated with exercise-induced PGC-1{alpha} and respiratory enzymes expression and aimed to demonstrate this under the physiological level. We subjected mice to a single bout of treadmill running and found that the exercise induced a biphasic increase in the expression of respiratory enzymes mRNA. The second phase of the increase was accompanied by an increase in PGC-1{alpha} protein, but the other was not. Administration of SB203580 (SB), an inhibitor of p38 MAPK, suppressed the increase in PGC-1{alpha} expression and respiratory enzymes mRNA in both phases. These data suggest that p38 MAPK is associated with the exercise-induced expression of PGC-1{alpha} and biphasic increase in respiratory enzyme mRNAs in mouse skeletal muscle under physiological conditions.

  18. The 5-HT3 receptor is essential for exercise-induced hippocampal neurogenesis and antidepressant effects.

    PubMed

    Kondo, M; Nakamura, Y; Ishida, Y; Shimada, S

    2015-11-01

    Exercise has a variety of beneficial effects on brain structure and function, such as hippocampal neurogenesis, mood and memory. Previous studies have shown that exercise enhances hippocampal neurogenesis, induces antidepressant effects and improves learning behavior. Brain serotonin (5-hydroxytryptamine, 5-HT) levels increase following exercise, and the 5-HT system has been suggested to have an important role in these exercise-induced neuronal effects. However, the precise mechanism remains unclear. In this study, analysis of the 5-HT type 3A receptor subunit-deficient (htr3a(-/-)) mice revealed that lack of the 5-HT type 3 (5-HT3) receptor resulted in loss of exercise-induced hippocampal neurogenesis and antidepressant effects, but not of learning enhancement. Furthermore, stimulation of the 5-HT3 receptor promoted neurogenesis. These findings demonstrate that the 5-HT3 receptor is the critical target of 5-HT action in the brain following exercise, and is indispensable for hippocampal neurogenesis and antidepressant effects induced by exercise. This is the first report of a pivotal 5-HT receptor subtype that has a fundamental role in exercise-induced morphological changes and psychological effects.

  19. Effects of a Strength Training Session After an Exercise Inducing Muscle Damage on Recovery Kinetics.

    PubMed

    Abaïdia, Abd-Elbasset; Delecroix, Barthélémy; Leduc, Cédric; Lamblin, Julien; McCall, Alan; Baquet, Georges; Dupont, Grégory

    2017-01-01

    Abaïdia, A-E, Delecroix, B, Leduc, C, Lamblin, J, McCall, A, Baquet, G, and Dupont, G. Effects of a strength training session after an exercise inducing muscle damage on recovery kinetics. J Strength Cond Res 31(1): 115-125, 2017-The purpose of this study was to investigate the effects of an upper-limb strength training session the day after an exercise inducing muscle damage on recovery of performance. In a randomized crossover design, subjects performed the day after the exercise, on 2 separate occasions (passive vs. active recovery conditions) a single-leg exercise (dominant in one condition and nondominant in the other condition) consisting of 5 sets of 15 eccentric contractions of the knee flexors. Active recovery consisted of performing an upper-body strength training session the day after the exercise. Creatine kinase, hamstring strength, and muscle soreness were assessed immediately and 20, 24, and 48 hours after exercise-induced muscle damage. The upper-body strength session, after muscle-damaging exercise accelerated the recovery of slow concentric force (effect size = 0.65; 90% confidence interval = -0.06 to 1.32), but did not affect the recovery kinetics for the other outcomes. The addition of an upper-body strength training session the day after muscle-damaging activity does not negatively affect the recovery kinetics. Upper-body strength training may be programmed the day after a competition.

  20. Mitochondrial cholesterol: mechanisms of import and effects on mitochondrial function.

    PubMed

    Martin, Laura A; Kennedy, Barry E; Karten, Barbara

    2016-04-01

    Mitochondria require cholesterol for biogenesis and membrane maintenance, and for the synthesis of steroids, oxysterols and hepatic bile acids. Multiple pathways mediate the transport of cholesterol from different subcellular pools to mitochondria. In steroidogenic cells, the steroidogenic acute regulatory protein (StAR) interacts with a mitochondrial protein complex to mediate cholesterol delivery to the inner mitochondrial membrane for conversion to pregnenolone. In non-steroidogenic cells, several members of a protein family defined by the presence of a StAR-related lipid transfer (START) domain play key roles in the delivery of cholesterol to mitochondrial membranes. Subdomains of the endoplasmic reticulum (ER), termed mitochondria-associated ER membranes (MAM), form membrane contact sites with mitochondria and may contribute to the transport of ER cholesterol to mitochondria, either independently or in conjunction with lipid-transfer proteins. Model systems of mitochondria enriched with cholesterol in vitro and mitochondria isolated from cells with (patho)physiological mitochondrial cholesterol accumulation clearly demonstrate that mitochondrial cholesterol levels affect mitochondrial function. Increased mitochondrial cholesterol levels have been observed in several diseases, including cancer, ischemia, steatohepatitis and neurodegenerative diseases, and influence disease pathology. Hence, a deeper understanding of the mechanisms maintaining mitochondrial cholesterol homeostasis may reveal additional targets for therapeutic intervention. Here we give a brief overview of mitochondrial cholesterol import in steroidogenic cells, and then focus on cholesterol trafficking pathways that deliver cholesterol to mitochondrial membranes in non-steroidogenic cells. We also briefly discuss the consequences of increased mitochondrial cholesterol levels on mitochondrial function and their potential role in disease pathology.

  1. Insights into chloroplast biogenesis and development.

    PubMed

    Pogson, Barry J; Ganguly, Diep; Albrecht-Borth, Verónica

    2015-09-01

    In recent years many advances have been made to obtain insight into chloroplast biogenesis and development. In plants several plastids types exist such as the proplastid (which is the progenitor of all plastids), leucoplasts (group of colourless plastids important for storage including elaioplasts (lipids), amyloplasts (starch) or proteinoplasts (proteins)), chromoplasts (yellow to orange-coloured due to carotenoids, in flowers or in old leaves as gerontoplasts), and the green chloroplasts. Chloroplasts are indispensable for plant development; not only by performing photosynthesis and thus rendering the plant photoautotrophic, but also for biochemical processes (which in some instances can also take place in other plastids types), such as the synthesis of pigments, lipids, and plant hormones and sensing environmental stimuli. Although we understand many aspects of these processes there are gaps in our understanding of the establishment of functional chloroplasts and their regulation. Why is that so? Even though chloroplast function is comparable in all plants and most of the algae, ferns and moss, detailed analyses have revealed many differences, specifically with respect to its biogenesis. As an update to our prior review on the genetic analysis of chloroplast biogenesis and development [1] herein we will focus on recent advances in Angiosperms (monocotyledonous and dicotyledonous plants) that provide novel insights and highlight the challenges and prospects for unravelling the regulation of chloroplast biogenesis specifically during the establishment of the young plants. This article is part of a Special Issue entitled: Chloroplast Biogenesis.

  2. Modulation of mitochondrial protein phosphorylation by soluble adenylyl cyclase ameliorates cytochrome oxidase defects

    PubMed Central

    Acin-Perez, Rebeca; Salazar, Eric; Brosel, Sonja; Yang, Hua; Schon, Eric A; Manfredi, Giovanni

    2009-01-01

    Phosphorylation of respiratory chain components has emerged as a mode of regulation of mitochondrial energy metabolism, but its mechanisms are still largely unexplored. A recently discovered intramitochondrial signalling pathway links CO2 generated by the Krebs cycle with the respiratory chain, through the action of a mitochondrial soluble adenylyl cyclase (mt-sAC). Cytochrome oxidase (COX), whose deficiency causes a number of fatal metabolic disorders, is a key mitochondrial enzyme activated by mt-sAC. We have now discovered that the mt-sAC pathway modulates mitochondrial biogenesis in a reactive oxygen species dependent manner, in cultured cells and in animals with COX deficiency. We show that upregulation of mt-sAC normalizes reactive oxygen species production and mitochondrial biogenesis, thereby restoring mitochondrial function. This is the first example of manipulation of a mitochondrial signalling pathway to achieve a direct positive modulation of COX, with clear implications for the development of novel approaches to treat mitochondrial diseases. PMID:20049744

  3. Mitochondrial protein translocases for survival and wellbeing.

    PubMed

    Sokol, Anna Magdalena; Sztolsztener, Malgorzata Eliza; Wasilewski, Michal; Heinz, Eva; Chacinska, Agnieszka

    2014-08-01

    Mitochondria are involved in many essential cellular activities. These broad functions explicate the need for the well-orchestrated biogenesis of mitochondrial proteins to avoid death and pathological consequences, both in unicellular and more complex organisms. Yeast as a model organism has been pivotal in identifying components and mechanisms that drive the transport and sorting of nuclear-encoded mitochondrial proteins. The machinery components that are involved in the import of mitochondrial proteins are generally evolutionarily conserved within the eukaryotic kingdom. However, topological and functional differences have been observed. We review the similarities and differences in mitochondrial translocases from yeast to human. Additionally, we provide a systematic overview of the contribution of mitochondrial import machineries to human pathologies, including cancer, mitochondrial diseases, and neurodegeneration.

  4. NITRIC OXIDE, MITOCHONDRIAL HYPERPOLARIZATION AND T-CELL ACTIVATION

    PubMed Central

    Nagy, Gyorgy; Koncz, Agnes; Fernandez, David; Perl, Andras

    2007-01-01

    T lymphocyte activation is associated with nitric oxide (NO) production that plays an essential role in multiple T cell functions. NO acts as a messenger, activating soluble guanyl cyclase and participating in the transduction signaling pathways involving cyclic GMP. NO modulates mitochondrial events that are involved in apoptosis and regulates mitochondrial membrane potential and mitochondrial biogenesis in many cell types, including lymphocytes. Mitochondrial hyperpolarization (MHP), an early and reversible event during both T lymphocyte activation and apoptosis, is regulated by NO. Here, we discuss recent evidence that NO-induced MHP represents a molecular switch in multiple T cell signaling pathways. Overproduction of NO in systemic lupus erythematosus (SLE) induces mitochondrial biogenesis and alters Ca2+ signaling. Thus, while NO plays a physiological role in lymphocyte cell signaling, its overproduction may disturb normal T cell function, contributing to the pathogenesis of autoimmunity. PMID:17462531

  5. Increased insulin sensitivity and distorted mitochondrial adaptations during muscle unloading.

    PubMed

    Qi, Zhengtang; Zhang, Yuan; Guo, Wei; Ji, Liu; Ding, Shuzhe

    2012-12-11

    We aimed to further investigate mitochondrial adaptations to muscle disuse and the consequent metabolic disorders. Male rats were submitted to hindlimb unloading (HU) for three weeks. Interestingly, HU increased insulin sensitivity index (ISI) and decreased blood level of triglyceride and insulin. In skeletal muscle, HU decreased expression of pyruvate dehydrogenase kinase 4 (PDK4) and its protein level in mitochondria. HU decreased mtDNA content and mitochondrial biogenesis biomarkers. Dynamin-related protein (Drp1) in mitochondria and Mfn2 mRNA level were decreased significantly by HU. Our findings provide more extensive insight into mitochondrial adaptations to muscle disuse, involving the shift of fuel utilization towards glucose, the decreased mitochondrial biogenesis and the distorted mitochondrial dynamics.

  6. Number matters: control of mammalian mitochondrial DNA copy number.

    PubMed

    Clay Montier, Laura L; Deng, Janice J; Bai, Yidong

    2009-03-01

    Regulation of mitochondrial biogenesis is essential for proper cellular functioning. Mitochondrial DNA (mtDNA) depletion and the resulting mitochondrial malfunction have been implicated in cancer, neurodegeneration, diabetes, aging, and many other human diseases. Although it is known that the dynamics of the mammalian mitochondrial genome are not linked with that of the nuclear genome, very little is known about the mechanism of mtDNA propagation. Nevertheless, our understanding of the mode of mtDNA replication has advanced in recent years, though not without some controversies. This review summarizes our current knowledge of mtDNA copy number control in mammalian cells, while focusing on both mtDNA replication and turnover. Although mtDNA copy number is seemingly in excess, we reason that mtDNA copy number control is an important aspect of mitochondrial genetics and biogenesis and is essential for normal cellular function.

  7. Biogenesis of endosome-derived transport carriers.

    PubMed

    Chi, Richard J; Harrison, Megan S; Burd, Christopher G

    2015-09-01

    Sorting of macromolecules within the endosomal system is vital for physiological control of nutrient homeostasis, cell motility, and proteostasis. Trafficking routes that export macromolecules from the endosome via vesicle and tubule transport carriers constitute plasma membrane recycling and retrograde endosome-to-Golgi pathways. Proteins of the sorting nexin family have been discovered to function at nearly every step of endosomal transport carrier biogenesis and it is becoming increasingly clear that they form the core machineries of cargo-specific transport pathways that are closely integrated with cellular physiology. Here, we summarize recent progress in elucidating the pathways that mediate the biogenesis of endosome-derived transport carriers.

  8. Evidence for Mitochondrial Respiratory Deficiency in Rat Rhabdomyosarcoma Cells

    PubMed Central

    Jahnke, Vanessa E.; Sabido, Odile; Defour, Aurélia; Castells, Josiane; Lefai, Etienne; Roussel, Damien; Freyssenet, Damien

    2010-01-01

    Background Mitochondria can sense signals linked to variations in energy demand to regulate nuclear gene expression. This retrograde signaling pathway is presumed to be involved in the regulation of myoblast proliferation and differentiation. Rhabdomyosarcoma cells are characterized by their failure to both irreversibly exit the cell cycle and complete myogenic differentiation. However, it is currently unknown whether mitochondria are involved in the failure of rhabdomyosarcoma cells to differentiate. Methodology/Principal Findings Mitochondrial biogenesis and metabolism were studied in rat L6E9 myoblasts and R1H rhabdomyosacoma cells during the cell cycle and after 36 hours of differentiation. Using a combination of flow cytometry, polarographic and molecular analyses, we evidenced a marked decrease in the cardiolipin content of R1H cells cultured in growth and differentiation media, together with a significant increase in the content of mitochondrial biogenesis factors and mitochondrial respiratory chain proteins. Altogether, these data indicate that the mitochondrial inner membrane composition and the overall process of mitochondrial biogenesis are markedly altered in R1H cells. Importantly, the dysregulation of protein-to-cardiolipin ratio was associated with major deficiencies in both basal and maximal mitochondrial respiration rates. This deficiency in mitochondrial respiration probably contributes to the inability of R1H cells to decrease mitochondrial H2O2 level at the onset of differentiation. Conclusion/Significance A defect in the regulation of mitochondrial biogenesis and mitochondrial metabolism may thus be an epigenetic mechanism that may contribute to the tumoral behavior of R1H cells. Our data underline the importance of mitochondria in the regulation of myogenic differentiation. PMID:20072609

  9. Melatonin: A Mitochondrial Targeting Molecule Involving Mitochondrial Protection and Dynamics

    PubMed Central

    Tan, Dun-Xian; Manchester, Lucien C.; Qin, Lilan; Reiter, Russel J.

    2016-01-01

    Melatonin has been speculated to be mainly synthesized by mitochondria. This speculation is supported by the recent discovery that aralkylamine N-acetyltransferase/serotonin N-acetyltransferase (AANAT/SNAT) is localized in mitochondria of oocytes and the isolated mitochondria generate melatonin. We have also speculated that melatonin is a mitochondria-targeted antioxidant. It accumulates in mitochondria with high concentration against a concentration gradient. This is probably achieved by an active transportation via mitochondrial melatonin transporter(s). Melatonin protects mitochondria by scavenging reactive oxygen species (ROS), inhibiting the mitochondrial permeability transition pore (MPTP), and activating uncoupling proteins (UCPs). Thus, melatonin maintains the optimal mitochondrial membrane potential and preserves mitochondrial functions. In addition, mitochondrial biogenesis and dynamics is also regulated by melatonin. In most cases, melatonin reduces mitochondrial fission and elevates their fusion. Mitochondrial dynamics exhibit an oscillatory pattern which matches the melatonin circadian secretory rhythm in pinealeocytes and probably in other cells. Recently, melatonin has been found to promote mitophagy and improve homeostasis of mitochondria. PMID:27999288

  10. Iron-sulfur cluster biogenesis in mammalian cells: new insights into the molecular mechanisms of cluster delivery

    PubMed Central

    Maio, Nunziata; Rouault, Tracey. A.

    2014-01-01

    Iron-sulfur (Fe-S) clusters are ancient, ubiquitous cofactors composed of iron and inorganic sulfur. The combination of the chemical reactivity of iron and sulfur, together with many variations of cluster composition, oxidation states and protein environments, enables Fe-S clusters to participate in numerous biological processes. Fe-S clusters are essential to redox catalysis in nitrogen fixation, mitochondrial respiration and photosynthesis, to regulatory sensing in key metabolic pathways (i. e. cellular iron homeostasis and oxidative stress response), and to the replication and maintenance of the nuclear genome. Fe-S cluster biogenesis is a multistep process that involves a complex sequence of catalyzed protein- protein interactions and coupled conformational changes between the components of several dedicated multimeric complexes. Intensive studies of the assembly process have clarified key points in the biogenesis of Fe-S proteins. However several critical questions still remain, such as: what is the role of frataxin? Why do some defects of Fe-S cluster biogenesis cause mitochondrial iron overload? How are specific Fe-S recipient proteins recognized in the process of Fe-S transfer? This review focuses on the basic steps of Fe-S cluster biogenesis, drawing attention to recent advances achieved on the identification of molecular features that guide selection of specific subsets of nascent Fe-S recipients by the cochaperone HSC20. Additionally, it outlines the distinctive phenotypes of human diseases due to mutations in the components of the basic pathway. PMID:25245479

  11. Short-term exercise training protects against doxorubicin-induced cardiac mitochondrial damage independent of HSP72.

    PubMed

    Kavazis, Andreas N; Smuder, Ashley J; Min, Kisuk; Tümer, Nihal; Powers, Scott K

    2010-11-01

    Doxorubicin (Dox) is an antitumor agent used in cancer treatment, but its clinical use is limited due to cardiotoxicity. Although exercise training can defend against Dox-mediated cardiac damage, the means for this cardioprotection remain unknown. To investigate the mechanism(s) responsible for exercise training-induced cardioprotection against Dox-mediated cardiotoxicity, we tested a two-pronged hypothesis: 1) exercise training protects against Dox-induced cardiotoxicity by preventing Dox-mediated mitochondrial damage/dysfunction and increased oxidative stress and 2) exercise training-induced cardiac expression of the inducible isoform of the 70-kDa heat shock protein 72 (HSP72) is essential to achieve exercise training-induced cardioprotection against Dox toxicity. Animals were randomly assigned to sedentary or exercise groups and paired with either placebo or Dox treatment (i.e., 20 mg/kg body wt ip Dox hydrochloride 24 h before euthanasia). Dox administration resulted in cardiac mitochondrial dysfunction, activation of proteases, and apoptosis. Exercise training increased cardiac antioxidant enzymes and HSP72 protein abundance and protected cardiac myocytes against Dox-induced mitochondrial damage, protease activation, and apoptosis. To determine whether exercise-induced expression of HSP72 in the heart is required for this cardioprotection, we utilized an innovative experimental strategy that successfully prevented exercise-induced increases in myocardial HSP72 levels. However, prevention of exercise-induced increases in myocardial HSP72 did not eliminate the exercise-induced cardioprotective phenotype that is resistant to Dox-mediated injury. Our results indicate that exercise training protects against the detrimental side effects of Dox in cardiac myocytes, in part, by protecting mitochondria against Dox-mediated damage. However, this exercise-induced cardioprotection is independent of myocardial HSP72 levels. Finally, our data are consistent with the

  12. Effect of lignocaine, sodium cromoglycate, and ipratropium bromide in exercise-induced asthma

    PubMed Central

    Tullett, WM; Patel, KR; Berkin, KE; Kerr, JW

    1982-01-01

    Eight patients with exercise-induced asthma participated in a single-blind trial comparing the protective effects of inhaled lignocaine (estimated dose 48 mg), sodium cromoglycate (estimated dose 12 mg), and ipratropium bromide (estimated dose 120 μg). Saline was used as control. Effects were assessed from the mean maximal percentage fall in forced expiratory volume in one second (FEV1) and maximal mid-expiratory flow rates (MMFR) after they had run on a treadmill for eight minutes. There was no significant change in baseline FEV1 or MMFR before each agent was given. Saline, lignocaine, and sodium cromoglycate did not alter the mean baseline FEV1 or MMFR significantly. Ipratropium caused bronchodilatation with an increase of 16·3% in the mean FEV1 (p<0·001) and of 43·4% in the mean MMFR (p<0·05). After exercise the maximal percentage falls in FEV1 (means and SEM) after saline, lignocaine, sodium cromoglycate, and ipratropium bromide were 38·1% (5·0), 34·5% (6·1), 11·3% (3·7), and 19·3% (7·4) respectively. Similarly, the mean maximal falls in MMFR after saline, lignocaine, sodium cromoglycate, and ipratropium bromide were 54·4% (5·2), 52·9% (7·7), 23·6% (6·6), and 32·1% (10·5) respectively. The inhibitory effects of sodium cromoglycate and ipratropium bromide were significant whereas lignocaine failed to produce an effect. These results suggest that mediator release is an important factor in exercise-induced asthma and that in some patients the effects of the mediators may be on the postsynaptic muscarinic receptors. Local anaesthesia of sensory vagal receptors, on the other hand, does not prevent exercise asthma and these receptors do not appear to have any important role in exercise-induced bronchoconstriction. PMID:6218645

  13. Nedocromil sodium versus sodium cromoglycate in treatment of exercise-induced bronchoconstriction: a systematic review.

    PubMed

    Kelly, K D; Spooner, C H; Rowe, B H

    2001-01-01

    The objective of this review was to compare the effects of prophylactic doses of nedocromil sodium (NCS) and sodium cromoglycate (SCG) on postexercise lung function, in persons diagnosed with exercise-induced bronchoconstriction. Randomized controlled trials were identified from the Cochrane Airways Review Group Asthma Register, plus hand searching for trials in journals, bibliographies of relevant studies and review articles. Randomized controlled trials comparing NCS to SCG in prophylactic treatment of exercise-induced bronchoconstriction were eligible. Studies were pooled using odds ratios (OR) for dichotomous outcomes or weighted mean differences (WMD) with 95% confidence intervals (95% CI) for continuous outcomes. No significant differences were noted between NCS and SCG with respect to the maximum per cent decrease in forced expiratory volume in one second (WMD=-0.88; 95% CI -4.50-2.74), complete protection (OR=0.95; 95% CI 0.50-1.81), clinical protection (OR=0.71; 95% CI 0.36-1.39), unpleasant taste (OR=6.85; 95% CI 0.77-60.73), or sore throat (OR=3.46; 95% CI 0.32-37.48). Subgroup analyses based on age, dosages of medications and timing of exercise postinhalation were consistent with the overall pooled analyses. No significant differences were evident between the effects of nedocromil sodium and sodium cromoglycate during the immediate postexercise period in adults and children with exercise-induced bronchoconstriction, with regards to maximum per cent decrease in forced expiratory volume in one second, complete protection, or clinical protection. Side-effect profiles were similar.

  14. Genetic influences on exercise-induced adult hippocampal neurogenesis across 12 divergent mouse strains

    PubMed Central

    Clark, Peter J.; Kohman, Rachel A.; Miller, Daniel S.; Bhattacharya, Tushar K.; Brzezinska, Weronika J.; Rhodes, Justin S.

    2011-01-01

    New neurons are continuously born in the hippocampus of several mammalian species throughout adulthood. Adult neurogenesis represents a natural model for understanding how to grow and incorporate new nerve cells into pre-existing circuits in the brain. Finding molecules or biological pathways that increase neurogenesis has broad potential for regenerative medicine. One strategy is to identify mouse strains that display large versus small increases in neurogenesis in response to wheel running so the strains can be contrasted to find common genes or biological pathways associated with enhanced neuron formation. Therefore, mice from 12 different isogenic strains were housed with or without running wheels for 43 days to measure the genetic regulation of exercise-induced neurogenesis. The first 10 days mice received daily injections of BrdU to label dividing cells. Neurogenesis was measured as the total number of BrdU cells co-expressing NeuN mature neuronal marker in the hippocampal granule cell layer by immunohistochemistry. Exercise increased neurogenesis in all strains, but the magnitude significantly depended on genotype. Strain means for distance run on wheels, but not distance traveled in cages without wheels, were significantly correlated with strain mean level of neurogenesis. Further, certain strains displayed greater neurogenesis than others for a fixed level of running. Strain means for neurogenesis under sedentary conditions were not correlated with neurogenesis under runner conditions suggesting that different genes influence baseline versus exercise-induced neurogenesis. Genetic contributions to exercise-induced hippocampal neurogenesis suggest that it may be possible to identify genes and pathways associated with enhanced neuroplastic responses to exercise. PMID:21223504

  15. Aerobic training suppresses exercise-induced lipid peroxidation and inflammation in overweight/obese adolescent girls.

    PubMed

    Youssef, Hala; Groussard, Carole; Lemoine-Morel, Sophie; Pincemail, Joel; Jacob, Christophe; Moussa, Elie; Fazah, Abdallah; Cillard, Josiane; Pineau, Jean-Claude; Delamarche, Arlette

    2015-02-01

    This study aimed to determine whether aerobic training could reduce lipid peroxidation and inflammation at rest and after maximal exhaustive exercise in overweight/obese adolescent girls. Thirty-nine adolescent girls (14-19 years old) were classified as nonobese or overweight/obese and then randomly assigned to either the nontrained or trained group (12-week multivariate aerobic training program). Measurements at the beginning of the experiment and at 3 months consisted of body composition, aerobic fitness (VO2peak) and the following blood assays: pre- and postexercise lipid peroxidation (15F2a-isoprostanes [F2-Isop], lipid hydroperoxide [ROOH], oxidized LDL [ox-LDL]) and inflammation (myeloperoxidase [MPO]) markers. In the overweight/ obese group, the training program significantly increased their fat-free mass (FFM) and decreased their percentage of fat mass (%FM) and hip circumference but did not modify their VO2peak. Conversely, in the nontrained overweight/obese group, weight and %FM increased, and VO2peak decreased, during the same period. Training also prevented exercise-induced lipid peroxidation and/or inflammation in overweight/obese girls (F2-Isop, ROOH, ox-LDL, MPO). In addition, in the trained overweight/obese group, exercise-induced changes in ROOH, ox-LDL and F2-Isop were correlated with improvements in anthropometric parameters (waist-to-hip ratio, %FM and FFM). In conclusion aerobic training increased tolerance to exercise-induced oxidative stress in overweight/obese adolescent girls partly as a result of improved body composition.

  16. Loss of functional endothelial connexin40 results in exercise-induced hypertension in mice.

    PubMed

    Morton, Susan K; Chaston, Daniel J; Howitt, Lauren; Heisler, Jillian; Nicholson, Bruce J; Fairweather, Stephen; Bröer, Stefan; Ashton, Anthony W; Matthaei, Klaus I; Hill, Caryl E

    2015-03-01

    During activity, coordinated vasodilation of microcirculatory networks with upstream supply vessels increases blood flow to skeletal and cardiac muscles and reduces peripheral resistance. Endothelial dysfunction in humans attenuates activity-dependent vasodilation, resulting in exercise-induced hypertension in otherwise normotensive individuals. Underpinning activity-dependent hyperemia is an ascending vasodilation in which the endothelial gap junction protein, connexin (Cx)40, plays an essential role. Because exercise-induced hypertension is proposed as a forerunner to clinical hypertension, we hypothesized that endothelial disruption of Cx40 function in mice may create an animal model of this condition. To this end, we created mice in which a mutant Cx40T152A was expressed alongside wildtype Cx40 selectively in the endothelium. Expression of the Cx40T152A transgene in Xenopus oocytes and mouse coronary endothelial cells in vitro impaired both electric and chemical conductance and acted as a dominant-negative against wildtype Cx40, Cx43, and Cx45, but not Cx37. Endothelial expression of Cx40T152A in Cx40T152ATg mice attenuated ascending vasodilation, without effect on radial coupling through myoendothelial gap junctions. Using radiotelemetry, Cx40T152ATg mice showed an activity-dependent increase in blood pressure, which was significantly greater than in wildtype mice, but significantly less than in chronically hypertensive, Cx40knockout mice. The increase in heart rate with activity was also greater than in wildtype or Cx40knockout mice. We conclude that the endothelial Cx40T152A mutation attenuates activity-dependent vasodilation, producing a model of exercise-induced hypertension. These data highlight the importance of endothelial coupling through Cx40 in regulating blood pressure during activity.

  17. Exploring the Mechanisms of Exercise-Induced Hypoalgesia Using Somatosensory and Laser Evoked Potentials

    PubMed Central

    Jones, Matthew D.; Taylor, Janet L.; Booth, John; Barry, Benjamin K.

    2016-01-01

    Exercise-induced hypoalgesia is well described, but the underlying mechanisms are unclear. The aim of this study was to examine the effect of exercise on somatosensory evoked potentials, laser evoked potentials, pressure pain thresholds and heat pain thresholds. These were recorded before and after 3-min of isometric elbow flexion exercise at 40% of the participant's maximal voluntary force, or an equivalent period of rest. Exercise-induced hypoalgesia was confirmed in two experiments (Experiment 1–SEPs; Experiment 2–LEPs) by increased pressure pain thresholds at biceps brachii (24.3 and 20.6% increase in Experiment 1 and 2, respectively; both d > 0.84 and p < 0.001) and first dorsal interosseous (18.8 and 21.5% increase in Experiment 1 and 2, respectively; both d > 0.57 and p < 0.001). In contrast, heat pain thresholds were not significantly different after exercise (forearm: 10.8% increase, d = 0.35, p = 0.10; hand: 3.6% increase, d = 0.06, p = 0.74). Contrasting effects of exercise on the amplitude of laser evoked potentials (14.6% decrease, d = −0.42, p = 0.004) and somatosensory evoked potentials (10.9% increase, d = −0.02, p = 1) were also observed, while an equivalent period of rest showed similar habituation (laser evoked potential: 7.3% decrease, d = −0.25, p = 0.14; somatosensory evoked potential: 20.7% decrease, d = −0.32, p = 0.006). The differential response of pressure pain thresholds and heat pain thresholds to exercise is consistent with relative insensitivity of thermal nociception to the acute hypoalgesic effects of exercise. Conflicting effects of exercise on somatosensory evoked potentials and laser evoked potentials were observed. This may reflect non-nociceptive contributions to the somatosensory evoked potential, but could also indicate that peripheral nociceptors contribute to exercise-induced hypoalgesia. PMID:27965587

  18. Exploring the Mechanisms of Exercise-Induced Hypoalgesia Using Somatosensory and Laser Evoked Potentials.

    PubMed

    Jones, Matthew D; Taylor, Janet L; Booth, John; Barry, Benjamin K

    2016-01-01

    Exercise-induced hypoalgesia is well described, but the underlying mechanisms are unclear. The aim of this study was to examine the effect of exercise on somatosensory evoked potentials, laser evoked potentials, pressure pain thresholds and heat pain thresholds. These were recorded before and after 3-min of isometric elbow flexion exercise at 40% of the participant's maximal voluntary force, or an equivalent period of rest. Exercise-induced hypoalgesia was confirmed in two experiments (Experiment 1-SEPs; Experiment 2-LEPs) by increased pressure pain thresholds at biceps brachii (24.3 and 20.6% increase in Experiment 1 and 2, respectively; both d > 0.84 and p < 0.001) and first dorsal interosseous (18.8 and 21.5% increase in Experiment 1 and 2, respectively; both d > 0.57 and p < 0.001). In contrast, heat pain thresholds were not significantly different after exercise (forearm: 10.8% increase, d = 0.35, p = 0.10; hand: 3.6% increase, d = 0.06, p = 0.74). Contrasting effects of exercise on the amplitude of laser evoked potentials (14.6% decrease, d = -0.42, p = 0.004) and somatosensory evoked potentials (10.9% increase, d = -0.02, p = 1) were also observed, while an equivalent period of rest showed similar habituation (laser evoked potential: 7.3% decrease, d = -0.25, p = 0.14; somatosensory evoked potential: 20.7% decrease, d = -0.32, p = 0.006). The differential response of pressure pain thresholds and heat pain thresholds to exercise is consistent with relative insensitivity of thermal nociception to the acute hypoalgesic effects of exercise. Conflicting effects of exercise on somatosensory evoked potentials and laser evoked potentials were observed. This may reflect non-nociceptive contributions to the somatosensory evoked potential, but could also indicate that peripheral nociceptors contribute to exercise-induced hypoalgesia.

  19. Exercise-induced hemostatic alterations are detectable by rotation thrombelastography (ROTEM): A marathon study.

    PubMed

    Sucker, Christoph; Zotz, Rainer B; Senft, Beate; Scharf, Rudiger E; Kröger, Knut; Erbel, Raimund; Möhlenkamp, Stefan

    2010-10-01

    Rotation thrombelastography (ROTEM) provides a whole blood assay that allows the assessment of plasmic- and platelet-related hemostasis in a single-step procedure. In our current study, we focused on the capability of the method to detect hemostatic alterations induced by physical exercise, enrolling 33 healthy participants of the Dusseldorf Marathon 2006. Venous blood drawn immediately before and after finishing the marathon was analyzed by a rotational thrombelastograph (Pentapharm, Munich, Germany). On initiation of blood coagulation by recalcification, standard ROTEM parameters were determined. Comparison of the results obtained before and after the physical exercise was performed using the Student t test for paired samples. As a result, the mean clotting time (CT) determined from blood samples obtained immediately after the marathon was significantly shorter (662.9 + or - 67.8 seconds vs 505.6 + or - 97.3 seconds, P = .002) and the mean maximal clot firmness was significantly broader (48.4 +/- 6.6 mm vs 51.5 +/- 4.5 mm, P = .0004) when compared to results obtained before the physical exercise. Differences between mean clot formation times (CFTs; 280.6 + 96 seconds vs 270.4 + or - 73.8 seconds) and mean alpha angles (45.9 degrees + or - 8 degrees vs 47.8 degrees + or - 5.8 degrees ) before and after the marathon were not statistically significant. Remarkably, some participants showed opposed results, particularly prolongation of CT and narrowing of maximum clot firmness (MCF). Our study demonstrates that ROTEM is sensitive to exercise-induced hemostatic alterations. The method appears to be capable of detecting even distinct changes in hemostasis in a single-step procedure. Further analyses are needed to clarify which hemostasis parameters influence ROTEM results and which ROTEM results are independent predictors of exercise-induced alterations of plasmic and platelet function. This might help to explain interindividual differences in exercise-induced

  20. Redox Regulation of Mitochondrial Function

    PubMed Central

    Handy, Diane E.

    2012-01-01

    Abstract Redox-dependent processes influence most cellular functions, such as differentiation, proliferation, and apoptosis. Mitochondria are at the center of these processes, as mitochondria both generate reactive oxygen species (ROS) that drive redox-sensitive events and respond to ROS-mediated changes in the cellular redox state. In this review, we examine the regulation of cellular ROS, their modes of production and removal, and the redox-sensitive targets that are modified by their flux. In particular, we focus on the actions of redox-sensitive targets that alter mitochondrial function and the role of these redox modifications on metabolism, mitochondrial biogenesis, receptor-mediated signaling, and apoptotic pathways. We also consider the role of mitochondria in modulating these pathways, and discuss how redox-dependent events may contribute to pathobiology by altering mitochondrial function. Antioxid. Redox Signal. 16, 1323–1367. PMID:22146081

  1. Therapeutic prospects for mitochondrial disease

    PubMed Central

    Schon, Eric A.; DiMauro, Salvatore; Hirano, Michio; Gilkerson, Robert W.

    2010-01-01

    Until even only a few years ago, the idea that effective therapies for human mitochondrial disorders resulting from dysfunction of the respiratory chain/oxidative phosphorylation system (OxPhos) could be developed was unimaginable. The obstacles to treating diseases caused by mutations in either mitochondrial DNA (mtDNA) or nuclear DNA (nDNA), and which had the potential to affect nearly every organ system, seemed overwhelming. However, while clinically applicable therapies still remain largely in the future, the landscape has changed dramatically; we can now envision the possibility of treating some of these disorders. Among these are techniques to upregulate mitochondrial biogenesis, to enhance organellar fusion and fission, to “shift heteroplasmy,” and to eliminate the burden of mutant mtDNAs via cytoplasmic transfer. PMID:20556877

  2. Where to from here for exercise-induced bronchoconstriction: the unanswered questions.

    PubMed

    Hallstrand, Teal S; Kippelen, Pascale; Larsson, Johan; Bougault, Valérie; van Leeuwen, Janneke C; Driessen, Jean M M; Brannan, John D

    2013-08-01

    The role of epithelial injury is an unanswered question in those with established asthma and in elite athletes who develop features of asthma and exercise-induced bronchorestriction (EIB) after years of training. The movement of water in response to changes in osmolarity is likely to be an important signal to the epithelium that may be central to the onset of EIB. It is generally accepted that the mast cell and its mediators play a major role in EIB and the presence of eosinophils is likely to enhance EIB severity.

  3. Exercise-induced changes in interleukin-10 in patients with knee osteoarthritis: new perspectives?

    PubMed

    Lems, Willem F; den Uyl, Debby

    2010-01-01

    Osteoarthritis (OA) of the knee is a common chronic disease leading to increased morbidity and reduced quality of life. Although exercise therapy has been shown to be beneficial for both pain and physical functioning, its underlying mechanism is not fully understood. However, a recent study found an exercise-induced increase in interleukin-10 levels, to which anti-inflammatory and chondroprotective properties are ascribed, in the (peri-)synovial fluid of patients with knee OA. These interesting results provide more insight into the effects of exercise in OA and need to be validated and confirmed. Hopefully, the study offers a promising basis for further research.

  4. Exercise-induced arterial hypoxemia is unaffected by intense physical training: a case report.

    PubMed

    Dominelli, Paolo B; Foster, Glen E; Dominelli, Giulio S; Henderson, William R; Koehle, Michael S; McKenzie, Donald C; Sheel, A William

    2014-02-01

    Exercise-induced arterial hypoxemia (EIAH) occurs in some healthy humans at sea-level, whereby the most aerobically trained individuals develop the most severe hypoxemia. A female competitive runner completed 2 maximal exercise tests. Maximal oxygen consumption increased by 15% between testing days, but the degree of hypoxemia remained similar (PaO2, SaO2; 82 and 80 mm Hg; 93.8% and 92.8%; first and second test, respectively). Our case indicates that EIAH does not necessarily worsen with aerobic training.

  5. Proteomic profiling of the mitochondrial ribosome identifies Atp25 as a composite mitochondrial precursor protein

    PubMed Central

    Woellhaf, Michael W.; Sommer, Frederik; Schroda, Michael; Herrmann, Johannes M.

    2016-01-01

    Whereas the structure and function of cytosolic ribosomes are well characterized, we only have a limited understanding of the mitochondrial translation apparatus. Using SILAC-based proteomic profiling, we identified 13 proteins that cofractionated with the mitochondrial ribosome, most of which play a role in translation or ribosomal biogenesis. One of these proteins is a homologue of the bacterial ribosome-silencing factor (Rsf). This protein is generated from the composite precursor protein Atp25 upon internal cleavage by the matrix processing peptidase MPP, and in this respect, it differs from all other characterized mitochondrial proteins of baker’s yeast. We observed that cytosolic expression of Rsf, but not of noncleaved Atp25 protein, is toxic. Our results suggest that eukaryotic cells face the challenge of avoiding negative interference from the biogenesis of their two distinct translation machineries. PMID:27582385

  6. Proteomic profiling of the mitochondrial ribosome identifies Atp25 as a composite mitochondrial precursor protein.

    PubMed

    Woellhaf, Michael W; Sommer, Frederik; Schroda, Michael; Herrmann, Johannes M

    2016-10-15

    Whereas the structure and function of cytosolic ribosomes are well characterized, we only have a limited understanding of the mitochondrial translation apparatus. Using SILAC-based proteomic profiling, we identified 13 proteins that cofractionated with the mitochondrial ribosome, most of which play a role in translation or ribosomal biogenesis. One of these proteins is a homologue of the bacterial ribosome-silencing factor (Rsf). This protein is generated from the composite precursor protein Atp25 upon internal cleavage by the matrix processing peptidase MPP, and in this respect, it differs from all other characterized mitochondrial proteins of baker's yeast. We observed that cytosolic expression of Rsf, but not of noncleaved Atp25 protein, is toxic. Our results suggest that eukaryotic cells face the challenge of avoiding negative interference from the biogenesis of their two distinct translation machineries.

  7. Protective effects of a natural product, curcumin, against amyloid β induced mitochondrial and synaptic toxicities in Alzheimer's disease.

    PubMed

    Reddy, P Hemachandra; Manczak, Maria; Yin, Xiangling; Grady, Mary Catharine; Mitchell, Andrew; Kandimalla, Ramesh; Kuruva, Chandra Sekhar

    2016-12-01

    The purpose of our study was to investigate the protective effects of a natural product-'curcumin'- in Alzheimer's disease (AD)-like neurons. Although much research has been done in AD, very little has been reported on the effects of curcumin on mitochondrial biogenesis, dynamics, function and synaptic activities. Therefore, the present study investigated the protective effects against amyloid β (Aβ) induced mitochondrial and synaptic toxicities. Using human neuroblastoma (SHSY5Y) cells, curcumin and Aβ, we studied the protective effects of curcumin against Aβ. Further, we also studied preventive (curcumin+Aβ) and intervention (Aβ+curcumin) effects of curcumin against Aβ in SHSY5Y cells. Using real time RT-PCR, immunoblotting and immunofluorescence analysis, we measured mRNA and protein levels of mitochondrial dynamics, mitochondrial biogenesis and synaptic genes. We also assessed mitochondrial function by measuring hydrogen peroxide, lipid peroxidation, cytochrome oxidase activity and mitochondrial ATP. Cell viability was studied using the MTT assay. Aβ was found to impair mitochondrial dynamics, reduce mitochondrial biogenesis and decrease synaptic activity and mitochondrial function. In contrast, curcumin enhanced mitochondrial fusion activity and reduced fission machinery, and increased biogenesis and synaptic proteins. Mitochondrial function and cell viability were elevated in curcumin treated cells. Interestingly, curcumin pre- and post-treated cells incubated with Aβ showed reduced mitochondrial dysfunction, and maintained cell viability and mitochondrial dynamics, mitochondrial biogenesis and synaptic activity. Further, the protective effects of curcumin were stronger in pretreated SHSY5Y cells than in post-treated cells, indicating that curcumin works better in prevention than treatment in AD-like neurons. Our findings suggest that curcumin is a promising drug molecule to treat AD patients.

  8. Protective effects of a natural product, curcumin, against amyloid β induced mitochondrial and synaptic toxicities in Alzheimer's disease

    PubMed Central

    Reddy, P Hemachandra; Manczak, Maria; Yin, Xiangling; Grady, Mary Catharine; Mitchell, Andrew; Kandimalla, Ramesh; Kuruva, Chandra Sekhar

    2016-01-01

    The purpose of our study was to investigate the protective effects of a natural product—‘curcumin’— in Alzheimer's disease (AD)-like neurons. Although much research has been done in AD, very little has been reported on the effects of curcumin on mitochondrial biogenesis, dynamics, function and synaptic activities. Therefore, the present study investigated the protective effects against amyloid β (Aβ) induced mitochondrial and synaptic toxicities. Using human neuroblastoma (SHSY5Y) cells, curcumin and Aβ, we studied the protective effects of curcumin against Aβ. Further, we also studied preventive (curcumin+Aβ) and intervention (Aβ+curcumin) effects of curcumin against Aβ in SHSY5Y cells. Using real time RT-PCR, immunoblotting and immunofluorescence analysis, we measured mRNA and protein levels of mitochondrial dynamics, mitochondrial biogenesis and synaptic genes. We also assessed mitochondrial function by measuring hydrogen peroxide, lipid peroxidation, cytochrome oxidase activity and mitochondrial ATP. Cell viability was studied using the MTT assay. Aβ was found to impair mitochondrial dynamics, reduce mitochondrial biogenesis and decrease synaptic activity and mitochondrial function. In contrast, curcumin enhanced mitochondrial fusion activity and reduced fission machinery, and increased biogenesis and synaptic proteins. Mitochondrial function and cell viability were elevated in curcumin treated cells. Interestingly, curcumin pre- and post-treated cells incubated with Aβ showed reduced mitochondrial dysfunction, and maintained cell viability and mitochondrial dynamics, mitochondrial biogenesis and synaptic activity. Further, the protective effects of curcumin were stronger in pretreated SHSY5Y cells than in post-treated cells, indicating that curcumin works better in prevention than treatment in AD-like neurons. Our findings suggest that curcumin is a promising drug molecule to treat AD patients. PMID:27521081

  9. Exercise improves mitochondrial and redox-regulated stress responses in the elderly: better late than never!

    PubMed

    Cobley, James N; Moult, Peter R; Burniston, Jatin G; Morton, James P; Close, Graeme L

    2015-04-01

    Ageing is associated with several physiological declines to both the cardiovascular (e.g. reduced aerobic capacity) and musculoskeletal system (muscle function and mass). Ageing may also impair the adaptive response of skeletal muscle mitochondria and redox-regulated stress responses to an acute exercise bout, at least in mice and rodents. This is a functionally important phenomenon, since (1) aberrant mitochondrial and redox homeostasis are implicated in the pathophysiology of musculoskeletal ageing and (2) the response to repeated exercise bouts promotes exercise adaptations and some of these adaptations (e.g. improved aerobic capacity and exercise-induced mitochondrial remodelling) offset age-related physiological decline. Exercise-induced mitochondrial remodelling is mediated by upstream signalling events that converge on downstream transcriptional co-factors and factors that orchestrate a co-ordinated nuclear and mitochondrial transcriptional response associated with mitochondrial remodelling. Recent translational human investigations have demonstrated similar exercise-induced mitochondrial signalling responses in older compared with younger skeletal muscle, regardless of training status. This is consistent with data indicating normative mitochondrial remodelling responses to long-term exercise training in the elderly. Thus, human ageing is not accompanied by diminished mitochondrial plasticity to acute and chronic exercise stimuli, at least for the signalling pathways measured to date. Exercise-induced increases in reactive oxygen and nitrogen species promote an acute redox-regulated stress response that manifests as increased heat shock protein and antioxidant enzyme content. In accordance with previous reports in rodents and mice, it appears that sedentary ageing is associated with a severely attenuated exercise-induced redox stress response that might be related to an absent redox signal. In this regard, regular exercise training affords some protection

  10. Mitochondrial respiration regulates adipogenic differentiation of human mesenchymal stem cells.

    PubMed

    Zhang, Yanmin; Marsboom, Glenn; Toth, Peter T; Rehman, Jalees

    2013-01-01

    Human mesenchymal stem cells (MSCs) are adult multipotent stem cells which can be isolated from bone marrow, adipose tissue as well as other tissues and have the capacity to differentiate into a variety of mesenchymal cell types such as adipocytes, osteoblasts and chondrocytes. Differentiation of stem cells into mature cell types is guided by growth factors and hormones, but recent studies suggest that metabolic shifts occur during differentiation and can modulate the differentiation process. We therefore investigated mitochondrial biogenesis, mitochondrial respiration and the mitochondrial membrane potential during adipogenic differentiation of human MSCs. In addition, we inhibited mitochondrial function to assess its effects on adipogenic differentiation. Our data show that mitochondrial biogenesis and oxygen consumption increase markedly during adipogenic differentiation, and that reducing mitochondrial respiration by hypoxia or by inhibition of the mitochondrial electron transport chain significantly suppresses adipogenic differentiation. Furthermore, we used a novel approach to suppress mitochondrial activity using a specific siRNA-based knockdown of the mitochondrial transcription factor A (TFAM), which also resulted in an inhibition of adipogenic differentiation. Taken together, our data demonstrates that increased mitochondrial activity is a prerequisite for MSC differentiation into adipocytes. These findings suggest that metabolic modulation of adult stem cells can maintain stem cell pluripotency or direct adult stem cell differentiation.

  11. Distinct Pathways Mediate the Sorting of Tail-anchored Mitochondrial Outer Membrane Proteins

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Little is known about the biogenesis of tail-anchored (TA) proteins localized to the mitochondrial outer membrane in plant cells. To address this issue, we screened all of the (>500) known and predicted TA proteins in Arabidopsis for those annotated, based on Gene Ontology, to possess mitochondrial...

  12. Formoterol restores mitochondrial and renal function after ischemia-reperfusion injury.

    PubMed

    Jesinkey, Sean R; Funk, Jason A; Stallons, L Jay; Wills, Lauren P; Megyesi, Judit K; Beeson, Craig C; Schnellmann, Rick G

    2014-06-01

    Mitochondrial biogenesis may be an adaptive response necessary for meeting the increased metabolic and energy demands during organ recovery after acute injury, and renal mitochondrial dysfunction has been implicated in the pathogenesis of AKI. We proposed that stimulation of mitochondrial biogenesis 24 hours after ischemia/reperfusion (I/R)-induced AKI, when renal dysfunction is maximal, would accelerate recovery of mitochondrial and renal function in mice. We recently showed that formoterol, a potent, highly specific, and long-acting β2-adrenergic agonist, induces renal mitochondrial biogenesis in naive mice. Animals were subjected to sham or I/R-induced AKI, followed by once-daily intraperitoneal injection with vehicle or formoterol beginning 24 hours after surgery and continuing through 144 hours after surgery. Treatment with formoterol restored renal function, rescued renal tubules from injury, and diminished necrosis after I/R-induced AKI. Concomitantly, formoterol stimulated mitochondrial biogenesis and restored the expression and function of mitochondrial proteins. Taken together, these results provide proof of principle that a novel drug therapy to treat AKI, and potentially other acute organ failures, works by restoring mitochondrial function and accelerating the recovery of renal function after injury has occurred.

  13. Exercise-induced interstitial pulmonary edema at sea-level in young and old healthy humans

    PubMed Central

    Taylor, Bryan J.; Carlson, Alex R.; Miller, Andrew D.; Johnson, Bruce D.

    2014-01-01

    We asked whether aged adults are more susceptible to exercise-induced pulmonary edema relative to younger individuals. Lung diffusing capacity for carbon monoxide (DLCO), alveolar-capillary membrane conductance (Dm) and pulmonary-capillary blood volume (Vc) were measured before and after exhaustive discontinuous incremental exercise in 10 young (YNG; 27±3 yr) and 10 old (OLD; 69±5 yr) males. In YNG subjects, Dm increased (11±7%, P=0.031), Vc decreased (−10±9%, P=0.01) and DLCO was unchanged (30.5±4.1 vs. 29.7±2.9 ml/min/mmHg, P=0.44) pre- to post-exercise. In OLD subjects, DLCO and Dm increased (11±14%, P=0.042; 16±14%, P=0.025) but Vc was unchanged (58±23 vs. 56±23 ml, P=0.570) pre- to post-exercise. Group-mean Dm/Vc was greater after vs. before exercise in the YNG and OLD subjects. However, Dm/Vc was lower post-exercise in 2 of the 10 YNG (−7±4%) and 2 of the 10 OLD subjects (−10±5%). These data suggest that exercise decreases interstitial lung fluid in most YNG and OLD subjects, with a small number exhibiting evidence for exercise-induced pulmonary edema. PMID:24200644

  14. Duration of action of sodium cromoglycate on exercise induced asthma: comparison of 2 formulations.

    PubMed Central

    Bar-Yishay, E; Gur, I; Levy, M; Volozni, D; Godfrey, S

    1983-01-01

    Thirteen asthmatic children aged 9-14 years participated in a double blind randomised trial to compare the effectiveness and duration of action of 2 formulations of sodium cromoglycate; one a 20 mg capsule of powdered sodium cromoglycate delivered by turbo inhaler (spinhaler), and the other 1 mg of aerosolised sodium cromoglycate delivered by pressurised cannister inhaler (aerosol). The children performed exercise tests on each of 3 days in a 10 day period--15 minutes, 2 hours, and 6 hours after inhalation of powder, aerosol, or a placebo. Two patients were not protected from exercise induced asthma by either formulation of sodium cromoglycate. Among the remaining patients both formulations gave good protection from exercise induced asthma 15 minutes after inhalation, and the effect of both wore off steadily over the next 6 hours. The spinhaler gave appreciably better protection than the aerosol at 15 minutes after inhalation, and was the only formulation to provide good protection at 2 hours and 6 hours. The more limited effectiveness of the aerosol may be explained by the lower dose of sodium cromoglycate and the more complicated inhalation technique required. PMID:6412638

  15. Exercise-Induced Norepinephrine Decreases Circulating Hematopoietic Stem and Progenitor Cell Colony-Forming Capacity

    PubMed Central

    Mangge, Harald; Pekovits, Karin; Fuchs, Robert; Allard, Nathalie; Schinagl, Lukas; Hofmann, Peter; Dohr, Gottfried; Wallner-Liebmann, Sandra; Domej, Wolfgang; Müller, Wolfram

    2014-01-01

    A recent study showed that ergometry increased circulating hematopoietic stem and progenitor cell (CPC) numbers, but reduced hematopoietic colony forming capacity/functionality under normoxia and normobaric hypoxia. Herein we investigated whether an exercise-induced elevated plasma free/bound norepinephrine (NE) concentration could be responsible for directly influencing CPC functionality. Venous blood was taken from ten healthy male subjects (25.3+/−4.4 yrs) before and 4 times after ergometry under normoxia and normobaric hypoxia (FiO2<0.15). The circulating hematopoietic stem and progenitor cell numbers were correlated with free/bound NE, free/bound epinephrine (EPI), cortisol (Co) and interleukin-6 (IL-6). Additionally, the influence of exercise-induced NE and blood lactate (La) on CPC functionality was analyzed in a randomly selected group of subjects (n = 6) in vitro under normoxia by secondary colony-forming unit granulocyte macrophage assays. Concentrations of free NE, EPI, Co and IL-6 were significantly increased post-exercise under normoxia/hypoxia. Ergometry-induced free NE concentrations found in vivo showed a significant impairment of CPC functionality in vitro under normoxia. Thus, ergometry-induced free NE was thought to trigger CPC mobilization 10 minutes post-exercise, but as previously shown impairs CPC proliferative capacity/functionality at the same time. The obtained results suggest that an ergometry-induced free NE concentration has a direct negative effect on CPC functionality. Cortisol may further influence CPC dynamics and functionality. PMID:25180783

  16. Sex Differences in Exercise-Induced Muscle Pain and Muscle Damage

    PubMed Central

    Dannecker, Erin A.; Liu, Ying; Rector, R. Scott; Thomas, Tom R.; Fillingim, Roger B.; Robinson, Michael E.

    2012-01-01

    There is uncertainty about sex differences in exercise-induced muscle pain and muscle damage due to several methodological weaknesses in the literature. This investigation tested the hypothesis that higher levels of exercise-induced muscle pain and muscle damage indicators would be found in women than men when several methodological improvements were executed in the same study. Participants (N = 33; 42% women) with an average age of 23 years (SD = 2.82) consented to participate. After a familiarization session, participants visited the laboratory before and across four days after eccentric exercise was completed to induce arm muscle pain and muscle damage. Our primary outcomes were arm pain ratings and pressure pain thresholds. However, we also measured the following indicators of muscle damage: arm girth; resting elbow extension; isometric elbow flexor strength; myoglobin (Mb); tumor necrosis factor (TNFa); interleukin 1beta (IL1b); and total nitric oxide (NO). Temporary induction of muscle damage was indicated by changes in all outcome measures except TNFa, and IL1b. In contrast to our hypotheses, women reported moderately lower and less frequent muscle pain than men. Also, women’s arm girth and Mb levels increased moderately less than men’s, but the differences were not significant. Few large sex differences were detected. PMID:23182229

  17. Physical and balance performance following exercise induced muscle damage in male soccer players

    PubMed Central

    Khan, Muzaffar Ahmad; Moiz, Jamal Ali; Raza, Shahid; Verma, Shalini; Shareef, M.Y.; Anwer, Shahnawaz; Alghadir, Ahmad

    2016-01-01

    [Purpose] The present study aimed to determine the changes in physical and balance performance following exercise-induced muscle damage using a sport-specific protocol. [Subjects and Methods] Fifteen collegiate soccer players were asked to perform a sport-specific sprint protocol to induce muscle damage. The markers of muscle damage (soreness, range of motion, limb girth, muscle strength, creatine kinase and lactate dehydrogenase), physical performance (speed, agility and power) and balance (static and dynamic balance) were assessed at baseline and 24, 48 and 72 hours following the sprint protocol. [Results] All variables, including the markers of muscle damage, physical performance and balance showed a significant difference when assessed at the 4 time points. [Conclusion] The study demonstrated that both the physical and balance performance were affected following repeated sprint protocol in soccer players. It is recommended the balance performance of an athlete be continually assessed following exercise-induced muscle damage so as to determine the appropriate return to sport decision thereby, minimizing the risk of further injury. PMID:27821967

  18. Benefits of dietary phytochemical supplementation on eccentric exercise-induced muscle damage: Is including antioxidants enough?

    PubMed

    Pereira Panza, Vilma Simões; Diefenthaeler, Fernando; da Silva, Edson Luiz

    2015-09-01

    The purpose of this review was to critically discuss studies that investigated the effects of supplementation with dietary antioxidant phytochemicals on recovery from eccentric exercise-induced muscle damage. The performance of physical activities that involve unaccustomed eccentric muscle actions-such as lowering a weight or downhill walking-can result in muscle damage, oxidative stress, and inflammation. These events may be accompanied by muscle weakness and delayed-onset muscle soreness. According to the current evidences, supplementation with dietary antioxidant phytochemicals appears to have the potential to attenuate symptoms associated with eccentric exercise-induced muscle damage. However, there are inconsistencies regarding the relationship between muscle damage and blood markers of oxidative stress and inflammation. Furthermore, the effectiveness of strategies appear to depend on a number of aspects inherent to phytochemical compounds as well as its food matrix. Methodological issues also may interfere with the proper interpretation of supplementation effects. Thus, the study may contribute to updating professionals involved in sport nutrition as well as highlighting the interest of scientists in new perspectives that can widen dietary strategies applied to training.

  19. Physical and balance performance following exercise induced muscle damage in male soccer players.

    PubMed

    Khan, Muzaffar Ahmad; Moiz, Jamal Ali; Raza, Shahid; Verma, Shalini; Shareef, M Y; Anwer, Shahnawaz; Alghadir, Ahmad

    2016-10-01

    [Purpose] The present study aimed to determine the changes in physical and balance performance following exercise-induced muscle damage using a sport-specific protocol. [Subjects and Methods] Fifteen collegiate soccer players were asked to perform a sport-specific sprint protocol to induce muscle damage. The markers of muscle damage (soreness, range of motion, limb girth, muscle strength, creatine kinase and lactate dehydrogenase), physical performance (speed, agility and power) and balance (static and dynamic balance) were assessed at baseline and 24, 48 and 72 hours following the sprint protocol. [Results] All variables, including the markers of muscle damage, physical performance and balance showed a significant difference when assessed at the 4 time points. [Conclusion] The study demonstrated that both the physical and balance performance were affected following repeated sprint protocol in soccer players. It is recommended the balance performance of an athlete be continually assessed following exercise-induced muscle damage so as to determine the appropriate return to sport decision thereby, minimizing the risk of further injury.

  20. Exercise-induced changes of the capillaries in the cortex of middle-aged rats.

    PubMed

    Huang, C-X; Qiu, X; Wang, S; Wu, H; Xia, L; Li, C; Gao, Y; Zhang, L; Xiu, Y; Chao, F; Tang, Y

    2013-03-13

    Previous studies have shown that running exercise could increase regional cerebral blood flow. There have been previous studies investigating the effects of running exercise on capillary density in the brain and showing that running exercise could induce brain angiogenesis. However, there have been no studies investigating the effects of running exercise on the total volume, total length and total surface area of the capillaries in the cortex. Moreover, sex differences in the effects of running exercise on the capillaries of the cortex have not previously been investigated. The current study was designed to investigate the effects of running exercise on the capillaries in the cortex of middle-aged rats using the new unbiased stereological methods. The present study found that the total length and total surface area of the capillaries in the cortex of running middle-aged female rats were significantly increased, compared to control rats. Our results also reveal that there are sex differences in the effects of running exercise on the capillaries in the cortex of middle-aged rats. These results demonstrate that exercise-induced increases of the capillaries in the female rat cortex might be one of the structural bases for the exercise-induced improvement in the spatial learning capacity of middle-aged female rats. These results provide a baseline for further studies that search for strategies to delay the deleterious effects of brain aging.

  1. Use of Saliva Biomarkers to Monitor Efficacy of Vitamin C in Exercise-Induced Oxidative Stress

    PubMed Central

    Evans, Levi W.; Omaye, Stanley T.

    2017-01-01

    Saliva is easily obtainable for medical research and requires little effort or training for collection. Because saliva contains a variety of biological compounds, including vitamin C, malondialdehyde, amylase, and proteomes, it has been successfully used as a biospecimen for the reflection of health status. A popular topic of discussion in medical research is the potential association between oxidative stress and negative outcomes. Systemic biomarkers that represent oxidative stress can be found in saliva. It is unclear, however, if saliva is an accurate biospecimen as is blood and/or plasma. Exercise can induce oxidative stress, resulting in a trend of antioxidant supplementation to combat its assumed detriments. Vitamin C is a popular antioxidant supplement in the realm of sports and exercise. One potential avenue for evaluating exercise induced oxidative stress is through assessment of biomarkers like vitamin C and malondialdehyde in saliva. At present, limited research has been done in this area. The current state of research involving exercise-induced oxidative stress, salivary biomarkers, and vitamin C supplementation is reviewed in this article. PMID:28085082

  2. Influence of menstrual status on fluid replacement after exercise induced dehydration in healthy young women.

    PubMed Central

    Maughan, R J; McArthur, M; Shirreffs, S M

    1996-01-01

    OBJECTIVE--To determine whether fluid replacement after exercise induced dehydration varies over the normal menstrual cycle. METHODS--Five subjects, with a regular menstrual cycle lasting 28 (SEM 2) d, were dehydrated by 1.8(0.1)% of their pre-exercise mass by cycle exercise in the heat. Trials were undertaken 2 d before (trial -2) and 5 and 19 d after the onset of menses (trials 6 and 20 respectively). After exercise, subjects ingested a fixed volume, equivalent to 150% of mass loss, of a commercially available sports drink over a 60 min period. RESULTS--Cumulative urine output [median (range)] over the 6 h following ingestion was the same on all trials: 714(469-750) ml on trial -2; 476(433-639) ml on trial 6; 534(195-852) ml on trial 20. There was no menstrual cycle effect on urinary electrolyte (Na+, K+, Cl-) excretion or serum electrolyte (Na+, K+, Cl-) concentrations. Plasma volume increased by 8-12% of the postexercise value following rehydration. The percentage of ingested fluid retained did not differ between trials at any time. Six hours after drink ingestion, net fluid balance was not different from the initial value on any of the trials. CONCLUSIONS--Acute replacement of exercise induced fluid losses is not affected by the normal menstrual cycle. PMID:8665117

  3. Food-dependent exercise-induced anaphylaxis: a case related to chickpea ingestion and review.

    PubMed

    Wong, Chet G; Mace, Sean R

    2007-12-15

    : Food-dependent exercise-induced anaphylaxis (FDEIA) is recognized as a distinct category of exercise-induced anaphylaxis (EIA) but is very likely underdiagnosed. This report describes a 41-year-old Indian woman who experienced two separate episodes of anaphylaxis while dancing after she had eaten chickpea-containing foods. The chickpea, a small legume, is a staple ingredient in culinary traditions from around the world, especially in India, the Middle East, and North Africa. Chickpea-containing dishes are also becoming more widespread in the Western world with the growing popularity of South Asian, Middle Eastern, and African cuisines. It is important to consider FDEIA in cases of unexplained anaphylaxis as reactions can occur several hours after ingesting the culprit food(s). Furthermore, no reaction occurs if a sensitized individual eats the culprit food(s) without exercising afterward; therefore, triggering foods can easily be overlooked. Current ideas on the pathophysiology, predisposing factors, workup, and treatment of FDEIA are also summarized here.

  4. The endocannabinoid system mediates aerobic exercise-induced antinociception in rats.

    PubMed

    Galdino, Giovane; Romero, Thiago R L; Silva, José Felipe P; Aguiar, Daniele C; de Paula, Ana Maria; Cruz, Jader S; Parrella, Cosimo; Piscitelli, Fabiana; Duarte, Igor D; Di Marzo, Vincenzo; Perez, Andrea C

    2014-02-01

    Exercise-induced antinociception is widely described in the literature, but the mechanisms involved in this phenomenon are poorly understood. Systemic (s.c.) and central (i.t., i.c.v.) pretreatment with CB₁ and CB₂ cannabinoid receptor antagonists (AM251 and AM630) blocked the antinociception induced by an aerobic exercise (AE) protocol in both mechanical and thermal nociceptive tests. Western blot analysis revealed an increase and activation of CB₁ receptors in the rat brain, and immunofluorescence analysis demonstrated an increase of activation and expression of CB₁ receptors in neurons of the periaqueductal gray matter (PAG) after exercise. Additionally, pretreatment (s.c., i.t. and i.c.v.) with endocannabinoid metabolizing enzyme inhibitors (MAFP and JZL184) and an anandamide reuptake inhibitor (VDM11) prolonged and intensified this antinociceptive effect. These results indicate that exercise could activate the endocannabinoid system, producing antinociception. Supporting this hypothesis, liquid-chromatography/mass-spectrometry measurements demonstrated that plasma levels of endocannabinoids (anandamide and 2-arachidonoylglycerol) and of anandamide-related mediators (palmitoylethanolamide and oleoylethanolamide) were increased after AE. Therefore, these results suggest that the endocannabinoid system mediates aerobic exercise-induced antinociception at peripheral and central levels.

  5. Acceleration slope of exercise-induced impacts is a determinant of changes in bone density.

    PubMed

    Heikkinen, Riikka; Vihriälä, Erkki; Vainionpää, Aki; Korpelainen, Raija; Jämsä, Timo

    2007-01-01

    High acceleration levels (>4g) seen during impact exercises have been shown to increase bone mineral density (BMD) in premenopausal women. The aim of this study was to examine how the other acceleration signal characteristics, i.e. the slope, area and energy of the signal are related to changes in bone density, using long-term quantification of physical activity. Daily physical activity was continuously assessed with a waist-worn accelerometer-based body movement monitor in 64 premenopausal women participating in a 12-month population-based exercise trial. The daily number of exercise-induced impacts at different slope, area and energy levels of the acceleration signal was analyzed. Physical activity inducing slopes 1000 m/s(3), acceleration peak areas 2m/s or signal energies 75 m(2)/s(3) was associated with BMD change in the hip (p<0.05). Impacts with the smallest slopes (<1000 m/s(3)) were positively associated with changes in calcaneal speed of ultrasound, while impacts with slopes 1500 m/s(3) or areas 4m/s were positively correlated with broadband ultrasound attenuation changes (p<0.05). We conclude that the acceleration slope of exercise-induced impacts is an important determinant of bone density. The slope threshold for improving BMD at the hip is 1000 m/s(3), which can be achieved during normal exercise including fast movements such as running and jumping.

  6. Cardiac nuclear receptors: architects of mitochondrial structure and function.

    PubMed

    Vega, Rick B; Kelly, Daniel P

    2017-04-03

    The adult heart is uniquely designed and equipped to provide a continuous supply of energy in the form of ATP to support persistent contractile function. This high-capacity energy transduction system is the result of a remarkable surge in mitochondrial biogenesis and maturation during the fetal-to-adult transition in cardiac development. Substantial evidence indicates that nuclear receptor signaling is integral to dynamic changes in the cardiac mitochondrial phenotype in response to developmental cues, in response to diverse postnatal physiologic conditions, and in disease states such as heart failure. A subset of cardiac-enriched nuclear receptors serve to match mitochondrial fuel preferences and capacity for ATP production with changing energy demands of the heart. In this Review, we describe the role of specific nuclear receptors and their coregulators in the dynamic control of mitochondrial biogenesis and energy metabolism in the normal and diseased heart.

  7. Visualization of mitochondrial DNA replication in individual cells by EdU signal amplification.

    PubMed

    Haines, Kristine M; Feldman, Eva L; Lentz, Stephen I

    2010-11-15

    Mitochondria are key regulators of cellular energy and mitochondrial biogenesis is an essential component of regulating mitochondria numbers in healthy cells. One approach for monitoring mitochondrial biogenesis is to measure the rate of mitochondrial DNA (mtDNA) replication. We developed a sensitive technique to label newly synthesized mtDNA in individual cells in order to study mtDNA biogenesis. The technique combines the incorporation of 5-ethynyl-2'-deoxyuridine (EdU) with a tyramide signal amplification (TSA) protocol to visualize mtDNA replication within subcellular compartments of neurons. EdU is superior to other thymidine analogs, such as 5-bromo-2-deoxyuridine (BrdU), because the initial click reaction to label EdU does not require the harsh acid treatments or enzyme digests that are required for exposing the BrdU epitope. The milder labeling of EdU allows for direct comparison of its incorporation with other cellular markers. The ability to visualize and quantify mtDNA biogenesis provides an essential tool for investigating the mechanisms used to regulate mitochondrial biogenesis and would provide insight into the pathogenesis associated with drug toxicity, aging, cancer and neurodegenerative diseases. Our technique is applicable to sensory neurons as well as other cell types. The use of this technique to measure mtDNA biogenesis has significant implications in furthering the understanding of both normal cellular physiology as well as impaired disease states.

  8. Mitochondrial dysfunction in myofibrillar myopathy.

    PubMed

    Vincent, Amy E; Grady, John P; Rocha, Mariana C; Alston, Charlotte L; Rygiel, Karolina A; Barresi, Rita; Taylor, Robert W; Turnbull, Doug M

    2016-10-01

    Myofibrillar myopathies (MFM) are characterised by focal myofibrillar destruction and accumulation of myofibrillar elements as protein aggregates. They are caused by mutations in the DES, MYOT, CRYAB, FLNC, BAG3, DNAJB6 and ZASP genes as well as other as yet unidentified genes. Previous studies have reported changes in mitochondrial morphology and cellular positioning, as well as clonally-expanded, large-scale mitochondrial DNA (mtDNA) deletions and focal respiratory chain deficiency in muscle of MFM patients. Here we examine skeletal muscle from patients with desmin (n = 6), ZASP (n = 1) and myotilin (n = 2) mutations and MFM protein aggregates, to understand how mitochondrial dysfunction may contribute to the underlying mechanisms causing disease pathology. We have used a validated quantitative immunofluorescent assay to study respiratory chain protein levels, together with oxidative enzyme histochemistry and single cell mitochondrial DNA analysis, to examine mitochondrial changes. Results demonstrate a small number of clonally-expanded mitochondrial DNA deletions, which we conclude are due to both ageing and disease pathology. Further to this we report higher levels of respiratory chain complex I and IV deficiency compared to age matched controls, although overall levels of respiratory deficient muscle fibres in patient biopsies are low. More strikingly, a significantly higher percentage of myofibrillar myopathy patient muscle fibres have a low mitochondrial mass compared to controls. We concluded this is mechanistically unrelated to desmin and myotilin protein aggregates; however, correlation between mitochondrial mass and muscle fibre area is found. We suggest this may be due to reduced mitochondrial biogenesis in combination with muscle fibre hypertrophy.

  9. Enantiomeric Natural Products: Occurrence and Biogenesis**

    PubMed Central

    Finefield, Jennifer M.; Sherman, David H.; Kreitman, Martin; Williams, Robert M.

    2012-01-01

    In Nature, chiral natural products are usually produced in optically pure form; however, on occasion Nature is known to produce enantiomerically opposite metabolites. These enantiomeric natural products can arise in Nature from a single species, or from different genera and/or species. Extensive research has been carried out over the years in an attempt to understand the biogenesis of naturally occurring enantiomers, however, many fascinating puzzles and stereochemical anomalies still remain. PMID:22555867

  10. Irisin Controls Growth, Intracellular Ca2+ Signals, and Mitochondrial Thermogenesis in Cardiomyoblasts.

    PubMed

    Xie, Chao; Zhang, Yuan; Tran, Tran D N; Wang, Hai; Li, Shiwu; George, Eva Vertes; Zhuang, Haoyang; Zhang, Peilan; Kandel, Avi; Lai, Yimu; Tang, Dongqi; Reeves, Westley H; Cheng, Henrique; Ding, Yousong; Yang, Li-Jun

    2015-01-01

    Exercise offers short-term and long-term health benefits, including an increased metabolic rate and energy expenditure in myocardium. The newly-discovered exercise-induced myokine, irisin, stimulates conversion of white into brown adipocytes as well as increased mitochondrial biogenesis and energy expenditure. Remarkably, irisin is highly expressed in myocardium, but its physiological effects in the heart are unknown. The objective of this work is to investigate irisin's potential multifaceted effects on cardiomyoblasts and myocardium. For this purpose, H9C2 cells were treated with recombinant irisin produced in yeast cells (r-irisin) and in HEK293 cells (hr-irisin) for examining its effects on cell proliferation by MTT [3-(4, 5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay and on gene transcription profiles by qRT-PCR. R-irisin and hr-irisin both inhibited cell proliferation and activated genes related to cardiomyocyte metabolic function and differentiation, including myocardin, follistatin, smooth muscle actin, and nuclear respiratory factor-1. Signal transduction pathways affected by r-irisin in H9C2 cells and C57BL/6 mice were examined by detecting phosphorylation of PI3K-AKT, p38, ERK or STAT3. We also measured intracellular Ca2+ signaling and mitochondrial thermogenesis and energy expenditure in r-irisin-treated H9C2 cells. The results showed that r-irisin, in a certain concentration rage, could activate PI3K-AKT and intracellular Ca2+ signaling and increase cellular oxygen consumption in H9C2 cells. Our study also suggests the existence of irisin-specific receptor on the membrane of H9C2 cells. In conclusion, irisin in a certain concentration rage increased myocardial cell metabolism, inhibited cell proliferation and promoted cell differentiation. These effects might be mediated through PI3K-AKT and Ca2+ signaling, which are known to activate expression of exercise-related genes such as follistatin and myocardin. This work supports the value

  11. Irisin Controls Growth, Intracellular Ca2+ Signals, and Mitochondrial Thermogenesis in Cardiomyoblasts

    PubMed Central

    Xie, Chao; Zhang, Yuan; Tran, Tran D. N.; Wang, Hai; Li, Shiwu; George, Eva Vertes; Zhuang, Haoyang; Zhang, Peilan; Kandel, Avi; Lai, Yimu; Tang, Dongqi; Reeves, Westley H.; Cheng, Henrique; Ding, Yousong; Yang, Li-Jun

    2015-01-01

    Exercise offers short-term and long-term health benefits, including an increased metabolic rate and energy expenditure in myocardium. The newly-discovered exercise-induced myokine, irisin, stimulates conversion of white into brown adipocytes as well as increased mitochondrial biogenesis and energy expenditure. Remarkably, irisin is highly expressed in myocardium, but its physiological effects in the heart are unknown. The objective of this work is to investigate irisin’s potential multifaceted effects on cardiomyoblasts and myocardium. For this purpose, H9C2 cells were treated with recombinant irisin produced in yeast cells (r-irisin) and in HEK293 cells (hr-irisin) for examining its effects on cell proliferation by MTT [3-(4, 5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay and on gene transcription profiles by qRT-PCR. R-irisin and hr-irisin both inhibited cell proliferation and activated genes related to cardiomyocyte metabolic function and differentiation, including myocardin, follistatin, smooth muscle actin, and nuclear respiratory factor-1. Signal transduction pathways affected by r-irisin in H9C2 cells and C57BL/6 mice were examined by detecting phosphorylation of PI3K-AKT, p38, ERK or STAT3. We also measured intracellular Ca2+ signaling and mitochondrial thermogenesis and energy expenditure in r-irisin-treated H9C2 cells. The results showed that r-irisin, in a certain concentration rage, could activate PI3K-AKT and intracellular Ca2+ signaling and increase cellular oxygen consumption in H9C2 cells. Our study also suggests the existence of irisin-specific receptor on the membrane of H9C2 cells. In conclusion, irisin in a certain concentration rage increased myocardial cell metabolism, inhibited cell proliferation and promoted cell differentiation. These effects might be mediated through PI3K-AKT and Ca2+ signaling, which are known to activate expression of exercise-related genes such as follistatin and myocardin. This work supports the value

  12. Mitochondrial aging and age-related dysfunction of mitochondria.

    PubMed

    Chistiakov, Dimitry A; Sobenin, Igor A; Revin, Victor V; Orekhov, Alexander N; Bobryshev, Yuri V

    2014-01-01

    Age-related changes in mitochondria are associated with decline in mitochondrial function. With advanced age, mitochondrial DNA volume, integrity and functionality decrease due to accumulation of mutations and oxidative damage induced by reactive oxygen species (ROS). In aged subjects, mitochondria are characterized by impaired function such as lowered oxidative capacity, reduced oxidative phosphorylation, decreased ATP production, significant increase in ROS generation, and diminished antioxidant defense. Mitochondrial biogenesis declines with age due to alterations in mitochondrial dynamics and inhibition of mitophagy, an autophagy process that removes dysfunctional mitochondria. Age-dependent abnormalities in mitochondrial quality control further weaken and impair mitochondrial function. In aged tissues, enhanced mitochondria-mediated apoptosis contributes to an increase in the percentage of apoptotic cells. However, implementation of strategies such as caloric restriction and regular physical training may delay mitochondrial aging and attenuate the age-related phenotype in humans.

  13. Exercise-induced albuminuria vs circadian variations in blood pressure in type 1 diabetes

    PubMed Central

    Tadida Meli, Isabelle Hota; Tankeu, Aurel T; Dehayem, Mesmin Y; Chelo, David; Noubiap, Jean Jacques N; Sobngwi, Eugene

    2017-01-01

    AIM To investigated the relationship between exercise-induced ambulatory blood pressure measurement (ABPM) abnormalities in type 1 diabetes mellitus (T1DM) adolescents. METHODS We conducted a case-control at the National Obesity Center of the Yaoundé Central Hospital, Cameroon. We compared 24 h ABPM and urinary albumin-to-creatinine ratio (ACR) at rest and after a standardized treadmill exercise between 20 Cameroonian T1DM patients and 20 matched controls. T1DM adolescents were aged 12-18 years, with diabetes for at least one year, without proteinuria, with normal office blood pressure (BP) and renal function according to the general reference population. Non-diabetic controls were adolescents of general population matched for sex, age and BMI. RESULTS Mean duration of diabetes was 4.2 ± 2.8 years. The mean 24 h systolic blood pressure (SBP) and diastolic blood pressure (DBP) were respectively 116 ± 9 mmHg in the diabetic group vs 111 ± 8 mmHg in the non-diabetic (P = 0.06), and 69 ± 7 mm Hg vs 66 ± 5 mm Hg (P = 0.19). There was no difference in the diurnal pattern of BP in diabetes patients and non-diabetic controls (SBP: 118 ± 10 mmHg vs 114 ± 10 mmHg, P = 0.11; DBP: 71 ± 7 mmHg vs 68 ± 6 mmHg, P = 0.22). Nighttime BP was higher in the diabetic group with respect to SBP (112 ± 11 mmHg vs 106 ± 7 mmHg, P = 0.06) and to the mean arterial pressure (MAP) (89 ± 9 mmHg vs 81 ± 6 mmHg, P = 0.06). ACR at rest was similar in both groups (5.5 mg/g vs 5.5 mg/g, P = 0.74), but significantly higher in diabetes patients after exercise (10.5 mg/g vs 5.5 mg/g, P = 0.03). SBP was higher in patients having exercise-induced albuminuria (116 ± 10 mmHg vs 108 ± 10 mmHg, P = 0.09). CONCLUSION Exercise-induced albuminuria could be useful for early diagnosis of kidney damage in adolescents with T1DM. PMID:28265345

  14. Mitochondrial dysfunction leads to nuclear genome instability: A link through iron-sulfur clusters

    PubMed Central

    Veatch, Joshua R.; McMurray, Michael A.; Nelson, Zara W.; Gottschling, Daniel E.

    2009-01-01

    Summary Mutations and deletions in the mitochondrial genome (mtDNA), as well as instability of the nuclear genome, are involved in multiple human diseases. Here we report that in Saccharomyces cerevisiae, loss of mtDNA leads to nuclear genome instability, through a process of cell cycle arrest and selection we define as a cellular crisis. This crisis is not mediated by the absence of respiration, but instead correlates with a reduction in the mitochondrial membrane potential. Analysis of cells undergoing this crisis identified a defect in iron-sulfur cluster (ISC) biogenesis, which requires normal mitochondrial function. We found that down-regulation of non-mitochondrial ISC protein biogenesis was sufficient to cause increased genomic instability in cells with intact mitochondrial function. These results suggest mitochondrial dysfunction stimulates nuclear genome instability by inhibiting the production of ISC-containing protein(s), which are required for maintenance of nuclear genome integrity. PMID:19563757

  15. Estrogen receptor-β in mitochondria: implications for mitochondrial bioenergetics and tumorigenesis.

    PubMed

    Liao, Tien-Ling; Tzeng, Chii-Ruey; Yu, Chao-Lan; Wang, Yi-Pei; Kao, Shu-Huei

    2015-09-01

    Estrogen enhances mitochondrial function by enhancing mitochondrial biogenesis and sustaining mitochondrial energy-transducing capacity. Shifts in mitochondrial bioenergetic pathways from oxidative phosphorylation to glycolysis have been hypothesized to be involved in estrogen-induced tumorigenesis. Studies have shown that mitochondria are an important target of estrogen. Estrogen receptor-β (ERβ) has been shown to localize to mitochondria in a ligand-dependent or -independent manner and can affect mitochondrial bioenergetics and anti-apoptotic signaling. However, the functional role of mitochondrial ERβ in tumorigenesis remains unclear. Clinical studies of ERβ-related tumorigenesis have shown that ERβ stimulates mitochondrial metabolism to meet the high energy demands of processes such as cell proliferation, cell survival, and transformation. Thus, in elucidating the precise role of mitochondrial ERβ in cell transformation and tumorigenesis, it will be particularly valuable to explore new approaches for the development of medical treatments targeting mitochondrial ERβ-mediated mitochondrial function and preventing apoptosis.

  16. Evidence of a bigenomic regulation of mitochondrial gene expression by thyroid hormone during rat brain development

    SciTech Connect

    Sinha, Rohit Anthony; Pathak, Amrita; Mohan, Vishwa; Babu, Satish; Pal, Amit; Khare, Drirh; Godbole, Madan M.

    2010-07-02

    Hypothyroidism during early mammalian brain development is associated with decreased expression of various mitochondrial encoded genes along with evidence for mitochondrial dysfunction. However, in-spite of the similarities between neurological disorders caused by perinatal hypothyroidism and those caused by various genetic mitochondrial defects we still do not know as to how thyroid hormone (TH) regulates mitochondrial transcription during development and whether this regulation by TH is nuclear mediated or through mitochondrial TH receptors? We here in rat cerebellum show that hypothyroidism causes reduction in expression of nuclear encoded genes controlling mitochondrial biogenesis like PGC-1{alpha}, NRF-1{alpha} and Tfam. Also, we for the first time demonstrate a mitochondrial localization of thyroid hormone receptor (mTR) isoform in developing brain capable of binding a TH response element (DR2) present in D-loop region of mitochondrial DNA. These results thus indicate an integrated nuclear-mitochondrial cross talk in regulation of mitochondrial transcription by TH during brain development.

  17. Exercise-induced bronchospasm in children with asthma in the United States: results from the Exercise-Induced Bronchospasm Landmark Survey.

    PubMed

    Ostrom, Nancy K; Eid, Nemr S; Craig, Timothy J; Colice, Gene L; Hayden, Mary Lou; Parsons, Jonathan P; Stoloff, Stuart W

    2011-01-01

    Despite the availability of effective therapies, uncontrolled asthma remains a common problem. Previous large surveys suggest that exercise-related respiratory symptoms may be a significant element of uncontrolled asthma. The Exercise-Induced Bronchospasm (EIB) Landmark Survey is the first comprehensive, national survey evaluating EIB awareness and impact among the general public, asthma patients, and health care providers. This study was designed to evaluate the prevalence and impact of exercise-related respiratory symptoms in children (aged 4-17 years) with asthma. A national survey was conducted with parents of 516 children diagnosed with asthma or taking medications for asthma in the prior year. The majority of parents reported that their child experienced one or more exercise-related respiratory symptom and almost one-half (47.4%) experienced four or more symptoms. Most commonly reported symptoms were coughing, shortness of breath, and wheezing. Respondents reported that asthma limited their child's ability to participate either "a lot" or "some" in sports (30%), other outdoor activities (26.3%), and normal physical exertion (20.9%). Only 23.1% of children with exercise-related respiratory symptoms were reported to take short-acting beta-agonists such as albuterol "always" or "most of the time" before exercising. Exercise-related respiratory symptoms among pediatric asthma patients are common and substantially limit the ability of children to participate normally and perform optimally in physical activities. Such symptoms may reflect uncontrolled underlying asthma that should be evaluated and treated with appropriate controller medications. Despite the availability of preventative therapy, many children do not use short-acting bronchodilators before exercise as recommended in national guidelines.

  18. Transcription of LINE-derived sequences in exercise-induced stress in horses.

    PubMed

    Capomaccio, S; Verini-Supplizi, A; Galla, G; Vitulo, N; Barcaccia, G; Felicetti, M; Silvestrelli, M; Cappelli, K

    2010-12-01

    A large proportion of mammalian genomes is represented by transposable elements (TE), most of them being long interspersed nuclear elements 1 (LINE-1 or L1). An increased expression of LINE-1 elements may play an important role in cellular stress-related conditions exerting drastic effects on the mammalian transcriptome. To understand the impact of TE on the known horse transcriptome, we masked the horse EST database, pointing out that the amount is consistent with other major vertebrates. A previously developed transcript-derived fragments (TDFs) dataset, deriving from exercise-stimulated horse peripheral blood mononuclear cells (PBMCs), was found to be enriched with L1 (26.8% in terms of bp). We investigated the involvement of TDFs in exercise-induced stress through bioinformatics and gene expression analysis. Results indicate that LINE-derived sequences are not only highly but also differentially expressed during physical effort, hinting at interesting scenarios in the regulation of gene expression in relation to exercise.

  19. Lactate as a Signaling Molecule That Regulates Exercise-Induced Adaptations

    PubMed Central

    Nalbandian, Minas; Takeda, Masaki

    2016-01-01

    Lactate (or its protonated form: lactic acid) has been studied by many exercise scientists. The lactate paradigm has been in constant change since lactate was first discovered in 1780. For many years, it was unfairly seen as primarily responsible for muscular fatigue during exercise and a waste product of glycolysis. The status of lactate has slowly changed to an energy source, and in the last two decades new evidence suggests that lactate may play a much bigger role than was previously believed: many adaptations to exercise may be mediated in some way by lactate. The mechanisms behind these adaptations are yet to be understood. The aim of this review is to present the state of lactate science, focusing on how this molecule may mediate exercise-induced adaptations. PMID:27740597

  20. Titin, a Central Mediator for Hypertrophic Signaling, Exercise-Induced Mechanosignaling and Skeletal Muscle Remodeling

    PubMed Central

    Krüger, Martina; Kötter, Sebastian

    2016-01-01

    Titin is a giant scaffold protein with multiple functions in striated muscle physiology. Due to the elastic I-band domains and the filament-like integration in the half-sarcomere titin is an important factor for sarcomere assembly and serves as an adaptable molecular spring that determines myofilament distensibility. Protein-interactions e.g., with muscle ankyrin repeat proteins or muscle LIM-protein link titin to hypertrophic signaling and via p62 and Muscle Ring Finger proteins to mechanisms that control protein quality control. This review summarizes our current knowledge on titin as a central node for exercise-induced mechanosignaling and remodeling and further highlights the pathophysiological implications. PMID:26973541

  1. Platelet activation during exercise induced asthma: effect of prophylaxis with cromoglycate and salbutamol.

    PubMed Central

    Johnson, C E; Belfield, P W; Davis, S; Cooke, N J; Spencer, A; Davies, J A

    1986-01-01

    Peak expiratory flow (PEF) and plasma concentrations of platelet factor 4 and beta thromboglobulin were measured before and after exercise in nine asthmatic patients and 12 non-asthmatic volunteers. Exercise was preceded by administration in random order of either placebo, salbutamol 200 micrograms, or sodium cromoglycate 2 mg from a pressurised inhaler. In control subjects there were minimal changes in PEF and plasma concentrations of platelet factor 4 and beta thromboglobulin. In the asthmatic patients the typical changes in PEF were seen on exercise; plasma concentrations of platelet factor 4 and beta thromboglobulin rose significantly in parallel, the rise preceding the fall in PEF. The changes in peak flow and platelet activation induced by exercise were attenuated by prior administration of salbutamol or cromoglycate. These results indicate that exercise induced asthma is associated with a rise in platelet release products similar to that observed in antigen induced asthma. PMID:2943049

  2. Exercise-induced up-regulation of MMP-1 and IL-8 genes in endurance horses

    PubMed Central

    Cappelli, Katia; Felicetti, Michela; Capomaccio, Stefano; Pieramati, Camillo; Silvestrelli, Maurizio; Verini-Supplizi, Andrea

    2009-01-01

    Background The stress response is a critical factor in the training of equine athletes; it is important for performance and for protection of the animal against physio-pathological disorders. In this study, the molecular mechanisms involved in the response to acute and strenuous exercise were investigated using peripheral blood mononuclear cells (PBMCs). Results Quantitative real-time PCR (qRT-PCR) was used to detect modifications in transcription levels of the genes for matrix metalloproteinase-1 (MMP-1) and interleukin 8 (IL-8), which were derived from previous genome-wide expression analysis. Significant up-regulation of these two genes was found in 10 horses that had completed a race of 90–120 km in a time-course experimental design. Conclusion These results suggest that MMP-1 and IL-8 are both involved in the exercise-induced stress response, and this represents a starting point from which to understand the adaptive responses to this phenomenon. PMID:19552796

  3. Short- and Long-term exercise induced alterations in haemostasis: a review of the literature.

    PubMed

    Posthuma, Jelle J; van der Meijden, Paola E J; Ten Cate, Hugo; Spronk, Henri M H

    2015-05-01

    Although regular exercise is beneficial for health, exercise-related thrombotic events, such as venous thromboembolism and myocardial infarctions, are occasionally observed. These events are characterized by a prothrombotic condition in which interactions between coagulation factors, the vessel wall and the fibrinolytic system play an important role. Apparently, various durations and intensities of exercise have different effects on haemostasis and especially high intensity exercise tends to increase the risk of thrombotic events. However, the mechanisms behind this have not been entirely established. In this review we provide an overview of the various effects of the different intensities and durations of exercise on haemostasis. Overall, the haemostatic profile is mainly affected by the intensity of exercise; and is more pronounced after high (>80%) compared to low intensity (<60%), as reflected by increased platelet and coagulant activity. These findings are in line with the increased risk of exercise-induced thrombotic events during high intensity exercise.

  4. Prevention of exercised induced cardiomyopathy following Pip-PMO treatment in dystrophic mdx mice.

    PubMed

    Betts, Corinne A; Saleh, Amer F; Carr, Carolyn A; Hammond, Suzan M; Coenen-Stass, Anna M L; Godfrey, Caroline; McClorey, Graham; Varela, Miguel A; Roberts, Thomas C; Clarke, Kieran; Gait, Michael J; Wood, Matthew J A

    2015-03-11

    Duchenne muscular dystrophy (DMD) is a fatal neuromuscular disorder caused by mutations in the Dmd gene. In addition to skeletal muscle wasting, DMD patients develop cardiomyopathy, which significantly contributes to mortality. Antisense oligonucleotides (AOs) are a promising DMD therapy, restoring functional dystrophin protein by exon skipping. However, a major limitation with current AOs is the absence of dystrophin correction in heart. Pip peptide-AOs demonstrate high activity in cardiac muscle. To determine their therapeutic value, dystrophic mdx mice were subject to forced exercise to model the DMD cardiac phenotype. Repeated peptide-AO treatments resulted in high levels of cardiac dystrophin protein, which prevented the exercised induced progression of cardiomyopathy, normalising heart size as well as stabilising other cardiac parameters. Treated mice also exhibited significantly reduced cardiac fibrosis and improved sarcolemmal integrity. This work demonstrates that high levels of cardiac dystrophin restored by Pip peptide-AOs prevents further deterioration of cardiomyopathy and pathology following exercise in dystrophic DMD mice.

  5. Exercise-Induced Cognitive Plasticity, Implications for Mild Cognitive Impairment and Alzheimer’s Disease

    PubMed Central

    Foster, Philip P.; Rosenblatt, Kevin P.; Kuljiš, Rodrigo O.

    2011-01-01

    Lifestyle factors such as intellectual stimulation, cognitive and social engagement, nutrition, and various types of exercise appear to reduce the risk for common age-associated disorders such as Alzheimer’s disease (AD) and vascular dementia. In fact, many studies have suggested that promoting physical activity can have a protective effect against cognitive deterioration later in life. Slowing or a deterioration of walking speed is associated with a poor performance in tests assessing psychomotor speed and verbal fluency in elderly individuals. Fitness training influences a wide range of cognitive processes, and the largest positive impact observed is for executive (a.k.a. frontal lobe) functions. Studies show that exercise improves additional cognitive functions such as tasks mediated by the hippocampus, and result in major changes in plasticity in the hippocampus. Interestingly, this exercise-induced plasticity is also pronounced in APOE ε4 carriers who express a risk factor for late-onset AD that may modulate the effect of treatments. Based on AD staging by Braak and Braak (1991) and Braak et al. (1993) we propose that the effects of exercise occur in two temporo-spatial continua of events. The “inward” continuum from isocortex (neocortex) to entorhinal cortex/hippocampus for amyloidosis and a reciprocal “outward” continuum for neurofibrillary alterations. The exercise-induced hypertrophy of the hippocampus at the core of these continua is evaluated in terms of potential for prevention to stave off neuronal degeneration. Exercise-induced production of growth factors such as the brain-derived neurotrophic factor (BDNF) has been shown to enhance neurogenesis and to play a key role in positive cognitive effects. Insulin-like growth factor (IGF-1) may mediate the exercise-induced response to exercise on BDNF, neurogenesis, and cognitive performance. It is also postulated to regulate brain amyloid β (Aβ) levels by increased clearance via the choroid

  6. Erythropoietin Activates Mitochondrial Biogenesis and Couples Red Cell Mass to Mitochondrial Mass in the Heart

    EPA Science Inventory

    RATIONALE: Erythropoietin (EPO) is often administered to cardiac patients with anemia, particularly from chronic kidney disease, and stimulation of erythropoiesis may stabilize left ventricular and renal function by recruiting protective effects beyond the correction of anemia. O...

  7. Rehydration with sodium-enriched coconut water after exercise-induced dehydration.

    PubMed

    Ismail, I; Singh, R; Sirisinghe, R G

    2007-07-01

    This crossover study assessed the effectiveness of plain water (PW), sports drink (SD), fresh young coconut water (CW) and sodium-enriched fresh young coconut water (SCW) on whole body rehydration (R) and plasma volume (PV) restoration after exercise-induced dehydration. Ten healthy male subjects ran at 65% of VO2max in an environmental temperature of 32.06 +/- 0.02 degree C with a relative humidity (rh) of 53.32 +/- 0.17% for 90 minutes to lose 3% body weight (BW). During the 2-hour rehydration period, subjects drank, in randomized order, PW, SD, CW or SCW equivalent to 120% of BW lost in three boluses representing 50, 40 and 30% of the fluid lost at 0, 30, and 60 minutes, respectively. In all trials subjects were still somewhat dehydrated even after the 2-hour rehydration period. Indexes of percent rehydration with PW, SD, CW and SCW were 58 +/- 2, 68 +/- 2, 65+/- 2 and 69 +/- 1%, respectively, with significantly better rehydration with SD and SCW. The rehydration indexes for SD and SCW were significantly lower than PW (p < 0.01). PV was restored to euhydration levels after 2 hours of rehydration with SD, CW and SCW but not with PW. The plasma glucose concentration were significantly higher when SD, CW and SCW were ingested. SCW was similar in sweetness to CW and SD but caused less nausea and stomach upset compared to SD and PW. In conclusion, ingesting SCW was as good as ingesting a commercial sports drink for whole body rehydration after exercise-induced dehydration but with better fluid tolerance.

  8. Dose-response study of sodium cromoglycate in exercise-induced asthma.

    PubMed Central

    Patel, K R; Berkin, K E; Kerr, J W

    1982-01-01

    Ten patients with exercise-induced asthma participated in a single-blind dose-response study comparing the protective effect of inhaled sodium cromoglycate in increasing concentrations from 2 to 40 mg/ml. Saline was used as a control. Effects were assessed from the mean maximal percentage fall in forced expiratory volume in one second (FEV1) after the patients had run on a treadmill for eight minutes. There was slight bronchodilation evident from the increase in baseline FEV1 after inhalation of sodium cromoglycate, the difference reaching statistical significance with the highest concentration (5.7%, p less than 0.05). After exercise the maximal percentage falls in FEV1 (means and SEM) after saline and after sodium cromoglycate at 2, 10, 20, and 40 mg/ml were 37.3 +/- 4.7, 17.3 +/- 4.1, 10 +/- 3.3, 7.6 +/- 2.4, and 12 +/- 2.9. Sodium cromoglycate inhibited the exercise-induced fall in FEV1 at all the concentrations used in the study (p less than 0.001) and its inhibitory effect increased from 2 to 20 mg/ml. The mean FEV1 returned to baseline values within 15 minutes at higher concentrations of sodium cromoglycate (20 and 40 mg/ml) and a small bronchodilator effect was noted at 30 minutes. The findings suggest that the protective effect of sodium cromoglycate in exercise asthma is dose related. At higher concentration the drug suppresses chemical mediator release from the lung mast cells and may also modify the bronchial reactivity to release mediators. PMID:6818707

  9. Physical activity levels determine exercise-induced changes in brain excitability

    PubMed Central

    Fassett, Hunter J.; Nelson, Aimee J.

    2017-01-01

    Emerging evidence suggests that regular physical activity can impact cortical function and facilitate plasticity. In the present study, we examined how physical activity levels influence corticospinal excitability and intracortical circuitry in motor cortex following a single session of moderate intensity aerobic exercise. We aimed to determine whether exercise-induced short-term plasticity differed between high versus low physically active individuals. Participants included twenty-eight young, healthy adults divided into two equal groups based on physical activity level determined by the International Physical Activity Questionnaire: low-to-moderate (LOW) and high (HIGH) physical activity. Transcranial magnetic stimulation was used to assess motor cortex excitability via motor evoked potential (MEP) recruitment curves for the first dorsal interosseous (FDI) muscle at rest (MEPREST) and during tonic contraction (MEPACTIVE), short-interval intracortical inhibition (SICI) and facilitation (SICF), and intracortical facilitation (ICF). All dependent measures were obtained in the resting FDI muscle, with the exception of AMT and MEPACTIVE recruitment curves that were obtained during tonic FDI contraction. Dependent measures were acquired before and following moderate intensity aerobic exercise (20 mins, ~60% of the age-predicted maximal heart rate) performed on a recumbent cycle ergometer. Results indicate that MEPREST recruitment curve amplitudes and area under the recruitment curve (AURC) were increased following exercise in the HIGH group only (p = 0.002 and p = 0.044, respectively). SICI and ICF were reduced following exercise irrespective of physical activity level (p = 0.007 and p = 0.04, respectively). MEPACTIVE recruitment curves and SICF were unaltered by exercise. These findings indicate that the propensity for exercise-induced plasticity is different in high versus low physically active individuals. Additionally, these data highlight that a single session of

  10. Increased renal tubular sodium reabsorption during exercise-induced hypervolemia in humans

    NASA Technical Reports Server (NTRS)

    Nagashima, K.; Wu, J.; Kavouras, S. A.; Mack, G. W.

    2001-01-01

    We tested the hypothesis that renal tubular Na(+) reabsorption increased during the first 24 h of exercise-induced plasma volume expansion. Renal function was assessed 1 day after no-exercise control (C) or intermittent cycle ergometer exercise (Ex, 85% of peak O(2) uptake) for 2 h before and 3 h after saline loading (12.5 ml/kg over 30 min) in seven subjects. Ex reduced renal blood flow (p-aminohippurate clearance) compared with C (0.83 +/- 0.12 vs. 1.49 +/- 0.24 l/min, P < 0.05) but did not influence glomerular filtration rates (97 +/- 10 ml/min, inulin clearance). Fractional tubular reabsorption of Na(+) in the proximal tubules was higher in Ex than in C (P < 0.05). Saline loading decreased fractional tubular reabsorption of Na(+) from 99.1 +/- 0.1 to 98.7 +/- 0.1% (P < 0.05) in C but not in Ex (99.3 +/- 0.1 to 99.4 +/- 0.1%). Saline loading reduced plasma renin activity and plasma arginine vasopressin levels in C and Ex, although the magnitude of decrease was greater in C (P < 0.05). These results indicate that, during the acute phase of exercise-induced plasma volume expansion, increased tubular Na(+) reabsorption is directed primarily to the proximal tubules and is associated with a decrease in renal blood flow. In addition, saline infusion caused a smaller reduction in fluid-regulating hormones in Ex. The attenuated volume-regulatory response acts to preserve distal tubular Na(+) reabsorption during saline infusion 24 h after exercise.

  11. Alcohol pharmacokinetics and risk-taking behaviour following exercise-induced dehydration.

    PubMed

    Irwin, Christopher; Goodwin, Alison; Leveritt, Michael; Davey, Andrew K; Desbrow, Ben

    2012-06-01

    This study investigated the influence of exercise-induced dehydration on alcohol pharmacokinetics, subjective ratings of impairment, and risk-taking behaviours. Twelve male volunteers participated in 3 experimental trials completed in a randomised cross over design separated by at least 7 days. In one trial, participants exercised to cause dehydration of ~2.5% body weight loss. For the other trials, participants were required to be in a rested and euhydrated state. A set volume of alcohol was then consumed in each trial and participants were monitored over a 4h period. Blood (BAC) and breath (BrAC) alcohol samples were collected throughout and analysed to calculate pharmacokinetic variables associated with the blood alcohol curve. Total urine production, estimates of BrAC, and subjective ratings of intoxication and impairment were also recorded throughout each trial. No difference was found in the pharmacokinetics of alcohol between any of the trial conditions. BrACs were higher than BACs for 2h following alcohol consumption, but lower at measures taken 3 and 4 h post ingestion. Participants' ratings of confusion and intoxication were significantly lower, and they were more willing to drive in the dehydration trial compared with one of the euhydration trials. These findings suggest that dehydration or other physiological changes associated with exercise may have an ability to influence the subjective effects of alcohol and increase the likelihood of risk-taking behaviours such as drink-driving. However, further research is required to examine the effects of alcohol under conditions of exercise-induced fluid loss in order to clarify these findings.

  12. Effects of Massage on Muscular Strength and Proprioception After Exercise-Induced Muscle Damage.

    PubMed

    Shin, Mal-Soon; Sung, Yun-Hee

    2015-08-01

    Exercise-induced muscle damage (EIMD), which is commonly associated with eccentric exercise, unaccustomed exercise, and resistance training, may lead to delayed onset muscle soreness, swelling, decreased muscle strength, and range of motion. Many researchers have evaluated various interventions to treat the signs and symptoms of EIMD. However, the effects of massage after EIMD are unclear. Here, we investigated the effect of massage on muscle strength and proprioception after EIMD. All subjects randomly were divided into an EIMD-treated control group (n = 10) and a massage-treated after EIMD experimental group (n = 11). Exercise-induced muscle damage was induced by repeated exercise. Massage treatment was provided by physiotherapist for 15 minutes. It consists of light stroking, milking, friction, and skin rolling. Lactate was evaluated by Lactate Pro analyzer in pre- and postexercise. Surface electromyography (muscle activity) and sonography (muscle thickness) were used to confirm the muscular characteristics. Proprioception was investigated by dual inclinometer. As a result, massage treatment on the gastrocnemius after EIMD increased activation of the medial gastrocnemius during contraction (p ≤ 0.05). In the lateral and medial gastrocnemius, the θs, which is the angle between muscle fibers and superficial aponeurosis, showed a significant change (p ≤ 0.05). However, there are no differences in the θd, which is the angle between muscle fibers and deep aponeurosis. We also found that proprioceptive acuity in the ankle joint was significantly greater in the massage-treated experimental group compared with that in the control group (p ≤ 0.05). These findings suggest that massage of the gastrocnemius after EIMD can improve muscle strength and proprioception by influencing the superficial layer of the gastrocnemius.

  13. Glycopyrrolate abolishes the exercise-induced increase in cerebral perfusion in humans.

    PubMed

    Seifert, Thomas; Fisher, James P; Young, Colin N; Hartwich, Doreen; Ogoh, Shigehiko; Raven, Peter B; Fadel, Paul J; Secher, Niels H

    2010-10-01

    Brain blood vessels contain muscarinic receptors that are important for cerebral blood flow (CBF) regulation, but whether a cholinergic receptor mechanism is involved in the exercise-induced increase in cerebral perfusion or affects cerebral metabolism remains unknown. We evaluated CBF and cerebral metabolism (from arterial and internal jugular venous O(2), glucose and lactate differences), as well as the middle cerebral artery mean blood velocity (MCA V(mean); transcranial Doppler ultrasound) during a sustained static handgrip contraction at 40% of maximal voluntary contraction (n = 9) and the MCA V(mean) during ergometer cycling (n = 8). Separate, randomized and counterbalanced trials were performed in control (no drug) conditions and following muscarinic cholinergic receptor blockade by glycopyrrolate. Glycopyrrolate increased resting heart rate from approximately 60 to approximately 110 beats min(-1) (P < 0.01) and cardiac output by approximately 40% (P < 0.05), but did not affect mean arterial pressure. The central cardiovascular responses to exercise with glycopyrrolate were similar to the control responses, except that cardiac output did not increase during static handgrip with glycopyrrolate. Glycopyrrolate did not significantly affect cerebral metabolism during static handgrip, but a parallel increase in MCA V(mean) (approximately 16%; P < 0.01) and CBF (approximately 12%; P < 0.01) during static handgrip, as well as the increase in MCA V(mean) during cycling (approximately 15%; P < 0.01), were abolished by glycopyrrolate (P < 0.05). Thus, during both cycling and static handgrip, a cholinergic receptor mechanism is important for the exercise-induced increase in cerebral perfusion without affecting the cerebral metabolic rate for oxygen.

  14. Protective role of L-carnitine supplementation against exhaustive exercise induced oxidative stress in rats.

    PubMed

    Síktar, Elif; Ekinci, Deniz; Síktar, Erdinç; Beydemir, Sükrü; Gülçin, Ilhami; Günay, Mehmet

    2011-10-15

    The objective of this study was to investigate temperature dependent effects of oral l-carnitine supplementation on exhaustive exercise induced oxidative damage in rats. 42 male Spraque Dawley rats were randomly divided into seven experimental groups. These groups were formed as three non-carnitine exercise groups, three carnitine-exercise groups and a sedentary group. l-carnitine was given intraperitoneally to the carnitine-exercise groups 1h before the exercise in 100mg/kg. Blood was collected to measure paraoxonase-1 (PON1) activity, plasma malondialdehyde (MDA), low-density lipoprotein (LDL) and cholesterol concentrations. These biomarkers were measured in venous blood samples collected before and after the rats swam in pools at different water temperatures (18°C, 28°C and 38°C). In the non-carnitine group, exercise caused a significant decrease in PON1 activity and a significant elevation in MDA concentration at 28°C compared to the sedentary group. No significant alterations were evidenced in LDL and cholesterol concentrations upon exercise. The decrease in PON1 activity became higher with increasing temperature whereas the elevation in MDA levels increased at 18°C. In the l-carnitine supplementation group, recovery in PON1 activity was observed significant at 28°C and very significant at 38°C. MDA concentration was almost the same with that of the non-carnitine group at 18 and 38°C, but it significantly decreased at 28°C. Considering the recovery in PON1 and MDA levels at 28°C, which is the temperature of the sedentary group; our results suggest that l-carnitine supplementation has a protective role on exhaustive exercise-induced oxidative stress. Findings of this study also demonstrate influences of thermal stress on these parameters during exhaustive exercise.

  15. Mitochondria Biogenesis and Bioenergetics Gene Profiles in Isogenic Prostate Cells with Different Malignant Phenotypes

    PubMed Central

    Burch, Tanya C.; Rhim, Johng S.

    2016-01-01

    Background. The most significant hallmarks of cancer are directly or indirectly linked to deregulated mitochondria. In this study, we sought to profile mitochondria associated genes in isogenic prostate cell lines with different tumorigenic phenotypes from the same patient. Results. Two isogenic human prostate cell lines RC77N/E (nonmalignant cells) and RC77T/E (malignant cells) were profiled for expression of mitochondrial biogenesis and energy metabolism genes by qRT-PCR using the Human Mitochondria and the Mitochondrial Energy Metabolism RT2 PCR arrays. Forty-seven genes were differentially regulated between the two cell lines. The interaction and regulatory networks of these genes were generated by Ingenuity Pathway Analysis. UCP2 was the most significantly upregulated gene in primary adenocarcinoma cells in the current study. The overexpression of UCP2 upon malignant transformation was further validated using human prostatectomy clinical specimens. Conclusions. This study demonstrates the overexpression of multiple genes that are involved in mitochondria biogenesis, bioenergetics, and modulation of apoptosis. These genes may play a role in malignant transformation and disease progression. The upregulation of some of these genes in clinical samples indicates that some of the differentially transcribed genes could be the potential targets for therapeutic interventions. PMID:27478826

  16. Increased dietary protein attenuates C-reactive protein and creatine kinase responses to exercise-induced energy deficit

    Technology Transfer Automated Retrieval System (TEKTRAN)

    We determined if dietary protein (P) modulates responses of C-reactive protein (CRP) and creatine kinase (CK), biomarkers of inflammation and muscle damage, during exercise-induced energy deficit (DEF). Thirteen healthy men (22 +/- 1 y, VO2peak 60 +/- 2 ml.kg-1.min-1) balanced energy expenditure (EE...

  17. The Free-Running Asthma Screening Test: An Approach to Screening for Exercise-Induced Asthma in Rural Alabama.

    ERIC Educational Resources Information Center

    Heaman, Doris J.; Estes, Jenny

    1997-01-01

    This study documented the prevalence of exercise-induced asthma (EIA) in rural elementary schools, examining the use of a free-running asthma screening test and peak expiratory flow-rate measurement for school screening. Results indicated that 5.7% of the students had EIA. Absenteeism and poverty were related to EIA. (SM)

  18. A Systematic Review of the Literature on Screening for Exercise-Induced Asthma: Considerations for School Nurses

    ERIC Educational Resources Information Center

    Worrell, Kelly; Shaw, Michele R.; Postma, Julie; Katz, Janet R.

    2015-01-01

    Asthma is a major cause of illness, missed school days, and hospitalization in children. One type of asthma common in children is exercise-induced asthma (EIA). EIA causes airway narrowing with symptoms of cough and shortness of breath during exercise. The purpose of this article is to review the literature relevant to screening children and…

  19. The Mitochondrial-Derived Peptide Humanin Protects RPE Cells From Oxidative Stress, Senescence, and Mitochondrial Dysfunction

    PubMed Central

    Sreekumar, Parameswaran G.; Ishikawa, Keijiro; Spee, Chris; Mehta, Hemal H.; Wan, Junxiang; Yen, Kelvin; Cohen, Pinchas; Kannan, Ram; Hinton, David R.

    2016-01-01

    Purpose To investigate the expression of humanin (HN) in human retinal pigment epithelial (hRPE) cells and its effect on oxidative stress–induced cell death, mitochondrial bioenergetics, and senescence. Methods Humanin localization in RPE cells and polarized RPE monolayers was assessed by confocal microscopy. Human RPE cells were treated with 150 μM tert-Butyl hydroperoxide (tBH) in the absence/presence of HN (0.5–10 μg/mL) for 24 hours. Mitochondrial respiration was measured by XF96 analyzer. Retinal pigment epithelial cell death and caspase-3 activation, mitochondrial biogenesis and senescence were analyzed by TUNEL, immunoblot analysis, mitochondrial DNA copy number, SA-β-Gal staining, and p16INK4a expression and HN levels by ELISA. Oxidative stress–induced changes in transepithelial resistance were studied in RPE monolayers with and without HN cotreatment. Results A prominent localization of HN was found in the cytoplasmic and mitochondrial compartments of hRPE. Humanin cotreatment inhibited tBH-induced reactive oxygen species formation and significantly restored mitochondrial bioenergetics in hRPE cells. Exogenous HN was taken up by RPE and colocalized with mitochondria. The oxidative stress–induced decrease in mitochondrial bioenergetics was prevented by HN cotreatment. Humanin treatment increased mitochondrial DNA copy number and upregulated mitochondrial transcription factor A, a key biogenesis regulator protein. Humanin protected RPE cells from oxidative stress–induced cell death by STAT3 phosphorylation and inhibiting caspase-3 activation. Humanin treatment inhibited oxidant-induced senescence. Polarized RPE demonstrated elevated cellular HN and increased resistance to cell death. Conclusions Humanin protected RPE cells against oxidative stress–induced cell death and restored mitochondrial function. Our data suggest a potential role for HN therapy in the prevention of retinal degeneration, including AMD. PMID:26990160

  20. Mitochondrial DNA content, an inaccurate biomarker of mitochondrial alteration in human immunodeficiency virus-related lipodystrophy.

    PubMed

    Kim, Min Ji; Jardel, Claude; Barthélémy, Cyrille; Jan, Véronique; Bastard, Jean Philippe; Fillaut-Chapin, Sandrine; Houry, Sydney; Capeau, Jacqueline; Lombès, Anne

    2008-05-01

    Lipoatrophy is a prevalent side effect of antiretroviral treatment of human immunodeficiency virus (HIV) infection. Its mechanisms are still disputed but include mitochondrial toxicity and, in particular, mitochondrial DNA (mtDNA) depletion induced by nucleoside reverse transcriptase inhibitors. To obtain an integrated evaluation of the mitochondrial alteration in lipoatrophy, we investigated the DNA, RNA, and protein levels in 15 samples of abdominal subcutaneous adipose tissue from HIV-infected patients with peripheral lipoatrophy and compared the results with those for 15 samples from age- and body mass index-matched controls. The DNA and RNA analyses used PCR-based techniques, while proteins were quantified with enzyme-linked immunosorbent assay and measurement of activities with spectrophotometric assays. Depletion of mtDNA and mtDNA-encoded MT-CO2 mRNA was present, but normal levels of mtDNA-dependent activity (cytochrome c oxidase) and protein (MT-CO2p) showed that it was compensated for. An increase in nuclear-DNA-dependent mitochondrial activities (citrate synthase and malate dehydrogenase) and protein (COX4I1p), as well as transcriptional up-regulation of nuclear-DNA-encoded mitochondrial genes (COX4I1 and UCP2), demonstrated increased mitochondrial biogenesis. However, the expression of the known transcription factors of mitochondrial biogenesis (TFAM, NRF1, GABPA, PPARGC1A, PPARGC1B, and PPRC1) was normal or decreased. Increased amounts of activated caspase 3 and of DDIT3 mRNA showed the induction of apoptosis and oxidative stress, respectively. The mtDNA content did not correlate with any other mitochondrial parameter. In conclusion, mtDNA content does not appear to be an accurate biomarker of mitochondrial alteration in lipoatrophic adipose tissue. The preservation of mtDNA-dependent mitochondrial functions occurred despite severe mtDNA depletion. The presence of significant oxidative stress and apoptosis did not correlate with the mtDNA content.

  1. Mitochondrial DNA Content, an Inaccurate Biomarker of Mitochondrial Alteration in Human Immunodeficiency Virus-Related Lipodystrophy▿

    PubMed Central

    Kim, Min Ji; Jardel, Claude; Barthélémy, Cyrille; Jan, Véronique; Bastard, Jean Philippe; Fillaut-Chapin, Sandrine; Houry, Sydney; Capeau, Jacqueline; Lombès, Anne

    2008-01-01

    Lipoatrophy is a prevalent side effect of antiretroviral treatment of human immunodeficiency virus (HIV) infection. Its mechanisms are still disputed but include mitochondrial toxicity and, in particular, mitochondrial DNA (mtDNA) depletion induced by nucleoside reverse transcriptase inhibitors. To obtain an integrated evaluation of the mitochondrial alteration in lipoatrophy, we investigated the DNA, RNA, and protein levels in 15 samples of abdominal subcutaneous adipose tissue from HIV-infected patients with peripheral lipoatrophy and compared the results with those for 15 samples from age- and body mass index-matched controls. The DNA and RNA analyses used PCR-based techniques, while proteins were quantified with enzyme-linked immunosorbent assay and measurement of activities with spectrophotometric assays. Depletion of mtDNA and mtDNA-encoded MT-CO2 mRNA was present, but normal levels of mtDNA-dependent activity (cytochrome c oxidase) and protein (MT-CO2p) showed that it was compensated for. An increase in nuclear-DNA-dependent mitochondrial activities (citrate synthase and malate dehydrogenase) and protein (COX4I1p), as well as transcriptional up-regulation of nuclear-DNA-encoded mitochondrial genes (COX4I1 and UCP2), demonstrated increased mitochondrial biogenesis. However, the expression of the known transcription factors of mitochondrial biogenesis (TFAM, NRF1, GABPA, PPARGC1A, PPARGC1B, and PPRC1) was normal or decreased. Increased amounts of activated caspase 3 and of DDIT3 mRNA showed the induction of apoptosis and oxidative stress, respectively. The mtDNA content did not correlate with any other mitochondrial parameter. In conclusion, mtDNA content does not appear to be an accurate biomarker of mitochondrial alteration in lipoatrophic adipose tissue. The preservation of mtDNA-dependent mitochondrial functions occurred despite severe mtDNA depletion. The presence of significant oxidative stress and apoptosis did not correlate with the mtDNA content. PMID

  2. Mitochondrial Machineries for Protein Import and Assembly.

    PubMed

    Wiedemann, Nils; Pfanner, Nikolaus

    2017-03-15

    Mitochondria are essential organelles with numerous functions in cellular metabolism and homeostasis. Most of the >1,000 different mitochondrial proteins are synthesized as precursors in the cytosol and are imported into mitochondria by five transport pathways. The protein import machineries of the mitochondrial membranes and aqueous compartments reveal a remarkable variability of mechanisms for protein recognition, translocation, and sorting. The protein translocases do not operate as separate entities but are connected to each other and to machineries with functions in energetics, membrane organization, and quality control. Here, we discuss the versatility and dynamic organization of the mitochondrial protein import machineries. Elucidating the molecular mechanisms of mitochondrial protein translocation is crucial for understanding the integration of protein translocases into a large network that controls organelle biogenesis, function, and dynamics. Expected final online publication date for the Annual Review of Biochemistry Volume 86 is June 20, 2017. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

  3. Mitochondrial RNA processing in trypanosomes.

    PubMed

    Aphasizhev, Ruslan; Aphasizheva, Inna

    2011-09-01

    The mitochondrial genome of trypanosomes is composed of ∼50 maxicircles and thousands of minicircles. Maxi-(∼25 kb) and mini-(∼1 kb)circles are catenated and packed into a dense structure called a kinetoplast. Both types of circular DNA are transcribed by a phage-like RNA polymerase: maxicircles yield multicistronic rRNA and mRNA precursors, while guide RNA (gRNA) precursors are produced from minicircles. To function in mitochondrial translation, pre-mRNAs must undergo a nucleolytic processing and 3' modifications, and often uridine insertion/deletion editing. gRNAs, which represent short (50-60 nt) RNAs directing editing reactions, are produced by 3' nucleolytic processing of a much longer precursor followed by 3' uridylation. Ribosomal RNAs are excised from precursors and their 3' ends are also trimmed and uridylated. All tRNAs are imported from the cytoplasm and some are further modified and edited in the mitochondrial matrix. Historically, the fascinating phenomenon of RNA editing has been extensively studied as an isolated pathway in which nuclear-encoded proteins mediate interactions of maxi- and minicircle transcripts to create open reading frames. However, recent studies unraveled a highly integrated network of mitochondrial genome expression including critical pre- and post-editing 3' mRNA processing, and gRNA and rRNA maturation steps. Here we focus on RNA 3' adenylation and uridylation as processes essential for biogenesis, stability and functioning of mitochondrial RNAs.

  4. Acute and chronic watercress supplementation attenuates exercise-induced peripheral mononuclear cell DNA damage and lipid peroxidation.

    PubMed

    Fogarty, Mark C; Hughes, Ciara M; Burke, George; Brown, John C; Davison, Gareth W

    2013-01-28

    Pharmacological antioxidant vitamins have previously been investigated for a prophylactic effect against exercise-induced oxidative stress. However, large doses are often required and may lead to a state of pro-oxidation and oxidative damage. Watercress contains an array of nutritional compounds such as β-carotene and α-tocopherol which may increase protection against exercise-induced oxidative stress. The present randomised controlled investigation was designed to test the hypothesis that acute (consumption 2 h before exercise) and chronic (8 weeks consumption) watercress supplementation can attenuate exercise-induced oxidative stress. A total of ten apparently healthy male subjects (age 23 (SD 4) years, stature 179 (SD 10) cm and body mass 74 (SD 15) kg) were recruited to complete the 8-week chronic watercress intervention period (and then 8 weeks of control, with no ingestion) of the experiment before crossing over in order to compete the single-dose acute phase (with control, no ingestion). Blood samples were taken at baseline (pre-supplementation), at rest (pre-exercise) and following exercise. Each subject completed an incremental exercise test to volitional exhaustion following chronic and acute watercress supplementation or control. The main findings show an exercise-induced increase in DNA damage and lipid peroxidation over both acute and chronic control supplementation phases (P< 0.05 v. supplementation), while acute and chronic watercress attenuated DNA damage and lipid peroxidation and decreased H₂O₂ accumulation following exhaustive exercise (P< 0.05 v. control). A marked increase in the main lipid-soluble antioxidants (α-tocopherol, γ-tocopherol and xanthophyll) was observed following watercress supplementation (P< 0.05 v. control) in both experimental phases. These findings suggest that short- and long-term watercress ingestion has potential antioxidant effects against exercise-induced DNA damage and lipid peroxidation.

  5. SIGNALING PATHWAYS IN MELANOSOME BIOGENESIS AND PATHOLOGY

    PubMed Central

    Schiaffino, Maria Vittoria

    2010-01-01

    Melanosomes are the specialized intracellular organelles of pigment cells devoted to the synthesis, storage and transport of melanin pigments, which are responsible for most visible pigmentation in mammals and other vertebrates. As a direct consequence, any genetic mutation resulting in alteration of melanosomal function, either because affecting pigment cell survival, migration and differentiation, or because interfering with melanosome biogenesis, transport and transfer to keratinocytes, is immediately translated into color variations of skin, fur, hair or eyes. Thus, over one hundred genes and proteins have been identified as pigmentary determinants in mammals, providing us with a deep understanding of this biological system, which functions by using mechanisms and processes that have parallels in other tissues and organs. In particular, many genes implicated in melanosome biogenesis have been characterized, so that melanosomes represent an incredible source of information and a model for organelles belonging to the secretory pathway. Furthermore, the function of melanosomes can be associated with common physiological phenotypes, such as variation of pigmentation among individuals, and with rare pathological conditions, such as albinism, characterized by severe visual defects. Among the most relevant mechanisms operating in melanosome biogenesis are the signal transduction pathways mediated by two peculiar G protein-coupled receptors: the melanocortin-1 receptor (MC1R), involved in the fair skin/red hair phenotype and skin cancer; and OA1 (GPR143), whose loss-of-function results in X-linked ocular albinism. This review will focus on the most recent novelties regarding the functioning of these two receptors, by highlighting emerging signaling mechanisms and general implications for cell biology and pathology. PMID:20381640

  6. Human telomerase: biogenesis, trafficking, recruitment, and activation.

    PubMed

    Schmidt, Jens C; Cech, Thomas R

    2015-06-01

    Telomerase is the ribonucleoprotein enzyme that catalyzes the extension of telomeric DNA in eukaryotes. Recent work has begun to reveal key aspects of the assembly of the human telomerase complex, its intracellular trafficking involving Cajal bodies, and its recruitment to telomeres. Once telomerase has been recruited to the telomere, it appears to undergo a separate activation step, which may include an increase in its repeat addition processivity. This review covers human telomerase biogenesis, trafficking, and activation, comparing key aspects with the analogous events in other species.

  7. MicroRNA biogenesis pathways in cancer

    PubMed Central

    Lin, Shuibin; Gregory, Richard I.

    2016-01-01

    MicroRNAs (miRNAs) are critical regulators of gene expression. Amplification and overexpression of individual ‘oncomiRs’ or genetic loss of tumour suppressor miRNAs are associated with human cancer and are sufficient to drive tumorigenesis in mouse models. Furthermore, global miRNA depletion caused by genetic and epigenetic alterations in components of the miRNA biogenesis machinery is oncogenic. This, together with the recent identification of novel miRNA regulatory factors and pathways, highlights the importance of miRNA dysregulation in cancer. PMID:25998712

  8. Human telomerase: biogenesis, trafficking, recruitment, and activation

    PubMed Central

    Schmidt, Jens C.

    2015-01-01

    Telomerase is the ribonucleoprotein enzyme that catalyzes the extension of telomeric DNA in eukaryotes. Recent work has begun to reveal key aspects of the assembly of the human telomerase complex, its intracellular trafficking involving Cajal bodies, and its recruitment to telomeres. Once telomerase has been recruited to the telomere, it appears to undergo a separate activation step, which may include an increase in its repeat addition processivity. This review covers human telomerase biogenesis, trafficking, and activation, comparing key aspects with the analogous events in other species. PMID:26063571

  9. Human disorders of peroxisome metabolism and biogenesis.

    PubMed

    Waterham, Hans R; Ferdinandusse, Sacha; Wanders, Ronald J A

    2016-05-01

    Peroxisomes are dynamic organelles that play an essential role in a variety of cellular catabolic and anabolic metabolic pathways, including fatty acid alpha- and beta-oxidation, and plasmalogen and bile acid synthesis. Defects in genes encoding peroxisomal proteins can result in a large variety of peroxisomal disorders either affecting specific metabolic pathways, i.e., the single peroxisomal enzyme deficiencies, or causing a generalized defect in function and assembly of peroxisomes, i.e., peroxisome biogenesis disorders. In this review, we discuss the clinical, biochemical, and genetic aspects of all human peroxisomal disorders currently known.

  10. Unravelling mitochondrial pathways to Parkinson's disease

    PubMed Central

    Celardo, I; Martins, L M; Gandhi, S

    2014-01-01

    Mitochondria are essential for cellular function due to their role in ATP production, calcium homeostasis and apoptotic signalling. Neurons are heavily reliant on mitochondrial integrity for their complex signalling, plasticity and excitability properties, and to ensure cell survival over decades. The maintenance of a pool of healthy mitochondria that can meet the bioenergetic demands of a neuron, is therefore of critical importance; this is achieved by maintaining a careful balance between mitochondrial biogenesis, mitochondrial trafficking, mitochondrial dynamics and mitophagy. The molecular mechanisms that underlie these processes are gradually being elucidated. It is widely recognized that mitochondrial dysfunction occurs in many neurodegenerative diseases, including Parkinson's disease. Mitochondrial dysfunction in the form of reduced bioenergetic capacity, increased oxidative stress and reduced resistance to stress, is observed in several Parkinson's disease models. However, identification of the recessive genes implicated in Parkinson's disease has revealed a common pathway involving mitochondrial dynamics, transport, turnover and mitophagy. This body of work has led to the hypothesis that the homeostatic mechanisms that ensure a healthy mitochondrial pool are key to neuronal function and integrity. In this paradigm, impaired mitochondrial dynamics and clearance result in the accumulation of damaged and dysfunctional mitochondria, which may directly induce neuronal dysfunction and death. In this review, we consider the mechanisms by which mitochondrial dysfunction may lead to neurodegeneration. In particular, we focus on the mechanisms that underlie mitochondrial homeostasis, and discuss their importance in neuronal integrity and neurodegeneration in Parkinson's disease. LINKED ARTICLES This article is part of a themed issue on Mitochondrial Pharmacology: Energy, Injury & Beyond. To view the other articles in this issue visit http://dx.doi.org/10.1111/bph

  11. The little big genome: the organization of mitochondrial DNA

    PubMed Central

    Garcia, Iraselia; Jones, Edith; Ramos, Manuel; Innis-Whitehouse, Wendy; Gilkerson, Robert

    2017-01-01

    The small (16,569 base pair) human mitochondrial genome plays a significant role in cell metabolism and homeostasis. Mitochondrial DNA (mtDNA) contributes to the generation of complexes which are essential to oxidative phosphorylation (OXPHOS). As such, mtDNA is directly integrated into mitochondrial biogenesis and signaling and regulates mitochondrial metabolism in concert with nuclear-encoded mitochondrial factors. Mitochondria are a highly dynamic, pleiomorphic network that undergoes fission and fusion events. Within this network, mtDNAs are packaged into structures called nucleoids which are actively distributed in discrete foci within the network. This sensitive organelle is frequently disrupted by insults such as oxidants and inflammatory cytokines, and undergoes genomic damage with double- and single-strand breaks that impair its function. Collectively, mtDNA is emerging as a highly sensitive indicator of cellular stress, which is directly integrated into the mitochondrial network as a contributor of a wide range of critical signaling pathways. PMID:27814641

  12. Effect of Submaximal Warm-up Exercise on Exercise-induced Asthma in African School Children

    PubMed Central

    Mtshali, BF; Mokwena, K; Oguntibeju, OO

    2015-01-01

    ABSTRACT Background: Regular physical activity has long been regarded as an important component of a healthy lifestyle. Exercise-induced asthma (EIA) is one of the major problems interfering with the performance of exercise. A warm-up exercise programme has been cited as a non-pharmacologic means of reducing EIA, but its effect has not been fully elucidated. Objective: The aims of this study were to determine the prevalence of unrecognized EIA in Pretoria primary school children, determine the effect of a warm-up exercise programme on EIA and to establish the relationship between history of allergy, family history of asthma and EIA. Methods: A random sample of 640 school children was selected. The study was divided into three phases. In phase one, a descriptive cross-sectional study was done using the standardized European Community Respiratory Health Survey (ECRHS) questionnaire. In phase two, non-asthmatic participants that returned a completed questionnaire were included in the field study. Pre-test and post-test experimental designs were used, where peak expiratory flow rate (PEFR) was measured at baseline and within ten minutes after exercise. A total of 340 subjects completed the Free Running Asthma Screening Test (FRAST); EIA was defined as a decrease in baseline PEFR ≥ 10% after exercise and 75 children (22%) had EIA. In phase three, 29 of the 75 subjects participated in the warm-up programme which was performed in the laboratory and subjects acted as their own controls. Predefined protocols for the study were followed. Results: Seventy-five (22%) of the 340 participants had EIA. The mean age, height and weight were 10.51 years, 139.26 cm and 33.45 kg, respectively. Exercise-induced asthma symptoms were cough (25%), chest pain (16%), wheeze (12%) and chest tightness (12%). The history of allergy was 75%, family history of allergy 40% and positive history of allergy when near animals, feathers or in dusty areas 38%. Wheezing during or after exercise

  13. Mitochondrial dynamics in the mouse liver infected by Schistosoma mansoni.

    PubMed

    Chen, Tina Tu-Wen; Wu, Lawrence Shih Hsin; Hsu, Paul Wei-Che; Pang, Cheng-Yoong; Lee, Kin-Mu; Cheng, Po-Ching; Peng, Shih-Yi

    2015-08-01

    Mitochondrial dynamics is crucial for regulation of cell homeostasis. Schistosoma mansoni is one of the most common parasites known to cause liver disease. Mice infected by S. mansoni show acute symptoms of schistosomiasis after 8 weeks. Hence, in this study, we attempted to assess the direct effects of S. mansoni infection on mice liver, and to explore the expression of mitochondrial morphology, dynamics, and function. Our recent findings show that S. mansoni infection changes mitochondrial morphology and affects mitochondrial functions, which attenuates mitochondrial membrane potential and ATP generation. S. mansoni-infected mice increases mitochondrial numbers by upregulating of genes involved in mitochondrial biogenesis, including peroxisome proliferator-activated receptor c co-activator 1α (PGC1α) and mitochondrial transcription factor A (Tfam). This may promote mitochondria generation for accelerating the recovery of mitochondrial functions. Moreover, S. mansoni would disrupt mitochondrial dynamics including induced mitochondrial fission and promoted mitochondrial fragmentation in mice liver. More importantly, S. mansoni further stimulated upregulation both extrinsic and intrinsic apoptosis pathway in infected mice liver. The intrinsic pathway was triggered by cytochrome c release. Additionally, NFκB (nuclear factor-kappa B, p65) could play a protective role to inhibit apoptosis through reducing active caspase-3 expression. Therefore, our results confirmed the liver damage mechanism of experimental schistosomiasis in mice model.

  14. Curcumin and Piperine Supplementation and Recovery Following Exercise Induced Muscle Damage: A Randomized Controlled Trial

    PubMed Central

    Delecroix, Barthélémy; Abaïdia, Abd Elbasset; Leduc, Cédric; Dawson, Brian; Dupont, Grégory

    2017-01-01

    The aim of this study was to analyze the effects of oral consumption of curcumin and piperine in combination on the recovery kinetics after exercise-induced muscle damage. Forty-eight hours before and following exercise-induced muscle damage, ten elite rugby players consumed curcumin and piperine (experimental condition) or placebo. A randomized cross-over design was performed. Concentric and isometric peak torque for the knee extensors, one leg 6 seconds sprint performance on a non-motorized treadmill, counter movement jump performance, blood creatine kinase concentration and muscle soreness were assessed immediately after exercise, then at 24h, 48h and 72h post-exercise. There were moderate to large effects of the exercise on the concentric peak torque for the knee extensors (Effect size (ES) = -1.12; Confidence interval at 90% (CI90%): -2.17 to -0.06), the one leg 6 seconds sprint performance (ES=-1.65; CI90% = -2.51to -0.80) and the counter movement jump performance (ES = -0.56; CI90% = -0.81 to -0.32) in the 48h following the exercise. There was also a large effect of the exercise on the creatine kinase level 72h after the exercise in the control group (ES = 3.61; CI90%: 0.24 to 6.98). This decrease in muscle function and this elevation in creatine kinase indicate that the exercise implemented was efficient to induce muscle damage. Twenty four hours post-exercise, the reduction (from baseline) in sprint mean power output was moderately lower in the experimental condition (-1.77 ± 7.25%; 1277 ± 153W) in comparison with the placebo condition (-13.6 ± 13.0%; 1130 ± 241W) (Effect Size = -1.12; Confidence Interval 90%=-1.86 to -0.86). However, no other effect was found between the two conditions. Curcumin and piperine supplementation before and after exercise can attenuate some, but not all, aspects of muscle damage. Key points When the recovery period between competitions was short, a curcumin and piperine supplementation could be an effective recovery

  15. The cytoprotective role of taurine in exercise-induced muscle injury.

    PubMed

    Dawson, R; Biasetti, M; Messina, S; Dominy, J

    2002-06-01

    Intense exercise is thought to increase oxidative stress and damage muscle tissue. Taurine is present in high concentration in skeletal muscle and may play a role in cellular defenses against free radical-mediated damage. The aim of this study was to determine if manipulating muscle levels of taurine would alter markers of free radical damage after exercise-induced injury. Adult male Sprague-Dawley rats were supplemented via the drinking water with either 3% (w/v) taurine (n = 10) or the competitive taurine transport inhibitor, beta-alanine (n = 10), for one month. Controls (n = 20) drank tap water containing 0.02% taurine and all rats were placed on a taurine free diet. All the rats except one group of sedentary controls (n = 10) were subjected to 90 minutes of downhill treadmill running. Markers of cellular injury and free radical damage were determined along with tissue amino acid content. The 3% taurine treatment raised plasma levels about 2-fold and 3% beta-alanine reduced plasma taurine levels about 50%. Taurine supplementation (TS) significantly increased plasma glutamate levels in exercised rats. Exercise reduced plasma methionine levels and taurine prevented its decline. Taurine supplementation increased muscle taurine content significantly in all muscles except the soleus. beta-alanine decreased muscle taurine content about 50% in all the muscles examined. Lipid peroxidation (TBARS) was significantly increased by exercise in the extensor digitorium longus (EDL) and gastrocnemius (GAST) muscles. Both taurine and beta-alanine completely blocked the increase in TBARs in the EDL, but had no effect in the GAST. Muscle content of the cytosolic enzyme, lactate dehydrogenase (LDH) was significantly decreased by exercise in the GAST muscle and this effect was attenuated by both taurine and beta-alanine. Muscle myeloperoxidase (MPO) activity was significantly elevated in the gastrocnemius muscle, but diet had no effect. MPO activity was significantly increased by

  16. Acute Exercise-Induced Response of Monocyte Subtypes in Chronic Heart and Renal Failure

    PubMed Central

    Van Craenenbroeck, Amaryllis H.; Hoymans, Vicky Y.; Verpooten, Gert A.; Vrints, Christiaan J.; Couttenye, Marie M.; Van Craenenbroeck, Emeline M.

    2014-01-01

    Purpose. Monocytes (Mon1-2-3) play a substantial role in low-grade inflammation associated with high cardiovascular morbidity and mortality of patients with chronic kidney disease (CKD) and chronic heart failure (CHF). The effect of an acute exercise bout on monocyte subsets in the setting of systemic inflammation is currently unknown. This study aims (1) to evaluate baseline distribution of monocyte subsets in CHF and CKD versus healthy subjects (HS) and (2) to evaluate the effect of an acute exercise bout. Exercise-induced IL-6 and MCP-1 release are related to the Mon1-2-3 response. Methods. Twenty CHF patients, 20 CKD patients, and 15 HS were included. Before and after a maximal cardiopulmonary exercise test, monocyte subsets were quantified by flow cytometry: CD14++CD16−CCR2+ (Mon1), CD14++CD16+CCR2+ (Mon2), and CD14+CD16++CCR2− (Mon3). Serum levels of IL-6 and MCP-1 were determined by ELISA. Results. Baseline distribution of Mon1-2-3 was comparable between the 3 groups. Following acute exercise, %Mon2 and %Mon3 increased significantly at the expense of a decrease in %Mon1 in HS and in CKD. This response was significantly attenuated in CHF (P < 0.05). In HS only, MCP-1 levels increased following exercise; IL-6 levels were unchanged. Circulatory power was a strong and independent predictor of the changes in Mon1 (β = −0.461, P < 0.001) and Mon3 (β = 0.449, P < 0.001); and baseline LVEF of the change in Mon2 (β = 0.441, P < 0.001). Conclusion. The response of monocytes to acute exercise is characterized by an increase in proangiogenic and proinflammatory Mon2 and Mon3 at the expense of phagocytic Mon1. This exercise-induced monocyte subset response is mainly driven by hemodynamic changes and not by preexistent low-grade inflammation. PMID:25587208

  17. The influence of ice slurry ingestion on maximal voluntary contraction following exercise-induced hyperthermia.

    PubMed

    Siegel, Rodney; Maté, Joseph; Watson, Greig; Nosaka, Kazunori; Laursen, Paul B

    2011-10-01

    The purpose of this study was to determine whether ingestion of a small bolus of ice slurry (1.25 g kg(-1)) could attenuate the reduction in maximal voluntary isometric contraction (MVC) torque output during a 2-min sustained task following exercise-induced hyperthermia. On two separate occasions, 10 males (age: 24 ± 3 years, .VO(2peak): 49.8 ± 4.7 ml kg(-1) min(-1)) ran to exhaustion at their first ventilatory threshold in a hot environment (34.1 ± 0.1°C, 49.5 ± 3.6% RH). Prior to and after exercise, subjects performed a 2-min sustained MVC of the right elbow flexors in a thermoneutral environment (24.6 ± 0.8°C, 37.2 ± 4.5% RH). The post exercise MVC was performed immediately following the ingestion of either 1.25 g kg(-1) of ice slurry (-1°C; ICE) or warm fluid (40°C; CON), in a counterbalanced and randomised order. Run time to exhaustion (42.4 ± 9.5 vs. 41.7 ± 8.7 min; p = 0.530), and rectal (39.08 ± 0.30 vs. 39.08 ± 0.30°C; p = 0.934) and skin temperatures (35.26 ± 0.65 vs. 35.28 ± 0.67°C; p = 0.922) and heart rate (189 ± 5 vs. 189 ± 6 beats min(-1); p = 0.830) at the end of the run were similar between trials. Torque output during the post-exercise 2-min sustained MVC was significantly higher (p = 0.001) following ICE (30.75 ± 16.40 Nm) compared with CON (28.69 ± 14.88 Nm). These results suggest that ice slurry ingestion attenuated the effects of exercise-induced hyperthermia on MVC, possibly via internal thermoreceptive and/or temperature-related sensory mechanisms.

  18. Myosin Light Chain Kinase (MLCK) Gene Influences Exercise Induced Muscle Damage during a Competitive Marathon

    PubMed Central

    Valero, Marjorie; Lara, Beatriz; Salinero, Juan José; Gallo-Salazar, César; Areces, Francisco

    2016-01-01

    Myosin light chain kinase (MLCK) phosphorylates the regulatory light chain (RLC) of myosin producing increases in force development during skeletal muscle contraction. It has been suggested that MLCK gene polymorphisms might alter RLC phosphorylation thereby decreasing the ability to produce force and to resist strain during voluntary muscle contractions. Thus, the genetic variations in the MLCK gene might predispose some individuals to higher values of muscle damage during exercise, especially during endurance competitions. The aim of this investigation was to determine the influence of MLCK genetic variants on exercise-induced muscle damage produced during a marathon. Sixty-seven experienced runners competed in a marathon race. The MLCK genotype (C37885A) of these marathoners was determined. Before and after the race, a sample of venous blood was obtained to assess changes in serum myoglobin concentrations and leg muscle power changes were measured during a countermovement jump. Self-reported leg muscle pain and fatigue were determined by questionnaires. A total of 59 marathoners (88.1%) were CC homozygotes and 8 marathoners (11.9%) were CA heterozygotes. The two groups of participants completed the race with a similar time (228 ± 33 vs 234 ± 39 min; P = 0.30) and similar self-reported values for fatigue (15 ± 2 vs 16 ± 2 A.U.; P = 0.21) and lower-limb muscle pain (6.2 ± 1.7 vs 6.6 ± 1.8 cm; P = 0.29). However, CC marathoners presented higher serum myoglobin concentrations (739 ± 792 vs 348 ± 144 μg·mL-1; P = 0.03) and greater pre-to-post- race leg muscle power reduction (-32.7 ± 15.7 vs -21.2 ± 21.6%; P = 0.05) than CA marathoners. CA heterozygotes for MLCK C37885A might present higher exercise-induced muscle damage after a marathon competition than CC counterparts. PMID:27483374

  19. Sex differences in exercise-induced diaphragmatic fatigue in endurance-trained athletes.

    PubMed

    Guenette, Jordan A; Romer, Lee M; Querido, Jordan S; Chua, Romeo; Eves, Neil D; Road, Jeremy D; McKenzie, Donald C; Sheel, A William

    2010-07-01

    There is evidence that female athletes may be more susceptible to exercise-induced arterial hypoxemia and expiratory flow limitation and have greater increases in operational lung volumes during exercise relative to men. These pulmonary limitations may ultimately lead to greater levels of diaphragmatic fatigue in women. Accordingly, the purpose of this study was to determine whether there are sex differences in the prevalence and severity of exercise-induced diaphragmatic fatigue in 38 healthy endurance-trained men (n = 19; maximal aerobic capacity = 64.0 +/- 1.9 ml x kg(-1) x min(-1)) and women (n = 19; maximal aerobic capacity = 57.1 +/- 1.5 ml x kg(-1) x min(-1)). Transdiaphragmatic pressure (Pdi) was calculated as the difference between gastric and esophageal pressures. Inspiratory pressure-time products of the diaphragm and esophagus were calculated as the product of breathing frequency and the Pdi and esophageal pressure time integrals, respectively. Cervical magnetic stimulation was used to measure potentiated Pdi twitches (Pdi,tw) before and 10, 30, and 60 min after a constant-load cycling test performed at 90% of peak work rate until exhaustion. Diaphragm fatigue was considered present if there was a >or=15% reduction in Pdi,tw after exercise. Diaphragm fatigue occurred in 11 of 19 men (58%) and 8 of 19 women (42%). The percent drop in Pdi,tw at 10, 30, and 60 min after exercise in men (n = 11) was 30.6 +/- 2.3, 20.7 +/- 3.2, and 13.3 +/- 4.5%, respectively, whereas results in women (n = 8) were 21.0 +/- 2.1, 11.6 +/- 2.9, and 9.7 +/- 4.2%, respectively, with sex differences occurring at 10 and 30 min (P < 0.05). Men continued to have a reduced contribution of the diaphragm to total inspiratory force output (pressure-time product of the diaphragm/pressure-time product of the esophagus) during exercise, whereas diaphragmatic contribution in women changed very little over time. The findings from this study point to a female diaphragm that is more resistant

  20. Dysfunctional breathing and reaching one’s physiological limit as causes of exercise-induced dyspnoea

    PubMed Central

    Everard, Mark L.

    2016-01-01

    Key points Excessive exercise-induced shortness of breath is a common complaint. For some, exercise-induced bronchoconstriction is the primary cause and for a small minority there may be an alternative organic pathology. However for many, the cause will be simply reaching their physiological limit or be due to a functional form of dysfunctional breathing, neither of which require drug therapy. The physiological limit category includes deconditioned individuals, such as those who have been through intensive care and require rehabilitation, as well as the unfit and the fit competitive athlete who has reached their limit with both of these latter groups requiring explanation and advice. Dysfunctional breathing is an umbrella term for an alteration in the normal biomechanical patterns of breathing that result in intermittent or chronic symptoms, which may be respiratory and/or nonrespiratory. This alteration may be due to structural causes or, much more commonly, be functional as exemplified by thoracic pattern disordered breathing (PDB) and extrathoracic paradoxical vocal fold motion disorder (pVFMD). Careful history and examination together with spirometry may identify those likely to have PDB and/or pVFMD. Where there is doubt about aetiology, cardiopulmonary exercise testing may be required to identify the deconditioned, unfit or fit individual reaching their physiological limit and PDB, while continuous laryngoscopy during exercise is increasingly becoming the benchmark for assessing extrathoracic causes. Accurate assessment and diagnosis can prevent excessive use of drug therapy and result in effective management of the cause of the individual’s complaint through cost-effective approaches such as reassurance, advice, breathing retraining and vocal exercises. This review provides an overview of the spectrum of conditions that can present as exercise-­induced breathlessness experienced by young subjects participating in sport and aims to promote understanding of

  1. Effect of age on exercise-induced alterations in cognitive executive function: relationship to cerebral perfusion.

    PubMed

    Lucas, Samuel J E; Ainslie, Philip N; Murrell, Carissa J; Thomas, Kate N; Franz, Elizabeth A; Cotter, James D

    2012-08-01

    Regular exercise improves the age-related decline in cerebral blood flow (CBF) and is associated with improved cognitive function; however, less is known about the direct relationship between CBF and cognitive function. We examined the influence of healthy aging on the capability of acute exercise to improve cognition, and whether exercise-induced improvements in cognition are related to CBF and cortical hemodynamics. Middle cerebral artery blood flow velocity (MCAv; Doppler) and cortical hemodynamics (NIRS) were measured in 13 young (24±5 y) and 9 older (62±3 y) participants at rest and during cycling at 30% and 70% of heart rate range (HRR). Cognitive performance was assessed using a computer-adapted Stroop task (i.e., test of executive function cognition) at rest and during exercise. Average response times on the Stroop task were slower for the older compared to younger group for both simple and difficult tasks (P<0.01). Independent of age, difficult-task response times improved during exercise (P<0.01), with the improvement greater at 70% HRR exercise (P=0.04 vs. 30% HRR). Higher MCAv was correlated with faster response times for simple and difficult tasks at rest (R(2)=0.47 and R(2)=0.47, respectively), but this relation uncoupled progressively during exercise. Exercise-induced increases in MCAv were similar and unaltered during cognitive tasks for both age groups. In contrast, prefrontal cortical hemodynamic NIRS measures [oxyhemoglobin (O(2)Hb) and total hemoglobin (tHb)] were differentially affected by exercise intensity, age and cognitive task; e.g., there were smaller increases in [O(2)Hb] and [tHb] in the older group between exercise intensities (P<0.05). These data indicate that: 1) Regardless of age, cognitive (executive) function is improved while exercising; 2) while MCAv is strongly related to cognition at rest, this relation becomes uncoupled during exercise, and 3) there is dissociation between global CBF and regional cortical oxygenation and

  2. Mitochondrial alteration in type 2 diabetes and obesity: an epigenetic link.

    PubMed

    Cheng, Zhiyong; Almeida, Fabio A

    2014-01-01

    The growing epidemic of type 2 diabetes mellitus (T2DM) and obesity is largely attributed to the current lifestyle of over-consumption and physical inactivity. As the primary platform controlling metabolic and energy homeostasis, mitochondria show aberrant changes in T2DM and obese subjects. While the underlying mechanism is under extensive investigation, epigenetic regulation is now emerging to play an important role in mitochondrial biogenesis, function, and dynamics. In line with lifestyle modifications preventing mitochondrial alterations and metabolic disorders, exercise has been shown to change DNA methylation of the promoter of PGC1α to favor gene expression responsible for mitochondrial biogenesis and function. In this article we discuss the epigenetic mechanism of mitochondrial alteration in T2DM and obesity, and the effects of lifestyle on epigenetic regulation. Future studies designed to further explore and integrate the epigenetic mechanisms with lifestyle modification may lead to interdisciplinary interventions and novel preventive options for mitochondrial alteration and metabolic disorders.

  3. Organelle biogenesis and intracellular lipid transport in eukaryotes.

    PubMed Central

    Voelker, D R

    1991-01-01

    The inter- and intramembrane transport of phospholipids, sphingolipids, and sterols involves the most fundamental processes of membrane biogenesis. Identification of the mechanisms involved in these lipid transport reactions has lagged significantly behind that for intermembrane protein traffic until recently. Application of methods that include fluorescently labeled and spin-labeled lipid analogs, new cellular fractionation techniques, topographically specific chemical modification techniques, the identification of organelle-specific metabolism, permeabilized cell methodology, and yeast molecular genetics has contributed to revealing a diverse biochemical array of transport processes for lipids. Compelling evidence now exists for ATP-dependent, ATP-independent, vesicle-dependent, and vesicle-independent transport processes that are lipid and membrane specific. ATP-dependent transport processes include the transbilayer movement of phosphatidylserine and phosphatidylethanolamine at the plasma membrane and the transport of phosphatidylserine from its site of synthesis to the mitochondria. ATP-independent processes include the transbilayer movement of virtually all lipids at the endoplasmic reticulum, the movement of phosphatidylserine between the inner and outer mitochondrial membranes, and the transfer of nascent phosphatidylcholine and phosphatidylethanolamine to the plasma membrane. The ATP-independent movement of lipids between organelles is believed to be due to the action of lipid transfer proteins, but this still remains to be proved. Vesicle-based transport mechanisms (which are also inherently ATP dependent) include the transport of nascent cholesterol, sphingomyelin, and glycosphingolipids from the Golgi apparatus to the plasma membrane and the recycling of sphingolipids and selected pools of phosphatidylcholine from the plasma membrane to the cell interior. The vesicles involved in cholesterol transport to the plasma membrane are different from those

  4. AMPK dysregulation promotes diabetes-related reduction of superoxide and mitochondrial function.

    PubMed

    Dugan, Laura L; You, Young-Hyun; Ali, Sameh S; Diamond-Stanic, Maggie; Miyamoto, Satoshi; DeCleves, Anne-Emilie; Andreyev, Aleksander; Quach, Tammy; Ly, San; Shekhtman, Grigory; Nguyen, William; Chepetan, Andre; Le, Thuy P; Wang, Lin; Xu, Ming; Paik, Kacie P; Fogo, Agnes; Viollet, Benoit; Murphy, Anne; Brosius, Frank; Naviaux, Robert K; Sharma, Kumar

    2013-11-01

    Diabetic microvascular complications have been considered to be mediated by a glucose-driven increase in mitochondrial superoxide anion production. Here, we report that superoxide production was reduced in the kidneys of a steptozotocin-induced mouse model of type 1 diabetes, as assessed by in vivo real-time transcutaneous fluorescence, confocal microscopy, and electron paramagnetic resonance analysis. Reduction of mitochondrial biogenesis and phosphorylation of pyruvate dehydrogenase (PDH) were observed in kidneys from diabetic mice. These observations were consistent with an overall reduction of mitochondrial glucose oxidation. Activity of AMPK, the major energy-sensing enzyme, was reduced in kidneys from both diabetic mice and humans. Mitochondrial biogenesis, PDH activity, and mitochondrial complex activity were rescued by treatment with the AMPK activator 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR). AICAR treatment induced superoxide production and was linked with glomerular matrix and albuminuria reduction in the diabetic kidney. Furthermore, diabetic heterozygous superoxide dismutase 2 (Sod2(+/-)) mice had no evidence of increased renal disease, and Ampka2(-/-) mice had increased albuminuria that was not reduced with AICAR treatment. Reduction of mitochondrial superoxide production with rotenone was sufficient to reduce AMPK phosphorylation in mouse kidneys. Taken together, these results demonstrate that diabetic kidneys have reduced superoxide and mitochondrial biogenesis and activation of AMPK enhances superoxide production and mitochondrial function while reducing disease activity.

  5. Redox mechanisms of cardiomyocyte mitochondrial protection

    PubMed Central

    Bartz, Raquel R.; Suliman, Hagir B.; Piantadosi, Claude A.

    2015-01-01

    Oxidative and nitrosative stress are primary contributors to the loss of myocardial tissue in insults ranging from ischemia/reperfusion injury from coronary artery disease and heart transplantation to sepsis-induced myocardial dysfunction and drug-induced myocardial damage. This cell damage caused by oxidative and nitrosative stress leads to mitochondrial protein, DNA, and lipid modifications, which inhibits energy production and contractile function, potentially leading to cell necrosis and/or apoptosis. However, cardiomyocytes have evolved an elegant set of redox-sensitive mechanisms that respond to and contain oxidative and nitrosative damage. These responses include the rapid induction of antioxidant enzymes, mitochondrial DNA repair mechanisms, selective mitochondrial autophagy (mitophagy), and mitochondrial biogenesis. Coordinated cytoplasmic to nuclear cell-signaling and mitochondrial transcriptional responses to the presence of elevated cytoplasmic oxidant production, e.g., H2O2, allows nuclear translocation of the Nfe2l2 transcription factor and up-regulation of downstream cytoprotective genes such as heme oxygenase-1 which generates physiologic signals, such as CO that up-regulates Nfe212 gene transcription. Simultaneously, a number of other DNA binding transcription factors are expressed and/or activated under redox control, such as Nuclear Respiratory Factor-1 (NRF-1), and lead to the induction of genes involved in both intracellular and mitochondria-specific repair mechanisms. The same insults, particularly those related to vascular stress and inflammation also produce elevated levels of nitric oxide, which also has mitochondrial protein thiol-protective functions and induces mitochondrial biogenesis through cyclic GMP-dependent and perhaps other pathways. This brief review provides an overview of these pathways and interconnected cardiac repair mechanisms. PMID:26578967

  6. Comparison of the protective effects of cromolyn sodium and nedocromil sodium in the treatment of exercise-induced asthma in children.

    PubMed

    de Benedictis, F M; Tuteri, G; Bertotto, A; Bruni, L; Vaccaro, R

    1994-10-01

    Seventeen children with asthma were studied in a double-blind, crossover, placebo-controlled study designed to compare the efficacy of cromolyn sodium with that of nedocromil sodium in preventing exercise-induced asthma. All drugs were delivered through a metered-dose inhaler (cromolyn sodium, 10 mg; nedocromil sodium, 4 mg; placebo, two puffs). Nedocromil sodium and cromolyn sodium provided significant, comparable protection from exercise-induced asthma, and both drugs were better than placebo. We conclude that nedocromil sodium and cromolyn sodium administered by a pressurized aerosol provide equal protection against exercise-induced asthma in children.

  7. The effects of pre-exercise vibration stimulation on the exercise-induced muscle damage

    PubMed Central

    Kim, Ji-Yun; Kang, Da-Haeng; Lee, Joon-Hee; O, Se-Min; Jeon, Jae-Keun

    2017-01-01

    [Purpose] To investigate the effects of pre-induced muscle damage vibration stimulation on the pressure-pain threshold and muscle-fatigue-related metabolites of exercise-induced muscle damage. [Subjects and Methods] Thirty healthy, adult male subjects were randomly assigned to the pre-induced muscle damage vibration stimulation group, post-induced muscle damage vibration stimulation group, or control group (n=10 per group). To investigate the effects of pre-induced muscle damage vibration stimulation, changes in the pressure-pain threshold (lb), creatine kinase level (U/L), and lactate dehydrogenase level (U/L) were measured and analyzed at baseline and at 24 hours, 48 hours, and 72 hours after exercise. [Results] The pressure-pain thresholds and concentrations of creatine kinase and lactate dehydrogenase varied significantly in each group and during each measurement period. There were interactions between the measurement periods and groups, and results of the post-hoc test showed that the pre-induced muscle damage vibration stimulation group had the highest efficacy among the groups. [Conclusion] Pre-induced muscle damage vibration stimulation is more effective than post-induced muscle damage vibration stimulation for preventing muscle damage. PMID:28210056

  8. Syndecan-4 Signaling Is Required for Exercise-Induced Cardiac Hypertrophy

    PubMed Central

    Xie, Jun; He, Guixin; Chen, Qinhua; Sun, Jiayin; Dai, Qin; Lu, Jianrong; Li, Guannan; Wu, Han; Li, Ran; Chen, Jianzhou; Xu, Wei; Xu, Biao

    2016-01-01

    Cardiac hypertrophy can be broadly classified as either physiological or pathological. Physiological stimuli such as exercise cause adaptive cardiac hypertrophy and normal heart function. Pathological stimuli including hypertension and aortic valvular stenosis cause maladaptive cardiac remodeling and ultimately heart failure. Syndecan-4 (synd4) is a transmembrane proteoglycan identified as being involved in cardiac adaptation after injury, but whether it takes part in physiological cardiac hypertrophy is unclear. We observed upregulation of synd4 in exercise-induced hypertrophic myocardium. To evaluate the role of synd4 in the physiological form of cardiac hypertrophy, mice lacking synd4 (synd4–/–) were exercised by swimming for 4 wks. Ultrasonic cardiogram (UCG) and histological analysis revealed that swimming induced the hypertrophic phenotype but was blunted in synd4–/– compared with wild-type (WT) mice. The swimming-induced activation of Akt, a key molecule in physiological hypertrophy was also more decreased than in WT controls. In cultured cardiomyocytes, synd4 overexpression could induce cell enlargement, protein synthesis and distinct physiological molecular alternation. Akt activation also was observed in synd4-overexpressed cardiomyocytes. Furthermore, inhibition of protein kinase C (PKC) prevented the synd4-induced hypertrophic phenotype and Akt phosphorylation. This study identified an essential role of synd4 in mediation of physiological cardiac hypertrophy. PMID:26835698

  9. Spontaneous decline in exercise-induced proteinuria during a 100-mile triathlon.

    PubMed

    Edes, T E; Shah, J H; Thornton, W H

    1990-09-01

    To study the effect of prolonged exercise on glomerular permeability and proteinuria, we collected serial urine samples from six athletes during a 100-mile triathlon. Urine collected just before, at the midpoint of, and immediately after the race was analyzed for creatinine by an automated chemistry analyzer, pack method, and for microalbumin by radioimmunoassay. By midrace, the urinary albumin-creatinine ratio increased from the prerace mean +/- SEM of 3.5 +/- 0.5 to 38.3 +/- 11.7 mg/g. The ratio then declined to 12.5 +/- 2.7 mg/g by the end of the race (P less than .04). Similarly, the urinary albumin level increased significantly from 5.9 +/- 0.7 to 80.5 +/- 26.8 micrograms/mL by midrace, followed by a decline to 39.2 +/- 12.9 micrograms/mL. The initial increase in albuminuria was expected and reflects the increase in exercise-induced cardiac output and glomerular permeability. The subsequent decline in albuminuria and albumin-creatinine ratio, despite continued exercise, was unexpected and indicates a decrease in glomerular permeability. Further study is warranted to determine the mechanism of this apparently protective renal response to prolonged exercise.

  10. Effects of grape seed extract supplementation on exercise-induced oxidative stress in rats.

    PubMed

    Belviranlı, Muaz; Gökbel, Hakkı; Okudan, Nilsel; Başaralı, Kemal

    2012-07-01

    The aim of the present study was to investigate the effects of grape seed extract (GSE) supplementation on exercise performance and oxidative stress in acutely and chronically exercised rats. A total of sixty-four male rats were used in the study. Rats were divided into six groups: control, chronic exercise control, acute exercise control (AEC), GSE-supplemented control, GSE-supplemented chronic exercise and GSE-supplemented acute exercise groups. Chronic exercise consisted of treadmill running at 25 m/min, 45 min/d, 5 d a week for 6 weeks. Rats in the acute exercise groups were run on the treadmill at 30 m/min until exhaustion. GSE were given at 100 mg/kg of body weight with drinking water for 6 weeks. Plasma was separated from blood samples for the analysis of oxidative stress markers. There was no significant difference in time of exhaustion between the acute exercise groups. Plasma malondialdehyde (MDA) levels were higher in the acute exercise groups and lower in the chronic exercise groups. GSE supplementation decreased MDA levels. Xanthine oxidase and adenosine deaminase activities were higher in the AEC group compared to all the other groups. NO levels were increased with both chronic exercise and GSE supplementation. Superoxide dismutase and glutathione peroxidase activities were lower in the acute exercised groups and higher in the chronic exercised groups. GSE supplementation caused an increase in antioxidant enzyme activities. In conclusion, GSE supplementation prevents exercise-induced oxidative stress by preventing lipid peroxidation and increasing antioxidant enzyme activities.

  11. Contrast Water Therapy and Exercise Induced Muscle Damage: A Systematic Review and Meta-Analysis

    PubMed Central

    Bieuzen, François; Bleakley, Chris M.; Costello, Joseph Thomas

    2013-01-01

    The aim of this systematic review was to examine the effect of Contrast Water Therapy (CWT) on recovery following exercise induced muscle damage. Controlled trials were identified from computerized literature searching and citation tracking performed up to February 2013. Eighteen trials met the inclusion criteria; all had a high risk of bias. Pooled data from 13 studies showed that CWT resulted in significantly greater improvements in muscle soreness at the five follow-up time points (<6, 24, 48, 72 and 96 hours) in comparison to passive recovery. Pooled data also showed that CWT significantly reduced muscle strength loss at each follow-up time (<6, 24, 48, 72 and 96 hours) in comparison to passive recovery. Despite comparing CWT to a large number of other recovery interventions, including cold water immersion, warm water immersion, compression, active recovery and stretching, there was little evidence for a superior treatment intervention. The current evidence base shows that CWT is superior to using passive recovery or rest after exercise; the magnitudes of these effects may be most relevant to an elite sporting population. There seems to be little difference in recovery outcome between CWT and other popular recovery interventions. PMID:23626806

  12. The prevalence of exercise-induced bronchospasm in soccer player children, ages 7 to 16 years.

    PubMed

    Ziaee, Vahid; Yousefi, Azizollah; Movahedi, Massoud; Mehrkhani, Farhad; Noorian, Rohollah

    2007-03-01

    This study represents an attempt to determine the prevalence of exercise-induced bronchospasm among soccer player children. A total of 234 soccer player boys of all soccer schools from Shahr-Rey enrolled in this study. They did not have any history of a recent or chronic respiratory tract disease, a history of allergic diseases, and history of bronchodilator drugs consumption during the 24 hours prior to the study. Pulmonary function test (PFT) was performed for each participant before exercise and 6 and 15 minutes after playing soccer. The diagnosis of EIB was by a decrease in forced expiratory volume in 1 second (FEV1) by at least 10% and in peak expiratory flow rate (PEFR) by at least 15% with exercise challenge. If there was reduction in one parameter alone, the participants were considered as prone to EIB. Considering both FEV1 and PEFR the prevalence of EIB was 2.1% and 18.4% were prone to EIB. If FEV1 or PEFR tests were used as criteria for diagnosis of airway obstruction, the prevalence of EIB would be 6% and 15.8%, respectively. There was no significant difference between the post of players, family history of allergic disease and EIB in soccer players. This study suggests that at least 2.1% of soccer players will develop bronchospasm even if they do not have any history of asthma and allergy.

  13. Exercise-induced muscle damage impairs insulin signaling pathway associated with IRS-1 oxidative modification.

    PubMed

    Aoi, W; Naito, Y; Tokuda, H; Tanimura, Y; Oya-Ito, T; Yoshikawa, T

    2012-01-01

    Strenuous exercise induces delayed-onset muscle damage including oxidative damage of cellular components. Oxidative stress to muscle cells impairs glucose uptake via disturbance of insulin signaling pathway. We investigated glucose uptake and insulin signaling in relation to oxidative protein modification in muscle after acute strenuous exercise. ICR mice were divided into sedentary and exercise groups. Mice in the exercise group performed downhill running exercise at 30 m/min for 30 min. At 24 hr after exercise, metabolic performance and insulin-signaling proteins in muscle tissues were examined. In whole body indirect calorimetry, carbohydrate utilization was decreased in the exercised mice along with reduction of the respiratory exchange ratio compared to the rested control mice. Insulin-stimulated uptake of 2-deoxy-[(3)H]glucose in damaged muscle was decreased after acute exercise. Tyrosine phosphorylation of insulin receptor substrate (IRS)-1 and phosphatidyl-3-kinase/Akt signaling were impaired by exercise, leading to inhibition of the membrane translocation of glucose transporter 4. We also found that acute exercise caused 4-hydroxy-nonenal modification of IRS-1 along with elevation of oxidative stress in muscle tissue. Impairment of insulin-induced glucose uptake into damaged muscle after strenuous exercise would be related to disturbance of insulin signal transduction by oxidative modification of IRS-1.

  14. Astragalus membranaceus improves exercise performance and ameliorates exercise-induced fatigue in trained mice.

    PubMed

    Yeh, Tzu-Shao; Chuang, Hsiao-Li; Huang, Wen-Ching; Chen, Yi-Ming; Huang, Chi-Chang; Hsu, Mei-Chich

    2014-03-03

    Astragalus membranaceus (AM) is a popular "Qi-tonifying" herb with a long history of use as a Traditional Chinese Medicine with multiple biological functions. However, evidence for the effects of AM on exercise performance and physical fatigue is limited. We evaluated the potential beneficial effects of AM on ergogenic and anti-fatigue functions following physiological challenge. Male ICR strain mice were randomly assigned to four groups (n = 10 per group) for treatment: (1) sedentary control and vehicle treatment (vehicle control); (2) exercise training with vehicle treatment (exercise control); and (3) exercise training with AM treatment at 0.615 g/kg/day (Ex-AM1) or (4) 3.075 g/kg/day (Ex-AM5). Both the vehicle and AM were orally administered for 6 weeks. Exercise performance and anti-fatigue function were evaluated by forelimb grip strength, exhaustive swimming time, and levels of serum lactate, ammonia, glucose, and creatine kinase after 15-min swimming exercise. Exercise training combined with AM supplementation increased endurance exercise capacity and increased hepatic and muscle glycogen content. AM reduced exercise-induced accumulation of the byproducts blood lactate and ammonia with acute exercise challenge. Moreover, we found no deleterious effects from AM treatment. Therefore, AM supplementation improved exercise performance and had anti-fatigue effects in mice. It may be an effective ergogenic aid in exercise training.

  15. Reported Exercise-Related Respiratory Symptoms and Exercise-Induced Bronchoconstriction in Asthmatic Children

    PubMed Central

    Inci, Demet; Guggenheim, Refoel; Altintas, Derya Ufuk; Wildhaber, Johannes H.; Moeller, Alexander

    2017-01-01

    Background Unlimited physical activity is one of the key issues of asthma control and management. We investigated how reliable reported exercise-related respiratory symptoms (ERRS) are in predicting exercise-induced bronchoconstriction (EIB) in asthmatic children. Methods In this prospective study, 179 asthmatic children aged 7 - 15 years were asked for specific questions on respiratory symptoms related to exercise and allocated into two groups according to whether they complained about symptoms. Group I (n = 134) consisted of children answering “yes” to one or more of the questions and group II (n = 45) consisted of children answering “no” to all of the questions. Results Sixty-four of 179 children showed a positive exercise challenge test (ECT). There was no difference in the frequency of a positive test between children in group I (n = 48) and group II (n = 12) (P = 0.47). The sensitivity of a positive report for ERRS to predict a positive ECT was only 37%, with a specificity of 0.72. Conclusion According to current guidelines, the report or lack of ERRS has direct consequences on treatment decisions. However, the history of ERRS did not predict EIB and one-third of asthmatic children without complaints of ERRS developed EIB during the ECT. This raises the question of the need for objective measures of bronchial hyperresponsiveness (BHR) in pediatric asthma management. PMID:28392861

  16. Exercise-induced ST segment elevation. Electrocardiographic, angiographic, and scintigraphic evaluation.

    PubMed Central

    Lahiri, A; Balasubramanian, V; Millar Craig, M W; Crawley, J; Raftery, E B

    1980-01-01

    Two hundred and fifteen patients with previous myocardial infarction were investigated between four and six months after the acute episode by computer assisted 12 lead exercise electrocardiography. Thirty-six (17%) out of this group showed ST segment elevation over the infarct zone, reflected by leads presenting with "QS" configuration. They were further investigated by serial thallium-201 scintigraphy, coronary arteriography, and left ventricular angiography. All showed left ventricular wall motion abnormalities and 89 per cent were diagnosed to have left ventricular "aneurysm" (dyskinesia and akinesia). In a further patient with a posterior aneurysm, the exercise-induced ST elevation could only be detected by using an oesophageal lead. We suggest that these changes reflect severe underlying left ventricular wall motion abnormalities in the presence or absence of reversible myocardial ischaemia. The mechanism of ST segment elevation in this situation, occurring in leads with a "QS" configuration, may be mechanical in the majority of the patients rather than due to reversible myocardial ischaemia. Images PMID:7378220

  17. Underweight and overweight men have greater exercise-induced dyspnoea than normal weight men

    PubMed Central

    Ali, Syed a.; Bokhari, Syed S. I.; Khan, Mohammed n.; Ahmad, Hakimuddin r.

    2012-01-01

    Introduction. Persons with high or low body mass index (BMI), involved in clinical or mechanistic trials involving exercise testing, might estimate dyspnoea differently from persons with a normal BMI. Aims. Our objective was to investigate the relationship between BMI and dyspnoea during exercise in normal subjects with varying BMI. Material and methods. A total of 37 subjects undertook progressive exercise testing. Subjects were divided into three groups: underweight (UW), normal weight (NW), and overweight (OW). Dyspnoea was estimated using the visual analogue scale (VAS). Spirometry, maximum voluntary ventilation (MVV), and respiratory muscle strength (RMS) were measured. Results and discussion. The intercept of the VAS/ventilation relationship was significantly higher in NW subjects compared to UW (P = 0.029) and OW subjects (P = 0.040). Relative to the OW group, FVC (P = 0.020), FEV1 (P = 0.024), MVV (P = 0.019), and RMS (P = 0.003) were significantly decreased in the UW group. The greater levels of dyspnoea in UW subjects could possibly be due to decreased RMS. Healthy persons should aim to achieve an optimum BMI range to have the lowest exercise-induced dyspnoea. PMID:22931098

  18. Assessment of eccentric exercise-induced oxidative stress using oxidation-reduction potential markers.

    PubMed

    Stagos, Dimitrios; Goutzourelas, Nikolaos; Ntontou, Amalia-Maria; Kafantaris, Ioannis; Deli, Chariklia K; Poulios, Athanasios; Jamurtas, Athanasios Z; Bar-Or, David; Kouretas, Dimitrios

    2015-01-01

    The aim of the present study was to investigate the use of static (sORP) and capacity ORP (cORP) oxidation-reduction potential markers as measured by the RedoxSYS Diagnostic System in plasma, for assessing eccentric exercise-induced oxidative stress. Nineteen volunteers performed eccentric exercise with the knee extensors. Blood was collected before, immediately after exercise, and 24, 48, and 72 h after exercise. Moreover, common redox biomarkers were measured, which were protein carbonyls, thiobarbituric acid-reactive substances, total antioxidant capacity in plasma, and catalase activity and glutathione levels in erythrocytes. When the participants were examined as one group, there were not significant differences in any marker after exercise. However, in 11 participants there was a high increase in cORP after exercise, while in 8 participants there was a high decrease. Thus, the participants were divided in low cORP group exhibiting significant decrease in cORP after exercise and in high cORP group exhibiting significant increase. Moreover, only in the low cORP group there was a significant increase in lipid peroxidation after exercise suggesting induction of oxidative stress. The results suggested that high decreases in cORP values after exercise may indicate induction of oxidative stress by eccentric exercise, while high increases in cORP values after exercise may indicate no existence of oxidative stress.

  19. Does exercise-induced muscle damage play a role in skeletal muscle hypertrophy?

    PubMed

    Schoenfeld, Brad J

    2012-05-01

    Exercise-induced muscle damage (EIMD) occurs primarily from the performance of unaccustomed exercise, and its severity is modulated by the type, intensity, and duration of training. Although concentric and isometric actions contribute to EIMD, the greatest damage to muscle tissue is seen with eccentric exercise, where muscles are forcibly lengthened. Damage can be specific to just a few macromolecules of tissue or result in large tears in the sarcolemma, basal lamina, and supportive connective tissue, and inducing injury to contractile elements and the cytoskeleton. Although EIMD can have detrimental short-term effects on markers of performance and pain, it has been hypothesized that the associated skeletal muscle inflammation and increased protein turnover are necessary for long-term hypertrophic adaptations. A theoretical basis for this belief has been proposed, whereby the structural changes associated with EIMD influence gene expression, resulting in a strengthening of the tissue and thus protection of the muscle against further injury. Other researchers, however, have questioned this hypothesis, noting that hypertrophy can occur in the relative absence of muscle damage. Therefore, the purpose of this article will be twofold: (a) to extensively review the literature and attempt to determine what, if any, role EIMD plays in promoting skeletal muscle hypertrophy and (b) to make applicable recommendations for resistance training program design.

  20. Impact of family hypertension history on exercise-induced cardiac remodeling.

    PubMed

    Baggish, Aaron L; Weiner, Rory B; Yared, Kibar; Wang, Francis; Kupperman, Eli; Hutter, Adolph M; Picard, Michael H; Wood, Malissa J

    2009-07-01

    Left ventricular (LV) hypertrophy is a well-established, but highly variable, finding among exercise-trained persons. The causes for the variability in LV remodeling in response to exercise training remain incompletely understood. The present study sought to determine whether a family history of hypertension is a determinant of the cardiac response to exercise training. The cardiac parameters in 60 collegiate rowers (30 men/30 women; age 19.8 +/- 1.1 years) with (family history positive [FH+], n = 22) and without (family history negative [FH-], n = 38) a FH of hypertension were studied with echocardiography before and after 90 days of rowing training. The LV mass increased significantly in both groups. However, the LV mass increased significantly more in FH- persons (Delta 17 +/- 5 g/m(2)) than in FH+ persons (Delta 9 +/- 6 g/m(2), p <0.001) with distinctly differently patterns of LV hypertrophy between the 2 groups. FH- athletes experienced eccentric LV hypertrophy (relative wall thickness index 0.39 +/- 0.4) characterized by LV dilation. In contrast, FH+ athletes developed concentric LV hypertrophy (relative wall thickness index 0.44 +/- 0.3; p <0.001) characterized by LV wall thickening. Furthermore, the eccentric LV remodeling in FH- athletes was associated with a more robust enhancement of LV diastolic function than the concentric LV remodeling that occurred in FH+ athletes. In conclusion, these findings suggest that patterns of exercise-induced LV remodeling are strongly associated with FH history status.

  1. Exercise-induced hemolysis in xerocytosis. Erythrocyte dehydration and shear sensitivity.

    PubMed Central

    Platt, O S; Lux, S E; Nathan, D G

    1981-01-01

    A patient with xerocytosis was found to have swimming-induced intravascular hemolysis and shortening of erythrocyte life-span. In a microviscometer, xerocytes were more susceptible than normal erythrocytes to hemolysis by shear stress. Fractionation of normal and abnormal cells on discontinuous Stractan density gradients revealed that increasingly dehydrated cells were increasingly more shear sensitive. This sensitivity was partially corrected by rehydrating xerocytic erythrocytes by means of the cation-ionophore nystatin in a high potassium buffer. Conversely, normal erythrocytes were rendered shear sensitive by dehydrating them with nystatin in a low potassium buffer. This effect of dehydration was entirely reversible if normal cells were dehydrated for less than 4 h but was only partially reversed after more prolonged dehydration. It is likely that dehydration of erythrocytes results in shear sensitivity primarily because of concentration of cell contents and reduced cellular deformability. With prolonged dehydration, secondary membrane changes may potentiate the primary effect. This increased shear sensitivity of dehydrated cells may explain atraumatic exercise-induced hemolysis in xerocytosis as cardiac output is shifted to vessels of exercising muscles with small diameters and high shear rates. PMID:7276163

  2. The right heart in athletes. Evidence for exercise-induced arrhythmogenic right ventricular cardiomyopathy.

    PubMed

    Heidbüchel, H; La Gerche, A

    2012-0