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Sample records for exercise-induced mitochondrial biogenesis

  1. Regulation of exercise-induced fiber type transformation, mitochondrial biogenesis, and angiogenesis in skeletal muscle

    PubMed Central

    Okutsu, Mitsuharu; Akhtar, Yasir N.; Lira, Vitor A.

    2011-01-01

    Skeletal muscle exhibits superb plasticity in response to changes in functional demands. Chronic increases of skeletal muscle contractile activity, such as endurance exercise, lead to a variety of physiological and biochemical adaptations in skeletal muscle, including mitochondrial biogenesis, angiogenesis, and fiber type transformation. These adaptive changes are the basis for the improvement of physical performance and other health benefits. This review focuses on recent findings in genetically engineered animal models designed to elucidate the mechanisms and functions of various signal transduction pathways and gene expression programs in exercise-induced skeletal muscle adaptations. PMID:21030673

  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. Deacetylation of PGC-1α by SIRT1: importance for skeletal muscle function and exercise-induced mitochondrial biogenesis.

    PubMed

    Gurd, Brendon J

    2011-10-01

    Activation of peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α)-mediated transcription is important for both the determination of mitochondrial content and the induction of mitochondrial biogenesis in skeletal muscle. SIRT1 (silent mating type information regulator 2 homolog 1) deactetylation is proposed as a potential activator of PGC-1α transcriptional activity. The current review examines the importance of SIRT1 deacetylation of PGC-1α in skeletal muscle. Models of SIRT1 overexpression and pharmacological activation are examined, but changes in SIRT1 expression and deacetylase activity following acute and chronic contractile activity will be emphasized. In addition, potential mechanisms of SIRT1 activation in skeletal muscle will be examined. The importance of the PGC-1α acetyltransferase GCN5 will also be briefly discussed. The current evidence supports the contribution of SIRT1 deacetylation of PGC-1α to exercise-induced mitochondrial biogenesis. Further research examining exercise-mediated activation of SIRT1 and the role of GCN5 in regulating PGC-1α transcriptional activity in skeletal muscle is required. PMID:21888529

  4. Regulation of mitochondrial biogenesis

    PubMed Central

    Jornayvaz, François R.; Shulman, Gerald I.

    2013-01-01

    Although it is well established that physical activity increases mitochondrial content in muscle, the molecular mechanisms underlying this process have only recently been elucidated. Mitochondrial dysfunction is an important component of different diseases associated with aging, such as Type 2 diabetes and Alzheimer’s disease. PGC-1α (peroxisome-proliferator-activated receptor γ co-activator-1α) is a co-transcriptional regulation factor that induces mitochondrial biogenesis by activating different transcription factors, including nuclear respiratory factor 1 and nuclear respiratory factor 2, which activate mitochondrial transcription factor A. The latter drives transcription and replication of mitochondrial DNA. PGC-1α itself is regulated by several different key factors involved in mitochondrial biogenesis, which will be reviewed in this chapter. Of those, AMPK (AMP-activated protein kinase) is of major importance. AMPK acts as an energy sensor of the cell and works as a key regulator of mitochondrial biogenesis. AMPK activity has been shown to decrease with age, which may contribute to decreased mitochondrial biogenesis and function with aging. Given the potentially important role of mitochondrial dysfunction in the pathogenesis of numerous diseases and in the process of aging, understanding the molecular mechanisms regulating mitochondrial biogenesis and function may provide potentially important novel therapeutic targets. PMID:20533901

  5. MYC and Mitochondrial Biogenesis

    PubMed Central

    Morrish, Fionnuala; Hockenbery, David

    2014-01-01

    Mitochondria, the powerhouses of the cell, face two imperatives concerning biogenesis. The first is the requirement for dividing cells to replicate their mitochondrial content by growth of existing mitochondria. The second is the dynamic regulation of mitochondrial content in response to organismal and cellular cues (e.g., exercise, caloric restriction, energy status, temperature). MYC provides the clearest example of a programmed expansion of mitochondrial content linked to the cell cycle. As an oncogene, MYC also presents intriguing questions about the role of its mitochondrial targets in cancer-related phenotypes, such as the Warburg effect and MYC-dependent apoptosis. PMID:24789872

  6. 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), myoclonic epilepsy with ragged-red fibers (MERRF), mitochondrial encephalomyopathy, lactic acidosis and strokelike episodes (MELAS), Leber's hereditary optic neuropathy (LHON), the syndrome of neurogenic muscle weakness, ataxia and retinitis pigmentosa (NARP), and Leigh's syndrome. Likewise, other diseases in which mitochondrial dysfunction plays a very important role include neurodegenerative diseases, diabetes or cancer. Generally, in mitochondrial diseases a mutation in the mitochondrial DNA leads to a loss of functionality of the OXPHOS system and thus to a depletion of ATP and overproduction of ROS, which can, in turn, induce further mtDNA mutations. The work by Yu-Ting Wu, Shi-Bei Wu, and Yau-Huei Wei (Department of Biochemistry and Molecular Biology, National Yang-Ming University, Taiwan) [4] focuses on the aforementioned mitochondrial diseases with special attention to the compensatory mechanisms that prompt mitochondria to produce more energy even under mitochondrial defect-conditions. These compensatory mechanisms include the overexpression of antioxidant enzymes, mitochondrial biogenesis and overexpression of respiratory complex subunits, as well as metabolic shift to glycolysis. The pathways observed to be related to mitochondrial biogenesis as a compensatory adaptation to the energetic deficits in mitochondrial diseases are described (PGC- 1, Sirtuins, AMPK). Several pharmacological strategies to trigger these signaling cascades, according to these authors, are the use of bezafibrate to activate the PPAR-PGC-1α axis, the activation of AMPK by resveratrol and the use of Sirt1 agonists such as quercetin or resveratrol. Other strategies currently used include the addition of antioxidant supplements to the diet (dietary supplementation with antioxidants) such as L-carnitine, coenzyme Q10,MitoQ10 and other mitochondria-targeted antioxidants,N-acetylcysteine (NAC), vitamin C, vitamin E vitamin K1, vitamin B, sodium pyruvate or -lipoic acid. As aforementioned, other diseases do not have exclusively a mitochondrial origin but they might have an important mitochondrial component both on their onset and on their development. This is the case of type 2 diabetes or neurodegenerative diseases. Type 2 diabetes is characterized by a peripheral insulin resistance accompanied by an increased secretion of insulin as a compensatory system. Among the explanations about the origin of insulin resistance Mónica Zamora and Josep A. Villena (Department of Experimental and Health Sciences, Universitat Pompeu Fabra / Laboratory of Metabolism and Obesity, Universitat Autònoma de Barcelona, Spain) [5] consider the hypothesis that mitochondrial dysfunction, e.g. impaired (mitochondrial) oxidative capacity of the cell or tissue, is one of the main underlying causes of insulin resistance and type 2 diabetes. Although this hypothesis is not free of controversy due to the uncertainty on the sequence of events during type 2 diabetes onset, e.g. whether mitochondrial dysfunction is the cause or the consequence of insulin resistance, it has been widely observed that improving mitochondrial function also improves insulin sensitivity and prevents type 2 diabetes. Thus restoring oxidative capacity by increasing mitochondrial mass appears as a suitable strategy to treat insulin resistance. The effort made by researchers trying to understand the signaling pathways mediating mitochondrial biogenesis has uncovered new potential pharmacological targets and opens the perspectives for the design of suitable treatments for insulin resistance. In addition some of the current used strategies could be used to treat insulin resistance such as lifestyle interventions (caloric restriction and endurance exercise) and pharmacological interventions (thiazolidinediones and other PPAR agonists, resveratrol and other calorie restriction mimetics, AMPK activators, ERR activators). Mitochondrial biogenesis is of special importance in modern neurochemistry because of the broad spectrum of human diseases arising from defects in mitochondrial ion and ROS homeostasis, energy production and morphology [1]. Parkinson´s Disease (PD) is a very good example of this important mitochondrial component on neurodegenerative diseases. Anuradha Yadav, Swati Agrawal, Shashi Kant Tiwari, and Rajnish K. Chaturvedi (CSIR-Indian Institute of Toxicology Research / Academy of Scientific and Innovative Research, India) [6] remark in their review the role of mitochondrial dysfunction in PD with special focus on the role of oxidative stress and bioenergetic deficits. These alterations may have their origin on pathogenic gene mutations in important genes such as DJ-1, -syn, parkin, PINK1 or LRRK2. These mutations, in turn, may cause defects in mitochondrial dynamics (key events like fission/fusion, biogenesis, trafficking in retrograde and anterograde directions, and mitophagy). This work reviews different strategies to enhance mitochondrial bioenergetics in order to ameliorate the neurodegenerative process, with an emphasis on clinical trials reports that indicate their potential. Among them creatine, Coenzyme Q10 and mitochondrial targeted antioxidants/peptides are reported to have the most remarkable effects in clinical trials. They highlight a dual effect of PGC-1α expression on PD prognosis. Whereas a modest expression of this transcriptional co-activator results in positive effects, a moderate to substantial overexpession may have deleterious consequences. As strategies to induce PGC-1α activation, these authors remark the possibility to activate Sirt1 with resveratrol, to use PPAR agonists such as pioglitazone, rosiglitazone, fenofibrate and bezafibrate. Other strategies include the triggering of Nrf2/antioxidant response element (ARE) pathway by triterpenoids (derivatives of oleanolic acid) or by Bacopa monniera, the enhancement of ATP production by carnitine and -lipoic acid. Mitochondrial dysfunctions are the prime source of neurodegenerative diseases and neurodevelopmental disorders. In the context of neural differentiation, Martine Uittenbogaard and Anne Chiaramello (Department of Anatomy and Regenerative Biology, George Washington University School of Medicine and Health Sciences, USA) [7] thoroughly describe the implication of mitochondrial biogenesis on neuronal differentiation, its timing, its regulation by specific signaling pathways and new potential therapeutic strategies. The maintenance of mitochondrial homeostasis is crucial for neuronal development. A mitochondrial dynamic balance is necessary between mitochondrial fusion, fission and quality control systems and mitochondrial biogenesis. Concerning the signaling pathways leading to mitochondrial biogenesis this review highlights the implication of different regulators such as AMPK, SIRT1, PGC-1α, NRF1, NRF2, Tfam, etc. on the specific case of neuronal development, providing examples of diseases in which these pathways are altered and transgenic mouse models lacking these regulators. A common hallmark of several neurodegenerative diseases (Huntington´s Disease, Alzheimer´s Disease and Parkinson´s Disease) is the impaired function or expression of PGC-1α, the master regulator of mitochondrial biogenesis. Among the promising strategies to ameliorate mitochondrial-based diseases these authors highlight the induction of PGC-1α via activation of PPAR receptors (rosiglitazone, bezafibrate) or modulating its activity by AMPK (AICAR, metformin, resveratrol) or SIRT1 (SRT1720 and several isoflavone-derived compounds). This article also presents a review of the current animal and cellular models useful to study mitochondriogenesis. Although it is known that many neurodegenerative and neurodevelopmental diseases are originated in mitochondria, the regulation of mitochondrial biogenesis has never been extensively studied. (ABSTRACT TRUNCATED) PMID:24606795

  7. Resveratrol induces mitochondrial biogenesis in endothelial cells.

    PubMed

    Csiszar, Anna; Labinskyy, Nazar; Pinto, John T; Ballabh, Praveen; Zhang, Hanrui; Losonczy, Gyorgy; Pearson, Kevin; de Cabo, Rafael; Pacher, Pal; Zhang, Cuihua; Ungvari, Zoltan

    2009-07-01

    Pathways that regulate mitochondrial biogenesis are potential therapeutic targets for the amelioration of endothelial dysfunction and vascular disease. Resveratrol was shown to impact mitochondrial function in skeletal muscle and the liver, but its role in mitochondrial biogenesis in endothelial cells remains poorly defined. The present study determined whether resveratrol induces mitochondrial biogenesis in cultured human coronary arterial endothelial cells (CAECs). In CAECs resveratrol increased mitochondrial mass and mitochondrial DNA content, upregulated protein expression of electron transport chain constituents, and induced mitochondrial biogenesis factors (proliferator-activated receptor-coactivator-1alpha, nuclear respiratory factor-1, mitochondrial transcription factor A). Sirtuin 1 (SIRT1) was induced, and endothelial nitric oxide (NO) synthase (eNOS) was upregulated in a SIRT1-dependent manner. Knockdown of SIRT1 (small interfering RNA) or inhibition of NO synthesis prevented resveratrol-induced mitochondrial biogenesis. In aortas of type 2 diabetic (db/db) mice impaired mitochondrial biogenesis was normalized by chronic resveratrol treatment, showing the in vivo relevance of our findings. Resveratrol increases mitochondrial content in endothelial cells via activating SIRT1. We propose that SIRT1, via a pathway that involves the upregulation of eNOS, induces mitochondrial biogenesis. Resveratrol induced mitochondrial biogenesis in the aortas of type 2 diabetic mice, suggesting the potential for new treatment approaches targeting endothelial mitochondria in metabolic diseases. PMID:19429820

  8. Adiponectin is sufficient, but not required, for exercise-induced increases in the expression of skeletal muscle mitochondrial enzymes

    PubMed Central

    Ritchie, Ian R W; MacDonald, Tara L; Wright, David C; Dyck, David J

    2014-01-01

    Adiponectin (Ad) has been proposed to be a regulator of mitochondrial biogenesis in skeletal muscle, and necessary for exercise-induced increases in mitochondrial content. We first confirmed that Ad could acutely increase the expression of mitochondrial proteins during a 10 h incubation in isolated soleus and extensor digitorum longus (EDL) muscles. Next, we further examined the role of Ad as a regulator of mitochondrial content using Ad knockout (AdKO) mice. The AdKO animals showed no differences in resting , respiratory exchange ratio, or in time to exhaustion during exercise when compared to wild-type (WT) mice. There was a reduction in resting palmitate oxidation in isolated soleus from AdKO animals (−23%, P < 0.05) but not EDL, and 5-aminoimidazole-4-carboxamide (AICAR)-stimulated palmitate oxidation was similar in both genotypes regardless of muscle. There were no differences in protein markers of mitochondrial content (COX4, CORE1, CS, PDHE1α) in red and white gastrocnemius between WT and AdKO animals. A single bout of treadmill running increased the phosphorylation of AMP-activated protein kinase (AMPK) and the mRNA expression of mitochondrial proteins in red and white gastrocnemius in both WT and AdKO animals, with no differences between genotypes. Finally, 8 weeks of chronic exercise training increased the protein content of mitochondrial markers similarly (∼25–35%) in red gastrocnemius from both WT and AdKO mice. Collectively, our results demonstrate that the absence of Ad is not accompanied by reductions in mitochondrial protein content, or a reduction in aerobic exercise capacity. We conclude that Ad is not required for the maintenance of mitochondrial content, or for exercise-induced increases in skeletal muscle mitochondrial proteins. PMID:24687585

  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. PMID:21507065

  10. 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

  11. Mitochondrial Biogenesis and Peroxisome Proliferator–Activated Receptor-γ Coactivator-1α (PGC-1α) Deacetylation by Physical Activity

    PubMed Central

    Li, Ling; Pan, Ruping; Li, Rong; Niemann, Bernd; Aurich, Anne-Cathleen; Chen, Ying; Rohrbach, Susanne

    2011-01-01

    OBJECTIVE Transcriptional peroxisome proliferator–activated receptor-γ coactivator-1α (PGC-1α) plays a key role in mitochondrial biogenesis and energy metabolism and is suggested to be involved in the exercise-induced increase in mitochondrial content. PGC-1α activity is regulated by posttranslational modifications, among them acetylation or phosphorylation. Accordingly, the deacetylase SIRT1 and the kinase AMPK increase PGC-1α activity. RESEARCH DESIGN AND METHODS We tested whether chronic treadmill exercise or a single exercise session modifies PGC-1α activation and mitochondrial biogenesis differentially in obese ob/ob mice with dysregulated adiponectin/leptin-mediated AMPK activation compared with C57BL/6J wild-type mice. RESULTS Exercise training (12 weeks) induced adiponectin and lowered plasma insulin and glucose, suggesting improved insulin sensitivity in wild-type mice. It enhanced mitochondrial biogenesis in red gastrocnemius muscle, as indicated by increased mRNA expression of transcriptional regulators and primary mitochondrial transcripts, increased mtDNA content, and citrate synthase activity. Parallel to this, we observed AMPK activation, PGC-1α deacetylation, and SIRT1 induction in trained wild-type mice. Although none of these exercise-induced changes were detected in ob/ob mice, comparable effects on mitochondrial respiration were observed. A single exercise session resulted in comparable changes in wild-type mice. These changes remained detectable 6 h after the exercise session but had disappeared after 24 h. Treatment of C2C12 myoblasts with leptin or adiponectin resulted in increased AMPK phosphorylation and PGC-1α deacetylation. CONCLUSIONS Chronic exercise induces mitochondrial biogenesis in wild-type mice, which may require intact AMPK activation by adipocytokines and involve SIRT1-dependent PGC-1α deacetylation. Trained ob/ob mice appear to have partially adapted to reduced mitochondrial biogenesis by AMPK/SIRT1/PGC-1α–independent mechanisms without mtDNA replication. PMID:20929977

  12. Estrogenic Control of Mitochondrial Function and Biogenesis

    PubMed Central

    Klinge, Carolyn M.

    2008-01-01

    Estrogens have cell-specific effects on a variety of physiological endpoints including regulation of mitochondrial biogenesis and activity. Estrogens regulate gene transcription by the classical genomic mechanism of binding to estrogen receptors ? and ? (ER? and ER?) as well as the more recently described nongenomic pathways involving plasma membrane-associated ERs that activate intracellular protein kinase-mediated phosphorylation signaling cascades. Here I will review the rapid and longer-term effects of estrogen on mitochondrial function. The identification of ER? and ER? within mitochondria of various cells and tissues is discussed with a model of estrogen regulation of the transcription of Nuclear Respiratory Factor-1 (NRF-1, NRF1). NRF-1 subsequently promotes transcription of mitochondrial transcription factor Tfam (mtDNA maintenance factor, also called mtTFA) and then Tfam targets mtDNA-encoded genes. The nuclear effects of estrogens on gene expression directly controlling mitochondrial biogenesis, oxygen consumption, mtDNA transcription, and apoptosis are reviewed. Overall, we are just beginning to evaluate the many direct and indirect effects of estrogens on mitochondrial activities. PMID:18846505

  13. Mitochondrial dynamic remodeling in strenuous exercise-induced muscle and mitochondrial dysfunction: regulatory effects of hydroxytyrosol.

    PubMed

    Feng, Zhihui; Bai, Liyuan; Yan, Jiong; Li, Yuan; Shen, Weili; Wang, Ying; Wertz, Karin; Weber, Peter; Zhang, Yong; Chen, Yan; Liu, Jiankang

    2011-05-15

    Physical exercise is considered to exert a positive effect on health, whereas strenuous or excessive exercise (Exe) causes fatigue and damage to muscle and immune functions. The underlying molecular mechanisms are still unclear. We designed a protocol to mimic Exe and explore the ensuing cellular damage and involvement of mitochondrial dynamics. We found that Exe was prone to decrease endurance capacity and induce damage to renal function and the immune system. Muscle atrophy markers atrogin-1 and MuRF1 mRNA were increased by Exe, accompanied by increased autophagy and mitochondrial fission in skeletal muscle. Exe caused a decrease in PGC-1α and complex I expression; it also activated JNK and Erk1/2 pathways and consequently induced p53, p21, and MnSOD expression in skeletal muscle. The involvement of oxidant-induced autophagy and mitochondrial dysfunction was confirmed in C2C12 myoblasts. Hydroxytyrosol (HT), a natural olive polyphenol, efficiently enhanced endurance capacity and prevented Exe-induced renal and immune system damage. Also, HT treatment inhibited both the Exe-induced increase in autophagy and mitochondrial fission and the decrease in PGC-1α expression. In addition, HT enhanced mitochondrial fusion and mitochondrial complex I and II activities in muscle of Exe rats. These results demonstrate that Exe-induced fatigue and damage to muscle and immune functions may be mediated via the regulation of mitochondrial dynamic remodeling, including the downregulation of mitochondrial biogenesis and upregulation of autophagy. HT supplementation may regulate mitochondrial dynamic remodeling and enhance antioxidant defenses and thus improve exercise capacity under Exe conditions. PMID:21421045

  14. Reactive Oxygen Species-Mediated Control of Mitochondrial Biogenesis

    PubMed Central

    Yoboue, Edgar D.; Devin, Anne

    2012-01-01

    Mitochondrial biogenesis is a complex process. It necessitates the contribution of both the nuclear and the mitochondrial genomes and therefore crosstalk between the nucleus and mitochondria. It is now well established that cellular mitochondrial content can vary according to a number of stimuli and physiological states in eukaryotes. The knowledge of the actors and signals regulating the mitochondrial biogenesis is thus of high importance. The cellular redox state has been considered for a long time as a key element in the regulation of various processes. In this paper, we report the involvement of the oxidative stress in the regulation of some actors of mitochondrial biogenesis. PMID:22693510

  15. Mitochondrial biogenesis during germination in maize embryos.

    PubMed

    Logan, D C; Millar, A H; Sweetlove, L J; Hill, S A; Leaver, C J

    2001-02-01

    Mitochondrial biogenesis and metabolism were investigated during maize (Zea mays) seed germination. Mitochondria from dry and imbibed seed exhibited NADH-dependent O(2) uptake that was completely inhibited by KCN and antimycin A. Mitochondria in the dry seed had a lower rate of succinate-dependent O(2) uptake relative to that measured in imbibed and germinated seed. The activities of the tricarboxylic acid (TCA) cycle enzymes, pyruvate dehydrogenase complex, 2-oxoglutarate dehydrogenase complex, NAD-malic enzyme, and citrate synthase, are similarly low in mitochondria from dry seed and this correlates with a lower relative abundance of the mitochondrial matrix-located citrate synthase and pyruvate dehydrogenase complex E1alpha-subunit polypeptides. Electron microscopy revealed that mitochondria in the dry seed have a poorly developed internal membrane structure with few cristae; following 24 h of germination the mitochondria developed a more normal structure with more developed cristae. The mitochondria from maize embryos could be fractionated into two subpopulations by Suc density gradient centrifugation: one subpopulation of buoyant density equivalent to 22% to 28% (w/w) Suc; the other equivalent to 37% to 42% (w/w) Suc. These two subpopulations had different activities of specific mitochondrial enzymes and contained different amounts of specific mitochondrial proteins as revealed by western-blot analysis. Both subpopulations from the dry embryo were comprised of poorly developed mitochondria. However, during imbibition mitochondria in the heavy fraction (37%-42% [w/w] Suc) progressively acquired characteristics of fully functional mitochondria found in the germinated seedling in terms of structure, enzymic activity, and protein complement. In contrast, mitochondria in the light fraction (22% to 28% [w/w] Suc) show no significant structural change during imbibition and the amounts of specific mitochondrial proteins decreased significantly during germination. PMID:11161024

  16. Fibroblast growth factor 21 and exercise-induced hepatic mitochondrial adaptations.

    PubMed

    Fletcher, Justin A; Linden, Melissa A; Sheldon, Ryan D; Meers, Grace M; Morris, E Matthew; Butterfield, Anthony; Perfield, James W; Thyfault, John P; Rector, R Scott

    2016-05-15

    Exercise stimulates hepatic mitochondrial adaptations; however, the mechanisms remain largely unknown. Here we tested whether FGF21 plays an obligatory role in exercise induced hepatic mitochondrial adaptations by testing exercise responses in FGF21 knockout mice. FGF21 knockout (FGF21-KO) and wild-type (WT) mice (11-12 wk of age) had access to voluntary running wheels for exercise (EX) or remained sedentary for 8 wk. FGF21 deficiency resulted in greater body weight, adiposity, serum cholesterol, insulin, and glucose concentrations compared with WT mice (P < 0.05). In addition, hepatic mitochondrial complete palmitate oxidation, β-hydroxyacyl-CoA dehydrogenase (β-HAD) activity, and nuclear content of PGC-1α were 30-50% lower in FGF21-KO mice compared with WT mice (P < 0.01). EX effectively lowered body weight, adiposity, serum triglycerides, free fatty acids, and insulin and normalized mitochondrial complete palmitate oxidation in the FGF21-KO mice, whereas the reduced hepatic β-HAD activity and lowered nuclear content of PGC-1α in FGF21-KO mice were not restored by EX. In addition, EX increased hepatic CPT-1α mRNA expression and ACC phosphorylation (a marker of increased AMPK activity) and reduced hepatic triacylglycerol content in both genotypes. However, FGF21-KO mice displayed a lower EX-induced increase in the mRNA expression of the hepatic gluconeogenic gene, PEPCK, compared with WT. In conclusion, FGF21 does not appear necessary for exercise-induced systemic and hepatic mitochondrial adaptations, but the increased adiposity, hyperinsulinemia, and impairments in hepatic mitochondrial function induced by FGF21 deficiency can be partially rescued by daily wheel running exercise. PMID:27012775

  17. The Protective Effects of Salidroside from Exhaustive Exercise-Induced Heart Injury by Enhancing the PGC-1 α–NRF1/NRF2 Pathway and Mitochondrial Respiratory Function in Rats

    PubMed Central

    Ping, Zheng; Zhang, Long-fei; Cui, Yu-juan; Chang, Yu-mei; Jiang, Cai-wu; Meng, Zhen-zhi; Xu, Peng; Liu, Hai-yan; Wang, Dong-ying; Cao, Xue-bin

    2015-01-01

    Objective. To test the hypothesis that salidroside (SAL) can protect heart from exhaustive exercise-induced injury by enhancing mitochondrial respiratory function and mitochondrial biogenesis key signaling pathway PGC-1α–NRF1/NRF2 in rats. Methods. Male Sprague-Dawley rats were divided into 4 groups: sedentary (C), exhaustive exercise (EE), low-dose SAL (LS), and high-dose SAL (HS). After one-time exhaustive swimming exercise, we measured the changes in cardiomyocyte ultrastructure and cardiac marker enzymes and mitochondrial electron transport system (ETS) complexes activities in situ. We also measured mitochondrial biogenesis master regulator PGC-1α and its downstream transcription factors, NRF1 and NRF2, expression at gene and protein levels. Results. Compared to C group, the EE group showed marked myocardium ultrastructure injury and decrease of mitochondrial respiratory function (P < 0.05) and protein levels of PGC-1α, NRF1, and NRF2 (P < 0.05) but a significant increase of PGC-1α, NRF1, and NRF2 genes levels (P < 0.05); compared to EE group, SAL ameliorated myocardium injury, increased mitochondrial respiratory function (P < 0.05), and elevated both gene and protein levels of PGC-1α, NRF-1, and NRF-2. Conclusion. Salidroside can protect the heart from exhaustive exercise-induced injury. It might act by improving myocardial mitochondrial respiratory function by stimulating the expression of PGC-1α–NRF1/NRF2 pathway. PMID:26167242

  18. Mitochondrial biogenesis and peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) deacetylation by physical activity: intact adipocytokine signaling is required.

    PubMed

    Li, Ling; Pan, Ruping; Li, Rong; Niemann, Bernd; Aurich, Anne-Cathleen; Chen, Ying; Rohrbach, Susanne

    2011-01-01

    OBJECTIVE Transcriptional peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) plays a key role in mitochondrial biogenesis and energy metabolism and is suggested to be involved in the exercise-induced increase in mitochondrial content. PGC-1α activity is regulated by posttranslational modifications, among them acetylation or phosphorylation. Accordingly, the deacetylase SIRT1 and the kinase AMPK increase PGC-1α activity. RESEARCH DESIGN AND METHODS We tested whether chronic treadmill exercise or a single exercise session modifies PGC-1α activation and mitochondrial biogenesis differentially in obese ob/ob mice with dysregulated adiponectin/leptin-mediated AMPK activation compared with C57BL/6J wild-type mice. RESULTS Exercise training (12 weeks) induced adiponectin and lowered plasma insulin and glucose, suggesting improved insulin sensitivity in wild-type mice. It enhanced mitochondrial biogenesis in red gastrocnemius muscle, as indicated by increased mRNA expression of transcriptional regulators and primary mitochondrial transcripts, increased mtDNA content, and citrate synthase activity. Parallel to this, we observed AMPK activation, PGC-1α deacetylation, and SIRT1 induction in trained wild-type mice. Although none of these exercise-induced changes were detected in ob/ob mice, comparable effects on mitochondrial respiration were observed. A single exercise session resulted in comparable changes in wild-type mice. These changes remained detectable 6 h after the exercise session but had disappeared after 24 h. Treatment of C2C12 myoblasts with leptin or adiponectin resulted in increased AMPK phosphorylation and PGC-1α deacetylation. CONCLUSIONS Chronic exercise induces mitochondrial biogenesis in wild-type mice, which may require intact AMPK activation by adipocytokines and involve SIRT1-dependent PGC-1α deacetylation. Trained ob/ob mice appear to have partially adapted to reduced mitochondrial biogenesis by AMPK/SIRT1/PGC-1α-independent mechanisms without mtDNA replication. PMID:20929977

  19. Regulation of Mitochondrial Biogenesis and Its Intersection with Inflammatory Responses

    PubMed Central

    Piantadosi, Claude A.

    2015-01-01

    Abstract Significance: Mitochondria play a vital role in cellular homeostasis and are susceptible to damage from inflammatory mediators released by the host defense. Cellular recovery depends, in part, on mitochondrial quality control programs, including mitochondrial biogenesis. Recent Advances: Early-phase inflammatory mediator proteins interact with PRRs to activate NF-κB-, MAPK-, and PKB/Akt-dependent pathways, resulting in increased expression or activity of coactivators and transcription factors (e.g., PGC-1α, NRF-1, NRF-2, and Nfe2l2) that regulate mitochondrial biogenesis. Inflammatory upregulation of NOS2-induced NO causes mitochondrial dysfunction, but NO is also a signaling molecule upregulating mitochondrial biogenesis via PGC-1α, participating in Nfe2l2-mediated antioxidant gene expression and modulating inflammation. NO and reactive oxygen species generated by the host inflammatory response induce the redox-sensitive HO-1/CO system, causing simultaneous induction of mitochondrial biogenesis and antioxidant gene expression. Critical Issues: Recent evidence suggests that mitochondrial biogenesis and mitophagy are coupled through redox pathways; for instance, parkin, which regulates mitophagy in chronic inflammation, may also modulate mitochondrial biogenesis and is upregulated through NF-κB. Further research on parkin in acute inflammation is ongoing. This highlights certain common features of the host response to acute and chronic inflammation, but caution is warranted in extrapolating findings across inflammatory conditions. Future Directions: Inflammatory mitochondrial dysfunction and oxidative stress initiate further inflammatory responses through DAMP/PRR interactions and by inflammasome activation, stimulating mitophagy. A deeper understanding of mitochondrial quality control programs' impact on intracellular inflammatory signaling will improve our approach to the restoration of mitochondrial homeostasis in the resolution of acute inflammation. Antioxid. Redox Signal. 22, 965–976. PMID:25556935

  20. Acute {beta}-adrenergic stimulation does not alter mitochondrial protein synthesis or markers of mitochondrial biogenesis in adult men.

    PubMed

    Robinson, Matthew M; Richards, Jennifer C; Hickey, Matthew S; Moore, Daniel R; Phillips, Stuart M; Bell, Christopher; Miller, Benjamin F

    2010-01-01

    Exercise-induced expression of peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha) is dramatically inhibited in mice pretreated with a beta-adrenergic receptor (beta-AR) antagonist, suggesting that beta-ARs play an important role in the regulation of skeletal muscle PGC-1alpha expression, and potentially, mitochondrial biogenesis. Accordingly, we hypothesized that acute beta-AR stimulation would induce transcriptional pathways involved in skeletal muscle mitochondrial biogenesis in humans. Whole body protein turnover (WBPT), myofibrillar protein synthesis (MyPS), skeletal muscle mitochondrial protein synthesis (MiPS), and mitochondrial biogenic signaling were determined in samples of vastus lateralis obtained on two separate occasions in 10 young adult males following 1 h of continuous intravenous administration of saline (CON) or a nonspecific beta-AR agonist [isoproterenol (ISO): 12 ng.kg fat free mass(-1).min(-1)], combined with coinfusion of [1,2](13)C-leucine. beta-AR stimulation induced appreciable increases in heart rate and systolic blood pressure (both P < 0.001) but did not affect mitochondrial biogenic signaling (no change in PGC-1alpha, TFAM, NRF-1, NRF-2, COX, or NADHox expression via RT-PCR; P > 0.05). Additionally, MiPS [CON: 0.099 +/- 0.028, ISO: 0.074 +/- 0.046 (mean +/- SD); P > 0.05] and MyPS (CON: 0.059 +/- 0.008, ISO: 0.055 +/- 0.009; P > 0.05), as well as measures of WBPT were unaffected. On the basis of this investigation, we conclude that acute intravenous beta-AR stimulation does not increase mitochondrial protein synthesis or biogenesis signals in skeletal muscle. PMID:19907002

  1. 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.

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

    PubMed

    Zhang, Gao; Frederick, Dennie T; Wu, Lawrence; Wei, Zhi; Krepler, Clemens; Srinivasan, Satish; Chae, Young Chan; Xu, Xiaowei; Choi, Harry; Dimwamwa, Elaida; Ope, Omotayo; 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; Liu, Qin; Brafford, Patricia; Weeraratna, Ashani; Davies, Michael A; Wargo, Jennifer A; Avadhani, Narayan G; Lu, Yiling; Mills, Gordon B; Altieri, Dario C; Flaherty, Keith T; Herlyn, Meenhard

    2016-05-01

    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

  3. Molecular Genetics of Mitochondrial Biogenesis in Maize.

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The mitochondrial genome encodes proteins essential for mitochondrial respiration and ATP synthesis. Nuclear gene products, however, are required for the expression of mitochondrial genes and the elaboration of functional mitochondrial protein complexes. We are exploiting a unique collection of maiz...

  4. Mitochondrial biogenesis and dynamics in the developing and diseased heart

    PubMed Central

    Dorn, Gerald W.; Vega, Rick B.; Kelly, Daniel P.

    2015-01-01

    The mitochondrion is a complex organelle that serves essential roles in energy transduction, ATP production, and a myriad of cellular signaling events. A finely tuned regulatory network orchestrates the biogenesis, maintenance, and turnover of mitochondria. The high-capacity mitochondrial system in the heart is regulated in a dynamic way to generate and consume enormous amounts of ATP in order to support the constant pumping function in the context of changing energy demands. This review describes the regulatory circuitry and downstream events involved in mitochondrial biogenesis and its coordination with mitochondrial dynamics in developing and diseased hearts. PMID:26443844

  5. Contribution of mitochondrial function to exercise-induced attenuation of renal dysfunction in spontaneously hypertensive rats.

    PubMed

    Gu, Qi; Zhao, Li; Ma, Yan-Ping; Liu, Jian-Dong

    2015-08-01

    It is well known that exercise training exhibits renal protective effects in animal models of hypertension and chronic renal failure. However, the mechanisms regulating these effects of exercise training remain unclear. This study aimed to investigate the role of mitochondrial function in exercise-induced attenuation of renal injury in spontaneously hypertensive rats (SHR). The adult male SHR and age-matched normotensive Wistar-Kyoto rats (WKY) were given moderate-intensity exercise for 12 weeks or treated with MitoQ10 for 8 weeks. In this work, exercise training in SHR reduced blood pressure, and effectively attenuated renal dysfunction, marked by reduced creatinine excretion, albuminuria, blood urea nitrogen, and glomerular sclerosis. Exercise training in SHR reduced MDA levels in plasma and kidneys and suppressed formation of 3-nitrotyrosine in kidneys. Exercise training suppressed mitochondrial ROS and [Formula: see text] formation, enhanced ATP formation, reduced mitochondrial swelling, and restored electron transport chain enzyme activity in kidneys of SHR. Furthermore, exercise training upregulated protein expression of uncoupling protein 2 and manganese superoxide dismutase in kidneys of SHR. In addition, treatment with mitochondria-targeted antioxidant MitoQ10 exhibited similar renal protective effects in SHR. In conclusion, chronic aerobic exercise training preserved mitochondrial function and abated oxidative stress in the kidneys of SHR, which may in part explain the protective effect of exercise on renal function and structure in hypertensive individuals. PMID:25963667

  6. Exercise-induced protection against reperfusion arrhythmia involves stabilization of mitochondrial energetics.

    PubMed

    Alleman, Rick J; Tsang, Alvin M; Ryan, Terence E; Patteson, Daniel J; McClung, Joseph M; Spangenburg, Espen E; Shaikh, Saame Raza; Neufer, P Darrell; Brown, David A

    2016-05-15

    Mitochondria influence cardiac electrophysiology through energy- and redox-sensitive ion channels in the sarcolemma, with the collapse of energetics believed to be centrally involved in arrhythmogenesis. This study was conducted to determine if preservation of mitochondrial membrane potential (ΔΨm) contributes to the antiarrhythmic effect of exercise. We utilized perfused hearts, isolated myocytes, and isolated mitochondria exposed to metabolic challenge to determine the effects of exercise on cardiac mitochondria. Hearts from sedentary (Sed) and exercised (Ex; 10 days of treadmill running) Sprague-Dawley rats were perfused on a two-photon microscope stage for simultaneous measurement of ΔΨm and ECG. After ischemia-reperfusion, the collapse of ΔΨm was commensurate with the onset of arrhythmia. Exercise preserved ΔΨm and decreased the incidence of fibrillation/tachycardia (P < 0.05). Our findings in intact hearts were corroborated in isolated myocytes exposed to in vitro hypoxia-reoxygenation, with Ex rats demonstrating enhanced redox control and sustained ΔΨm during reoxygenation. Finally, we induced anoxia-reoxygenation in isolated mitochondria using high-resolution respirometry with simultaneous measurement of respiration and H2O2 Mitochondria from Ex rats sustained respiration with lower rates of H2O2 emission than Sed rats. Exercise helps sustain postischemic mitochondrial bioenergetics and redox homeostasis, which is associated with preserved ΔΨm and protection against reperfusion arrhythmia. The reduction of fatal ventricular arrhythmias through exercise-induced mitochondrial adaptations indicates that mitochondrial therapeutics may be an effective target for the treatment of heart disease. PMID:26945082

  7. Stress triggers mitochondrial biogenesis to preserve steroidogenesis in Leydig cells.

    PubMed

    Gak, Igor A; Radovic, Sava M; Dukic, Aleksandra R; Janjic, Marija M; Stojkov-Mimic, Natasa J; Kostic, Tatjana S; Andric, Silvana A

    2015-10-01

    Adaptability to stress is a fundamental prerequisite for survival. Mitochondria are a key component of the stress response in all cells. For steroid-hormones-producing cells, including also Leydig cells of testes, the mitochondria are a key control point for the steroid biosynthesis and regulation. However, the mitochondrial biogenesis in steroidogenic cells has never been explored. Here we show that increased mitochondrial biogenesis is the adaptive response of testosterone-producing Leydig cells from stressed rats. All markers of mitochondrial biogenesis together with transcription factors and related kinases are up-regulated in Leydig cells from rats exposed to repeated psychophysical stress. This is followed with increased mitochondrial mass. The expression of PGC1, master regulator of mitochondrial biogenesis and integrator of environmental signals, is stimulated by cAMP-PRKA, cGMP, and β-adrenergic receptors. Accordingly, stress-triggered mitochondrial biogenesis represents an adaptive mechanism and does not only correlate with but also is an essential for testosterone production, being both events depend on the same regulators. Here we propose that all events induced by acute stress, the most common stress in human society, provoke adaptive response of testosterone-producing Leydig cells and activate PGC1, a protein required to make new mitochondria but also protector against the oxidative damage. Given the importance of mitochondria for steroid hormones production and stress response, as well as the role of steroid hormones in stress response and metabolic syndrome, we anticipate our result to be a starting point for more investigations since stress is a constant factor in life and has become one of the most significant health problems in modern societies. PMID:26036344

  8. Exercise-induced heart mitochondrial cholesterol depletion influences the inhibition of mitochondrial swelling.

    PubMed

    Ziolkowski, Wieslaw; Vadhana M S, Dhivya; Kaczor, Jan Jacek; Olek, Robert Antoni; Flis, Damian Jozef; Halon, Malgorzata; Wozniak, Michal; Fedeli, Donatella; Carloni, Manuel; Antosiewicz, Jedrzej; Gabbianelli, Rosita

    2013-10-01

    The significance of the reduction of the cholesterol pool in heart mitochondria after exercise is still unknown. Recently, published data have suggested that cholesterol may influence the components of mitochondrial contact site and affect mitochondrial swelling. Therefore, the aim of this study was to determine whether the decreased cholesterol content in heart mitochondria caused by prolonged swimming may provoke changes in their bioenergetics and result in an increased resistance to calcium chloride-induced mitochondrial swelling. Male Wistar rats were divided into a sedentary control group and an exercise group. The rats exercised for 3 h, burdened with an additional 3% of their body weight. Their hearts were removed immediately after completing the exercise. The left ventricle was divided and used for experiments. Mitochondrial cholesterol content, membrane fluidity and mitochondrial bioenergetics were measured in the control and exercised rat heart mitochondria. To assess whether mitochondrial modifications are linked to disruption of lipid microdomains, methyl-β-cyclodextrin, a well-known lipid microdomain-disrupting agent and cholesterol chelator, was applied to the mitochondria of the control group. Cholesterol depletion, increased membrane fluidity and increased resistance to calcium chloride-induced swelling were observed in postexercise heart crude mitochondrial fraction. Similar results were achieved in control mitochondria treated with 2% methyl-β-cyclodextrin. All of the mitochondrial bioenergetics parameters were similar between the groups. Therefore, the disruption of raft-like microdomains appears to be an adaptive change in the rat heart following exercise. PMID:23733522

  9. Mitochondrial Dysregulation in the Pathogenesis of Diabetes: Potential for Mitochondrial Biogenesis-Mediated Interventions

    PubMed Central

    Joseph, Anna-Maria; Joanisse, Denis R.; Baillot, Richard G.; Hood, David A.

    2012-01-01

    Muscle mitochondrial metabolism is a tightly controlled process that involves the coordination of signaling pathways and factors from both the nuclear and mitochondrial genomes. Perhaps the most important pathway regulating metabolism in muscle is mitochondrial biogenesis. In response to physiological stimuli such as exercise, retrograde signaling pathways are activated that allow crosstalk between the nucleus and mitochondria, upregulating hundreds of genes and leading to higher mitochondrial content and increased oxidation of substrates. With type 2 diabetes, these processes can become dysregulated and the ability of the cell to respond to nutrient and energy fluctuations is diminished. This, coupled with reduced mitochondrial content and altered mitochondrial morphology, has been directly linked to the pathogenesis of this disease. In this paper, we will discuss our current understanding of mitochondrial dysregulation in skeletal muscle as it relates to type 2 diabetes, placing particular emphasis on the pathways of mitochondrial biogenesis and mitochondrial dynamics, and the therapeutic value of exercise and other interventions. PMID:22203837

  10. Quercetin increases brain and muscle mitochondrial biogenesis and exercise tolerance.

    PubMed

    Davis, J Mark; Murphy, E Angela; Carmichael, Martin D; Davis, Ben

    2009-04-01

    Quercetin is one of a broad group of natural polyphenolic flavonoid substances that are being investigated for their widespread health benefits. These benefits have generally been ascribed to its combination of antioxidant and anti-inflammatory activity, but recent in vitro evidence suggests that improved mitochondrial biogenesis could play an important role. In addition, the in vivo effects of quercetin on mitochondrial biogenesis exercise tolerance are unknown. We examined the effects of 7 days of quercetin feedings in mice on markers of mitochondrial biogenesis in skeletal muscle and brain, and on endurance exercise tolerance. Mice were randomly assigned to one of the following three treatment groups: placebo, 12.5 mg/kg quercetin, or 25 mg/kg quercetin. Following 7 days of treatment, mice were killed, and soleus muscle and brain were analyzed for mRNA expression of peroxisome proliferator-activated receptor-gamma coactivator (PGC-1alpha) and sirtuin 1 (SIRT1), and mitochondrial DNA (mtDNA) and cytochrome c. Additional mice underwent a treadmill performance run to fatigue or were placed in voluntary activity wheel cages, and their voluntary activity (distance, time, and peak speed) was recorded. Quercetin increased mRNA expression of PGC-1alpha and SIRT1 (P < 0.05), mtDNA (P < 0.05) and cytochrome c concentration (P < 0.05). These changes in markers of mitochondrial biogenesis were associated with an increase in both maximal endurance capacity (P < 0.05) and voluntary wheel-running activity (P < 0.05). These benefits of querectin on fitness without exercise training may have important implications for enhancement of athletic and military performance and may also extend to prevention and/or treatment of chronic diseases. PMID:19211721

  11. Relationships between exercise, mitochondrial biogenesis and type 2 diabetes.

    PubMed

    Joseph, Anna-Maria; Hood, David A

    2014-01-01

    Skeletal muscle is the major site of insulin-stimulated glucose utilization in the body. Central to this process is oxidative metabolism, which is controlled by mitochondria. Therefore, defects in the biogenesis of this organelle can impact the ability of muscle to oxidize substrates and can have grave consequences on the action of insulin on glucose uptake. In healthy muscle, glucose and free fatty acids (FFAs) are efficiently metabolized preventing the accumulation of harmful lipid by-products. In contrast, in pre-diabetic conditions, reduced oxidative capacity, high levels of reactive oxygen species, and chronic elevations in FFAs culminate in greater intramyocellular lipids and lipid metabolites that interfere with insulin signaling pathways, and contribute to lower insulin sensitivity. While the extent of the involvement of mitochondria in insulin resistance and type 2 diabetes (T2D) is still an ongoing debate, there is compelling evidence to suggest that dysfunction in mitochondria, mediated by changes in gene expression, morphology, and mitochondrial turnover, contributes to the dysregulation of insulin signaling pathways observed with this metabolic syndrome. In the present review, we discuss our current understanding of mitochondrial biogenesis and highlight how dysfunction in key mitochondrial biogenesis pathways may play an important role in the pathogenesis of T2D. Moreover, we provide evidence supporting the therapeutic value of exercise in the prevention and treatment of metabolic syndromes such as T2D. PMID:25226800

  12. Coordination of plant mitochondrial biogenesis: keeping pace with cellular requirements

    PubMed Central

    Welchen, Elina; García, Lucila; Mansilla, Natanael; Gonzalez, Daniel H.

    2014-01-01

    Plant mitochondria are complex organelles that carry out numerous metabolic processes related with the generation of energy for cellular functions and the synthesis and degradation of several compounds. Mitochondria are semiautonomous and dynamic organelles changing in shape, number, and composition depending on tissue or developmental stage. The biogenesis of functional mitochondria requires the coordination of genes present both in the nucleus and the organelle. In addition, due to their central role, all processes held inside mitochondria must be finely coordinated with those in other organelles according to cellular demands. Coordination is achieved by transcriptional control of nuclear genes encoding mitochondrial proteins by specific transcription factors that recognize conserved elements in their promoter regions. In turn, the expression of most of these transcription factors is linked to developmental and environmental cues, according to the availability of nutrients, light–dark cycles, and warning signals generated in response to stress conditions. Among the signals impacting in the expression of nuclear genes, retrograde signals that originate inside mitochondria help to adjust mitochondrial biogenesis to organelle demands. Adding more complexity, several nuclear encoded proteins are dual localized to mitochondria and either chloroplasts or the nucleus. Dual targeting might establish a crosstalk between the nucleus and cell organelles to ensure a fine coordination of cellular activities. In this article, we discuss how the different levels of coordination of mitochondrial biogenesis interconnect to optimize the function of the organelle according to both internal and external demands. PMID:24409193

  13. Impaired Mitochondrial Biogenesis in Adipose Tissue in Acquired Obesity.

    PubMed

    Heinonen, Sini; Buzkova, Jana; Muniandy, Maheswary; Kaksonen, Risto; Ollikainen, Miina; Ismail, Khadeeja; Hakkarainen, Antti; Lundbom, Jesse; Lundbom, Nina; Vuolteenaho, Katriina; Moilanen, Eeva; Kaprio, Jaakko; Rissanen, Aila; Suomalainen, Anu; Pietiläinen, Kirsi H

    2015-09-01

    Low mitochondrial number and activity have been suggested as underlying factors in obesity, type 2 diabetes, and metabolic syndrome. However, the stage at which mitochondrial dysfunction manifests in adipose tissue after the onset of obesity remains unknown. Here we examined subcutaneous adipose tissue (SAT) samples from healthy monozygotic twin pairs, 22.8-36.2 years of age, who were discordant (ΔBMI >3 kg/m(2), mean length of discordance 6.3 ± 0.3 years, n = 26) and concordant (ΔBMI <3 kg/m(2), n = 14) for body weight, and assessed their detailed mitochondrial metabolic characteristics: mitochondrial-related transcriptomes with dysregulated pathways, mitochondrial DNA (mtDNA) amount, mtDNA-encoded transcripts, and mitochondrial oxidative phosphorylation (OXPHOS) protein levels. We report global expressional downregulation of mitochondrial oxidative pathways with concomitant downregulation of mtDNA amount, mtDNA-dependent translation system, and protein levels of the OXPHOS machinery in the obese compared with the lean co-twins. Pathway analysis indicated downshifting of fatty acid oxidation, ketone body production and breakdown, and the tricarboxylic acid cycle, which inversely correlated with adiposity, insulin resistance, and inflammatory cytokines. Our results suggest that mitochondrial biogenesis, oxidative metabolic pathways, and OXPHOS proteins in SAT are downregulated in acquired obesity, and are associated with metabolic disturbances already at the preclinical stage. PMID:25972572

  14. Promotion of mitochondrial biogenesis by necdin protects neurons against mitochondrial insults

    PubMed Central

    Hasegawa, Koichi; Yasuda, Toru; Shiraishi, Chinatsu; Fujiwara, Kazushiro; Przedborski, Serge; Mochizuki, Hideki; Yoshikawa, Kazuaki

    2016-01-01

    Neurons rely heavily on mitochondria for their function and survival. Mitochondrial dysfunction contributes to the pathogenesis of neurodegenerative diseases such as Parkinson's disease. PGC-1α is a master regulator of mitochondrial biogenesis and function. Here we identify necdin as a potent PGC-1α stabilizer that promotes mitochondrial biogenesis via PGC-1α in mammalian neurons. Expression of genes encoding mitochondria-specific proteins decreases significantly in necdin-null cortical neurons, where mitochondrial function and expression of the PGC-1α protein are reduced. Necdin strongly stabilizes PGC-1α by inhibiting its ubiquitin-dependent degradation. Forced expression of necdin enhances mitochondrial function in primary cortical neurons and human SH-SY5Y neuroblastoma cells to prevent mitochondrial respiratory chain inhibitor-induced degeneration. Moreover, overexpression of necdin in the substantia nigra in vivo of adult mice protects dopaminergic neurons against degeneration in experimental Parkinson's disease. These data reveal that necdin promotes mitochondrial biogenesis through stabilization of endogenous PGC-1α to exert neuroprotection against mitochondrial insults. PMID:26971449

  15. 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. PMID:26770647

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

    PubMed Central

    Li, Haiying; Miao, Weiguo; Ma, Jingfen; Xv, Zhen; 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. PMID:26770647

  17. Resveratrol Regulates Mitochondrial Biogenesis and Fission/Fusion to Attenuate Rotenone-Induced Neurotoxicity

    PubMed Central

    Peng, Kaige; Tao, Yuan; Zhang, Jun; Wang, Jian; Ye, Feng; Dan, Guorong; Zhao, Yuanpeng; Cai, Ying; Zhao, Jiqing; Wu, Qiang; Zou, Zhongmin; Cao, Jia; Sai, Yan

    2016-01-01

    It has been confirmed that mitochondrial impairment may underlie both sporadic and familial Parkinson's disease (PD). Mitochondrial fission/fusion and biogenesis are key processes in regulating mitochondrial homeostasis. Therefore, we explored whether the protective effect of resveratrol in rotenone-induced neurotoxicity was associated with mitochondrial fission/fusion and biogenesis. The results showed that resveratrol could not only promote mitochondrial mass and DNA copy number but also improve mitochondrial homeostasis and neuron function in rats and PC12 cells damaged by rotenone. We also observed effects with alterations in proteins known to regulate mitochondrial fission/fusion and biogenesis in rotenone-induced neurotoxicity. Therefore, our findings suggest that resveratrol may prevent rotenone-induced neurotoxicity through regulating mitochondrial fission/fusion and biogenesis. PMID:26770656

  18. 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...

  19. CLUH regulates mitochondrial biogenesis by binding mRNAs of nuclear-encoded mitochondrial proteins

    PubMed Central

    Gao, Jie; Schatton, Désirée; Martinelli, Paola; Hansen, Henriette; Pla-Martin, David; Barth, Esther; Becker, Christian; Altmueller, Janine; Frommolt, Peter; Sardiello, Marco

    2014-01-01

    Mitochondrial function requires coordination of two genomes for protein biogenesis, efficient quality control mechanisms, and appropriate distribution of the organelles within the cell. How these mechanisms are integrated is currently not understood. Loss of the Clu1/CluA homologue (CLUH) gene led to clustering of the mitochondrial network by an unknown mechanism. We find that CLUH is coregulated both with genes encoding mitochondrial proteins and with genes involved in ribosomal biogenesis and translation. Our functional analysis identifies CLUH as a cytosolic messenger ribonucleic acid (RNA; mRNA)–binding protein. RNA immunoprecipitation experiments followed by next-generation sequencing demonstrated that CLUH specifically binds a subset of mRNAs encoding mitochondrial proteins. CLUH depletion decreased the levels of proteins translated by target transcripts and caused mitochondrial clustering. A fraction of CLUH colocalizes with tyrosinated tubulin and can be detected close to mitochondria, suggesting a role in regulating transport or translation of target transcripts close to mitochondria. Our data unravel a novel mechanism linking mitochondrial biogenesis and distribution. PMID:25349259

  20. Quercetin induces mitochondrial biogenesis through activation of HO-1 in HepG2 cells.

    PubMed

    Rayamajhi, Nabin; Kim, Seul-Ki; Go, Hiroe; Joe, Yeonsoo; Callaway, Zak; Kang, Jae-Gu; Ryter, Stefan W; Chung, Hun Taeg

    2013-01-01

    The regeneration of mitochondria by regulated biogenesis plays an important homeostatic role in cells and tissues and furthermore may provide an adaptive mechanism in certain diseases such as sepsis. The heme oxygenase (HO-1)/carbon monoxide (CO) system is an inducible cytoprotective mechanism in mammalian cells. Natural antioxidants can provide therapeutic benefit, in part, by inducing the HO-1/CO system. This study focused on the mechanism by which the natural antioxidant quercetin can induce mitochondrial biogenesis in HepG2 cells. We found that quercetin treatment induced expression of mitochondrial biogenesis activators (PGC-1 α , NRF-1, TFAM), mitochondrial DNA (mtDNA), and proteins (COX IV) in HepG2 cells. The HO inhibitor SnPP and the CO scavenger hemoglobin reversed the effects of quercetin on mitochondrial biogenesis in HepG2 cells. The stimulatory effects of quercetin on mitochondrial biogenesis could be recapitulated in vivo in liver tissue and antagonized by SnPP. Finally, quercetin conferred an anti-inflammatory effect in the liver of mice treated with LPS and prevented impairment of mitochondrial biogenesis by LPS in vivo. These salutary effects of quercetin in vivo were also antagonized by SnPP. Thus, our results suggest that quercetin enhances mitochondrial biogenesis mainly via the HO-1/CO system in vitro and in vivo. The beneficial effects of quercetin may provide a therapeutic basis in inflammatory diseases and sepsis. PMID:24288584

  1. Resveratrol Induces Hepatic Mitochondrial Biogenesis Through the Sequential Activation of Nitric Oxide and Carbon Monoxide Production

    PubMed Central

    Kim, Seul-Ki; Joe, Yeonsoo; Zheng, Min; Kim, Hyo Jeong; Yu, Jae-Kyoung; Cho, Gyeong Jae; Chang, Ki Churl; Kim, Hyoung Kyu; Han, Jin; Ryter, Stefan W.

    2014-01-01

    Abstract Aims: Nitric oxide (NO) can induce mitochondrial biogenesis in cultured cells, through increased guanosine 3′,5′-monophosphate (cGMP), and activation of peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α). We sought to determine the role of NO, heme oxygenase-1 (HO-1), and its reaction product (carbon monoxide [CO]) in the induction of mitochondrial biogenesis by the natural antioxidant resveratrol. Results: S-nitroso-N-acetylpenicillamine (SNAP), an NO donor, induced mitochondrial biogenesis in HepG2 hepatoma cells, and in vivo, through stimulation of PGC-1α. NO-induced mitochondrial biogenesis required cGMP, and was mimicked by the cGMP analogue (8-bromoguanosine 3′,5′-cyclic monophosphate [8-Br-cGMP]). Activation of mitochondrial biogenesis by SNAP required HO-1, as it could be reversed by genetic interference of HO-1; and by treatment with the HO inhibitor tin-protoporphyrin-IX (SnPP) in vitro and in vivo. Cobalt protoporphyrin (CoPP)-IX, an HO-1 inducing agent, stimulated mitochondrial biogenesis in HepG2 cells, which could be reversed by the CO scavenger hemoglobin. Application of CO, using the CO-releasing molecule-3 (CORM-3), stimulated mitochondrial biogenesis in HepG2 cells, in a cGMP-dependent manner. Both CoPP and CORM-3-induced mitochondrial biogenesis required NF-E2-related factor-2 (Nrf2) activation and phosphorylation of Akt. The natural antioxidant resveratrol induced mitochondrial biogenesis in HepG2 cells, in a manner dependent on NO biosynthesis, cGMP synthesis, Nrf2-dependent HO-1 activation, and endogenous CO production. Furthermore, resveratrol preserved mitochondrial biogenesis during lipopolysaccharides-induced hepatic inflammation in vivo. Innovation and Conclusions: The complex interplay between endogenous NO and CO production may underlie the mechanism by which natural antioxidants induce mitochondrial biogenesis. Strategies aimed at improving mitochondrial biogenesis may be used as therapeutics for the treatment of diseases involving mitochondrial dysfunction. Antioxid. Redox Signal. 20, 2589–2605. PMID:24041027

  2. Sirt3 Protects Cortical Neurons against Oxidative Stress via Regulating Mitochondrial Ca2+ and Mitochondrial Biogenesis

    PubMed Central

    Dai, Shu-Hui; Chen, Tao; Wang, Yu-Hai; Zhu, Jie; Luo, Peng; Rao, Wei; Yang, Yue-Fan; Fei, Zhou; Jiang, Xiao-Fan

    2014-01-01

    Oxidative stress is a well-established event in the pathology of several neurobiological diseases. Sirt3 is a nicotinamide adenine nucleotide (NAD+)-dependent protein deacetylase that regulates mitochondrial function and metabolism in response to caloric restriction and stress. This study aims to investigate the role of Sirt3 in H2O2 induced oxidative neuronal injury in primary cultured rat cortical neurons. We found that H2O2 treatment significantly increased the expression of Sirt3 in a time-dependent manner at both mRNA and protein levels. Knockdown of Sirt3 with a specific small interfering RNA (siRNA) exacerbated H2O2-induced neuronal injury, whereas overexpression of Sirt3 by lentivirus transfection inhibited H2O2-induced neuronal damage reduced the generation of reactive oxygen species (ROS), and increased the activities of endogenous antioxidant enzymes. In addition, the intra-mitochondrial Ca2+ overload, but not cytosolic Ca2+ increase after H2O2 treatment, was strongly attenuated after Sirt3 overexpression. Overexpression of Sirt3 also increased the content of mitochondrial DNA (mtDNA) and the expression of mitochondrial biogenesis related transcription factors. All these results suggest that Sirt3 acts as a prosurvival factor playing an essential role to protect cortical neurons under H2O2 induced oxidative stress, possibly through regulating mitochondrial Ca2+ homeostasis and mitochondrial biogenesis. PMID:25196599

  3. 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.

  4. 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. PMID:26902121

  5. The CO/HO system reverses inhibition of mitochondrial biogenesis and prevents murine doxorubicin cardiomyopathy

    PubMed Central

    Suliman, Hagir B.; Carraway, Martha Sue; Ali, Abdelwahid S.; Reynolds, Chrystal M.; Welty-Wolf, Karen E.; Piantadosi, Claude A.

    2007-01-01

    The clinical utility of anthracycline anticancer agents, especially doxorubicin, is limited by a progressive toxic cardiomyopathy linked to mitochondrial damage and cardiomyocyte apoptosis. Here we demonstrate that the post-doxorubicin mouse heart fails to upregulate the nuclear program for mitochondrial biogenesis and its associated intrinsic antiapoptosis proteins, leading to severe mitochondrial DNA (mtDNA) depletion, sarcomere destruction, apoptosis, necrosis, and excessive wall stress and fibrosis. Furthermore, we exploited recent evidence that mitochondrial biogenesis is regulated by the CO/heme oxygenase (CO/HO) system to ameliorate doxorubicin cardiomyopathy in mice. We found that the myocardial pathology was averted by periodic CO inhalation, which restored mitochondrial biogenesis and circumvented intrinsic apoptosis through caspase-3 and apoptosis-inducing factor. Moreover, CO simultaneously reversed doxorubicin-induced loss of DNA binding by GATA-4 and restored critical sarcomeric proteins. In isolated rat cardiac cells, HO-1 enzyme overexpression prevented doxorubicin-induced mtDNA depletion and apoptosis via activation of Akt1/PKB and guanylate cyclase, while HO-1 gene silencing exacerbated doxorubicin-induced mtDNA depletion and apoptosis. Thus doxorubicin disrupts cardiac mitochondrial biogenesis, which promotes intrinsic apoptosis, while CO/HO promotes mitochondrial biogenesis and opposes apoptosis, forestalling fibrosis and cardiomyopathy. These findings imply that the therapeutic index of anthracycline cancer chemotherapeutics can be improved by the protection of cardiac mitochondrial biogenesis. PMID:18037988

  6. The protease Omi regulates mitochondrial biogenesis through the GSK3β/PGC-1α pathway

    PubMed Central

    Xu, R; Hu, Q; Ma, Q; Liu, C; Wang, G

    2014-01-01

    Loss of the mitochondrial protease activity of Omi causes mitochondrial dysfunction, neurodegeneration with parkinsonian features and premature death in mnd2 (motor neuron degeneration 2) mice. However, the detailed mechanisms underlying this pathology remain largely unknown. Here, we report that Omi participates in the process of mitochondrial biogenesis, which has been linked to several neurodegenerative diseases. The mitochondrial biogenesis is deficit in mnd2 mice, evidenced by severe decreases of mitochondrial components, mitochondrial DNA and mitochondrial density. Omi cleaves glycogen synthase kinase 3β (GSK3β), a kinase promoting PPARγ coactivator-1α (PGC-1α) degradation, to regulate PGC-1α, a factor important for the mitochondrial biogenesis. In mnd2 mice, GSK3β abundance is increased and PGC-1α abundance is decreased significantly. Inhibition of GSK3β by SB216763 or overexpression of PGC-1α can restore mitochondrial biogenesis in mnd2 mice or Omi-knockdown N2a cells. Furthermore, there is a significant improvement of the movement ability of mnd2 mice after SB216763 treatment. Thus, our study identified Omi as a novel regulator of mitochondrial biogenesis, involving in Omi protease-deficient-induced neurodegeneration. PMID:25118933

  7. Exercise Increases Mitochondrial PGC-1α Content and Promotes Nuclear-Mitochondrial Cross-talk to Coordinate Mitochondrial Biogenesis*

    PubMed Central

    Safdar, Adeel; Little, Jonathan P.; Stokl, Andrew J.; Hettinga, Bart P.; Akhtar, Mahmood; Tarnopolsky, Mark A.

    2011-01-01

    Endurance exercise is known to induce metabolic adaptations in skeletal muscle via activation of the transcriptional co-activator peroxisome proliferator-activated receptor γ co-activator 1α (PGC-1α). PGC-1α regulates mitochondrial biogenesis via regulating transcription of nuclear-encoded mitochondrial genes. Recently, PGC-1α has been shown to reside in mitochondria; however, the physiological consequences of mitochondrial PGC-1α remain unknown. We sought to delineate if an acute bout of endurance exercise can mediate an increase in mitochondrial PGC-1α content where it may co-activate mitochondrial transcription factor A to promote mtDNA transcription. C57Bl/6J mice (n = 12/group; ♀ = ♂) were randomly assigned to sedentary (SED), forced-endurance (END) exercise (15 m/min for 90 min), or forced endurance +3 h of recovery (END+3h) group. The END group was sacrificed immediately after exercise, whereas the SED and END+3h groups were euthanized 3 h after acute exercise. Acute exercise coordinately increased the mRNA expression of nuclear and mitochondrial DNA-encoded mitochondrial transcripts. Nuclear and mitochondrial abundance of PGC-1α in END and END+3h groups was significantly higher versus SED mice. In mitochondria, PGC-1α is in a complex with mitochondrial transcription factor A at mtDNA D-loop, and this interaction was positively modulated by exercise, similar to the increased binding of PGC-1α at the NRF-1 promoter. We conclude that in response to acute altered energy demands, PGC-1α re-localizes into nuclear and mitochondrial compartments where it functions as a transcriptional co-activator for both nuclear and mitochondrial DNA transcription factors. These results suggest that PGC-1α may dynamically facilitate nuclear-mitochondrial DNA cross-talk to promote net mitochondrial biogenesis. PMID:21245132

  8. The β2-Adrenoceptor Agonist Formoterol Stimulates Mitochondrial Biogenesis

    PubMed Central

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

    2012-01-01

    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 β3-AR agonist), and formoterol (selective β2-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 β2-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 that increased mitochondrial respiratory capacity. These data provide compelling evidence for the use and development of β2-AR ligands for therapeutic MB. PMID:22490378

  9. Role of mitochondrial inner membrane organizing system in protein biogenesis of the mitochondrial outer membrane

    PubMed Central

    Bohnert, Maria; Wenz, Lena-Sophie; Zerbes, Ralf M.; Horvath, Susanne E.; Stroud, David A.; von der Malsburg, Karina; Müller, Judith M.; Oeljeklaus, Silke; Perschil, Inge; Warscheid, Bettina; Chacinska, Agnieszka; Veenhuis, Marten; van der Klei, Ida J.; Daum, Günther; Wiedemann, Nils; Becker, Thomas; Pfanner, Nikolaus; van der Laan, Martin

    2012-01-01

    Mitochondria contain two membranes, the outer membrane and the inner membrane with folded cristae. The mitochondrial inner membrane organizing system (MINOS) is a large protein complex required for maintaining inner membrane architecture. MINOS interacts with both preprotein transport machineries of the outer membrane, the translocase of the outer membrane (TOM) and the sorting and assembly machinery (SAM). It is unknown, however, whether MINOS plays a role in the biogenesis of outer membrane proteins. We have dissected the interaction of MINOS with TOM and SAM and report that MINOS binds to both translocases independently. MINOS binds to the SAM complex via the conserved polypeptide transport–associated domain of Sam50. Mitochondria lacking mitofilin, the large core subunit of MINOS, are impaired in the biogenesis of β-barrel proteins of the outer membrane, whereas mutant mitochondria lacking any of the other five MINOS subunits import β-barrel proteins in a manner similar to wild-type mitochondria. We show that mitofilin is required at an early stage of β-barrel biogenesis that includes the initial translocation through the TOM complex. We conclude that MINOS interacts with TOM and SAM independently and that the core subunit mitofilin is involved in biogenesis of outer membrane β-barrel proteins. PMID:22918945

  10. 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. PMID:20473509

  11. 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. PMID:24228194

  12. Mild heat stress induces mitochondrial biogenesis in C2C12 myotubes.

    PubMed

    Liu, Chien-Ting; Brooks, George A

    2012-02-01

    During endurance exercise, most (≈75%) of the energy derived from the oxidation of metabolic fuels and ATP hydrolysis of muscle contraction is liberated as heat, the accumulation of which leads to an increase in body temperature. For example, the temperature of exercising muscles can rise to 40°C. Although severe heat injury can be deleterious, several beneficial effects of mild heat stress (HS), such as the improvement of insulin sensitivity in patients with type 2 diabetes, have been reported. However, among all cellular events induced by mild HS from physical activities, the direct effects and mechanisms of mild HS on mitochondrial biogenesis in skeletal muscle are least characterized. AMP-activated protein kinase (AMPK) and sirtuin 1 (SIRT1) are key energy-sensing molecules regulating mitochondrial biogenesis. In C2C12 myotubes, we found that 1 h mild HS at 40°C upregulated both AMPK activity and SIRT1 expression, as well as increased the expression of several mitochondrial biogenesis regulatory genes including peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α) and transcription factors involved in mitochondrial biogenesis. In particular, PGC-1α expression was found to be transcriptionally regulated by mild HS. Additionally, after repeated mild HS for 5 days, protein levels of PGC-1α and several mitochondrial oxidative phosphorylation subunits were also upregulated. Repeated mild HS also significantly increased mitochondrial DNA copy number. In conclusion, these data show that mild HS is sufficient to induce mitochondrial biogenesis in C2C12 myotubes. Temperature-induced mitochondrial biogenesis correlates with activation of the AMPK-SIRT1-PGC-1α pathway. Therefore, it is possible that muscle heat production during exercise plays a role in mitochondrial biogenesis. PMID:22052865

  13. Resveratrol protects cardiomyocytes from oxidative stress through SIRT1 and mitochondrial biogenesis signaling pathways.

    PubMed

    Li, Yong-guang; Zhu, Wei; Tao, Jian-ping; Xin, Ping; Liu, Ming-ya; Li, Jing-bo; Wei, Meng

    2013-08-23

    Reactive oxygen species (ROS) is generated by oxidative stress and plays an important role in various cardiac pathologies. The SIRT1 signaling pathway and mitochondrial biogenesis play essential roles in mediating the production of ROS. SIRT1 activated by resveratrol protects cardiomyocytes from oxidative stress, but the exact mechanisms by which SIRT1 prevents oxidative stress, and its relationship with mitochondrial biogenesis, remain unclear. In this study, it was observed that after stimulation with 50μMH2O2 for 6h, H9C2 cells produced excessive ROS and downregulated SIRT1. The mitochondrial protein NDUFA13 was also downregulated by ROS mediated by SIRT1. Resveratrol induced the expression of SIRT1 and mitochondrial genes NDUFA1, NDUFA2, NDUFA13 and Mn-SOD. However, the production of these genes was reversed by SIRT1 inhibitor nicotinamide. These results suggest that resveratrol inhibits ROS generation in cardiomyocytes via SIRT1 and mitochondrial biogenesis signaling pathways. PMID:23891692

  14. GPER mediates the effects of 17β-estradiol in cardiac mitochondrial biogenesis and function.

    PubMed

    Sbert-Roig, Miquel; Bauzá-Thorbrügge, Marco; Galmés-Pascual, Bel M; Capllonch-Amer, Gabriela; García-Palmer, Francisco J; Lladó, Isabel; Proenza, Ana M; Gianotti, Magdalena

    2016-01-15

    Considering the sexual dimorphism described in cardiac mitochondrial function and oxidative stress, we aimed to investigate the role of 17β-estradiol (E2) in these sex differences and the contribution of E2 receptors to these effects. As a model of chronic deprivation of ovarian hormones, we used ovariectomized (OVX) rats, half of which were treated with E2. Ovariectomy decreased markers of cardiac mitochondrial biogenesis and function and also increased oxidative stress, whereas E2 counteracted these effects. In H9c2 cardiomyocytes we observed that G-protein coupled estrogen receptor (GPER) agonist mimicked the effects of E2 in enhancing mitochondrial function and biogenesis, whereas GPER inhibitor neutralized them. These data suggest that E2 enhances mitochondrial function and decreases oxidative stress in cardiac muscle, thus it could be responsible for the sexual dimorphism observed in mitochondrial biogenesis and function in this tissue. These effects seem to be mediated through GPER stimulation. PMID:26628039

  15. Sirtuin 1-mediated Effects of Exercise and Resveratrol on Mitochondrial Biogenesis*

    PubMed Central

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

    2013-01-01

    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. PMID:23329826

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

    PubMed

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

    2013-03-01

    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. PMID:23329826

  17. 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

  18. Mitochondrial Rab GAPs govern autophagosome biogenesis during mitophagy.

    PubMed

    Yamano, Koji; Fogel, Adam I; Wang, Chunxin; van der Bliek, Alexander M; Youle, Richard J

    2014-01-01

    Damaged mitochondria can be selectively eliminated by mitophagy. Although two gene products mutated in Parkinson's disease, PINK1, and Parkin have been found to play a central role in triggering mitophagy in mammals, how the pre-autophagosomal isolation membrane selectively and accurately engulfs damaged mitochondria remains unclear. In this study, we demonstrate that TBC1D15, a mitochondrial Rab GTPase-activating protein (Rab-GAP), governs autophagosome biogenesis and morphology downstream of Parkin activation. To constrain autophagosome morphogenesis to that of the cargo, TBC1D15 inhibits Rab7 activity and associates with both the mitochondria through binding Fis1 and the isolation membrane through the interactions with LC3/GABARAP family members. Another TBC family member TBC1D17, also participates in mitophagy and forms homodimers and heterodimers with TBC1D15. These results demonstrate that TBC1D15 and TBC1D17 mediate proper autophagic encapsulation of mitochondria by regulating Rab7 activity at the interface between mitochondria and isolation membranes. DOI: http://dx.doi.org/10.7554/eLife.01612.001. PMID:24569479

  19. Mitochondrial Rab GAPs govern autophagosome biogenesis during mitophagy

    PubMed Central

    Yamano, Koji; Fogel, Adam I; Wang, Chunxin; van der Bliek, Alexander M; Youle, Richard J

    2014-01-01

    Damaged mitochondria can be selectively eliminated by mitophagy. Although two gene products mutated in Parkinson’s disease, PINK1, and Parkin have been found to play a central role in triggering mitophagy in mammals, how the pre-autophagosomal isolation membrane selectively and accurately engulfs damaged mitochondria remains unclear. In this study, we demonstrate that TBC1D15, a mitochondrial Rab GTPase-activating protein (Rab-GAP), governs autophagosome biogenesis and morphology downstream of Parkin activation. To constrain autophagosome morphogenesis to that of the cargo, TBC1D15 inhibits Rab7 activity and associates with both the mitochondria through binding Fis1 and the isolation membrane through the interactions with LC3/GABARAP family members. Another TBC family member TBC1D17, also participates in mitophagy and forms homodimers and heterodimers with TBC1D15. These results demonstrate that TBC1D15 and TBC1D17 mediate proper autophagic encapsulation of mitochondria by regulating Rab7 activity at the interface between mitochondria and isolation membranes. DOI: http://dx.doi.org/10.7554/eLife.01612.001 PMID:24569479

  20. Stimulatory Effects of Balanced Deep Sea Water on Mitochondrial Biogenesis and Function

    PubMed Central

    Ha, Byung Geun; Park, Jung-Eun; Cho, Hyun-Jung; Shon, Yun Hee

    2015-01-01

    The worldwide prevalence of metabolic diseases, including obesity and diabetes, is increasing. Mitochondrial dysfunction is recognized as a core feature of these diseases. Emerging evidence also suggests that defects in mitochondrial biogenesis, number, morphology, fusion, and fission, contribute to the development and progression of metabolic diseases. Our previous studies revealed that balanced deep-sea water (BDSW) has potential as a treatment for diabetes and obesity. In this study, we aimed to investigate the mechanism by which BDSW regulates diabetes and obesity by studying its effects on mitochondrial metabolism. To determine whether BDSW regulates mitochondrial biogenesis and function, we investigated its effects on mitochondrial DNA (mtDNA) content, mitochondrial enzyme activity, and the expression of transcription factors and mitochondria specific genes, as well as on the phosphorylation of signaling molecules associated with mitochondria biogenesis and its function in C2C12 myotubes. BDSW increased mitochondrial biogenesis in a time and dose-dependent manner. Quantitative real-time PCR revealed that BDSW enhances gene expression of PGC-1α, NRF1, and TFAM for mitochondrial transcription; MFN1/2 and DRP1 for mitochondrial fusion; OPA1 for mitochondrial fission; TOMM40 and TIMM44 for mitochondrial protein import; CPT-1α and MCAD for fatty acid oxidation; CYTC for oxidative phosphorylation. Upregulation of these genes was validated by increased mitochondria staining, CS activity, CytC oxidase activity, NAD+ to NADH ratio, and the phosphorylation of signaling molecules such as AMPK and SIRT1. Moreover, drinking BDSW remarkably improved mtDNA content in the muscles of HFD-induced obese mice. Taken together, these results suggest that the stimulatory effect of BDSW on mitochondrial biogenesis and function may provide further insights into the regulatory mechanism of BDSW-induced anti-diabetic and anti-obesity action. PMID:26068191

  1. N-acetylcysteine inhibits the upregulation of mitochondrial biogenesis genes in livers from rats fed ethanol chronically

    PubMed Central

    Caro, Andres A.; Bell, Matthew; Ejiofor, Shannon; Zurcher, Grant; Petersen, Dennis R.; Ronis, Martin J. J.

    2014-01-01

    Background Chronic ethanol administration to experimental animals induces hepatic oxidative stress and upregulates mitochondrial biogenesis. The mechanisms by which chronic ethanol upregulates mitochondrial biogenesis have not been fully explored. In this work, we hypothesized that oxidative stress is a factor that triggers mitochondrial biogenesis after chronic ethanol feeding. If our hypothesis is correct, co-administration of antioxidants should prevent upregulation of mitochondrial biogenesis genes. Methods Rats were fed an ethanol-containing diet intragastrically by total enteral nutrition for 150 days, in the absence or presence of the antioxidant N-acetylcysteine (NAC) at 1.7 g/kg/day; control rats were administered isocaloric diets where carbohydrates substituted for ethanol calories. Results Ethanol administration significantly increased hepatic oxidative stress, evidenced as decreased liver total glutathione and GSH/GSSG ratio. These effects were inhibited by co-administration of ethanol and NAC. Chronic ethanol increased the expression of mitochondrial biogenesis genes including peroxisome proliferator activated receptor gamma-coactivator-1 alpha and mitochondrial transcription factor A, and mitochondrial DNA; co-administration of ethanol and NAC prevented these effects. Chronic ethanol administration was associated with decreased mitochondrial mass, inactivation and depletion of mitochondrial complex I and complex IV, and increased hepatic mitochondrial oxidative damage, effects that were not prevented by NAC. Conclusions These results suggest that oxidative stress caused by chronic ethanol triggered the upregulation of mitochondrial biogenesis genes in rat liver, because an antioxidant such as NAC prevented both effects. Because NAC did not prevent liver mitochondrial oxidative damage, extra-mitochondrial effects of reactive oxygen species may regulate mitochondrial biogenesis. In spite of the induction of hepatic mitochondrial biogenesis genes by chronic ethanol, mitochondrial mass and function decreased probably in association with mitochondrial oxidative damage. These results also predict that the effectiveness of NAC as an antioxidant therapy for chronic alcoholism will be limited by its limited antioxidant effects in mitochondria, and its inhibitory effect on mitochondrial biogenesis. PMID:25581647

  2. 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

  3. 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.

  4. 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.

  5. The Effects of NAD+ on Apoptotic Neuronal Death and Mitochondrial Biogenesis and Function after Glutamate Excitotoxicity

    PubMed Central

    Wang, Xiaowan; Li, Hailong; Ding, Shinghua

    2014-01-01

    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. PMID:25387075

  6. Acute Exercise Induced Mitochondrial H2O2 Production in Mouse Skeletal Muscle: Association with p66Shc and FOXO3a Signaling and Antioxidant Enzymes

    PubMed Central

    Wang, Ping; Qi, Zhengtang; Cui, Di; Ding, Shuzhe

    2015-01-01

    Exercise induced skeletal muscle phenotype change involves a complex interplay between signaling pathways and downstream regulators. This study aims to investigate the effect of acute exercise on mitochondrial H2O2 production and its association with p66Shc, FOXO3a, and antioxidant enzymes. Male ICR/CD-1 mice were subjected to an acute exercise. Muscle tissues (gastrocnemius and quadriceps femoris) were taken after exercise to measure mitochondrial H2O2 content, expression of p66Shc and FOXO3a, and the activity of antioxidant enzymes. The results showed that acute exercise significantly increased mitochondrial H2O2 content and expressions of p66Shc and FOXO3a in a time-dependent manner, with a linear correlation between the increase in H2O2 content and p66Shc or FOXO3a expression. The activity of mitochondrial catalase was slightly reduced in the 90 min exercise group, but it was significantly higher in groups with 120 and 150 min exercise compared to that of 90 min exercise group. The activity of SOD was not significantly affected. The results indicate that acute exercise increases mitochondrial H2O2 production in the skeletal muscle, which is associated with the upregulation of p66Shc and FOXO3a. The association of p66Shc and FOXO3a signaling with exercise induced H2O2 generation may play a role in regulating cellular oxidative stress during acute exercise. PMID:25874020

  7. Acute exercise induced mitochondrial H₂O₂ production in mouse skeletal muscle: association with p(66Shc) and FOXO3a signaling and antioxidant enzymes.

    PubMed

    Wang, Ping; Li, Chun Guang; Qi, Zhengtang; Cui, Di; Ding, Shuzhe

    2015-01-01

    Exercise induced skeletal muscle phenotype change involves a complex interplay between signaling pathways and downstream regulators. This study aims to investigate the effect of acute exercise on mitochondrial H2O2 production and its association with p(66Shc), FOXO3a, and antioxidant enzymes. Male ICR/CD-1 mice were subjected to an acute exercise. Muscle tissues (gastrocnemius and quadriceps femoris) were taken after exercise to measure mitochondrial H2O2 content, expression of p(66Shc) and FOXO3a, and the activity of antioxidant enzymes. The results showed that acute exercise significantly increased mitochondrial H2O2 content and expressions of p(66Shc) and FOXO3a in a time-dependent manner, with a linear correlation between the increase in H2O2 content and p(66Shc) or FOXO3a expression. The activity of mitochondrial catalase was slightly reduced in the 90 min exercise group, but it was significantly higher in groups with 120 and 150 min exercise compared to that of 90 min exercise group. The activity of SOD was not significantly affected. The results indicate that acute exercise increases mitochondrial H2O2 production in the skeletal muscle, which is associated with the upregulation of p(66Shc) and FOXO3a. The association of p(66Shc) and FOXO3a signaling with exercise induced H2O2 generation may play a role in regulating cellular oxidative stress during acute exercise. PMID:25874020

  8. Exercise-Mediated Wall Shear Stress Increases Mitochondrial Biogenesis in Vascular Endothelium

    PubMed Central

    Kim, Boa; Lee, Hojun; Kawata, Keisuke; Park, Joon-Young

    2014-01-01

    Objective Enhancing structural and functional integrity of mitochondria is an emerging therapeutic option against endothelial dysfunction. In this study, we sought to investigate the effect of fluid shear stress on mitochondrial biogenesis and mitochondrial respiratory function in endothelial cells (ECs) using in vitro and in vivo complementary studies. Methods and Results Human aortic- or umbilical vein-derived ECs were exposed to laminar shear stress (20 dyne/cm2) for various durations using a cone-and-plate shear apparatus. We observed significant increases in the expression of key genes related to mitochondrial biogenesis and mitochondrial quality control as well as mtDNA content and mitochondrial mass under the shear stress conditions. Mitochondrial respiratory function was enhanced when cells were intermittently exposed to laminar shear stress for 72 hrs. Also, shear-exposed cells showed diminished glycolysis and decreased mitochondrial membrane potential (ΔΨm). Likewise, in in vivo experiments, mice that were subjected to a voluntary wheel running exercise for 5 weeks showed significantly higher mitochondrial content determined by en face staining in the conduit (greater and lesser curvature of the aortic arch and thoracic aorta) and muscle feed (femoral artery) arteries compared to the sedentary control mice. Interestingly, however, the mitochondrial biogenesis was not observed in the mesenteric artery. This region-specific adaptation is likely due to the differential blood flow redistribution during exercise in the different vessel beds. Conclusion Taken together, our findings suggest that exercise enhances mitochondrial biogenesis in vascular endothelium through a shear stress-dependent mechanism. Our findings may suggest a novel mitochondrial pathway by which a chronic exercise may be beneficial for vascular function. PMID:25375175

  9. 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 ...

  10. 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. PMID:25780774

  11. Complementary RNA and Protein Profiling Identifies Iron as a Key Regulator of Mitochondrial Biogenesis

    PubMed Central

    Rensvold, Jarred W.; Ong, Shao-En; Jeevananthan, Athavi; Carr, Steven A.; Mootha, Vamsi K.; Pagliarini, David J.

    2013-01-01

    Summary Mitochondria are centers of metabolism and signaling whose content and function must adapt to changing cellular environments. The biological signals that initiate mitochondrial restructuring and the cellular processes that drive this adaptive response are largely obscure. To better define these systems, we performed matched quantitative genomic and proteomic analyses of mouse muscle cells as they performed mitochondrial biogenesis. We find that proteins involved in cellular iron homeostasis are highly coordinated with this process and that depletion of cellular iron results in a rapid, dose-dependent decrease of select mitochondrial protein levels and oxidative capacity. We further show that this process is universal across a broad range of cell types and fully reversed when iron is reintroduced. Collectively, our work reveals that cellular iron is a key regulator of mitochondrial biogenesis, and provides quantitative data sets that can be leveraged to explore posttranscriptional and posttranslational processes that are essential for mitochondrial adaptation. PMID:23318259

  12. Stomatin-Like Protein 2 Binds Cardiolipin and Regulates Mitochondrial Biogenesis and Function▿

    PubMed Central

    Christie, Darah A.; Lemke, Caitlin D.; Elias, Isaac M.; Chau, Luan A.; Kirchhof, Mark G.; Li, Bo; Ball, Eric H.; Dunn, Stanley D.; Hatch, Grant M.; Madrenas, Joaquín

    2011-01-01

    Stomatin-like protein 2 (SLP-2) is a widely expressed mitochondrial inner membrane protein of unknown function. Here we show that human SLP-2 interacts with prohibitin-1 and -2 and binds to the mitochondrial membrane phospholipid cardiolipin. Upregulation of SLP-2 expression increases cardiolipin content and the formation of metabolically active mitochondrial membranes and induces mitochondrial biogenesis. In human T lymphocytes, these events correlate with increased complex I and II activities, increased intracellular ATP stores, and increased resistance to apoptosis through the intrinsic pathway, ultimately enhancing cellular responses. We propose that the function of SLP-2 is to recruit prohibitins to cardiolipin to form cardiolipin-enriched microdomains in which electron transport complexes are optimally assembled. Likely through the prohibitin functional interactome, SLP-2 then regulates mitochondrial biogenesis and function. PMID:21746876

  13. 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. PMID:23070475

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

    PubMed Central

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

    2012-01-01

    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-1? and MitoNEET, which are established molecules that drive mitochondrial biogenesis and increased mitochondrial oxidative phosphorylation (OXPHOS). Interestingly, both PGC-1? 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-1? 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-1?, PGC-1?, 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. PMID:23070475

  15. 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 ...

  16. 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. PMID:21590341

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

    PubMed Central

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

    2015-01-01

    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. PMID:26596249

  18. 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. PMID:26882442

  19. Transcriptional Control of Mitochondrial Biogenesis and Its Interface with Inflammatory Processes

    PubMed Central

    Piantadosi, Claude A.; Suliman, Hagir B.

    2012-01-01

    Background Cells avoid major mitochondrial damage and energy failure during systemic inflammatory states, such as severe acute infections, by specific targeting of the inflammatory response and by inducing anti-inflammatory and anti-oxidant defenses. Recent evidence indicates that these cell defenses also include mitochondrial biogenesis and the clearance of damaged mitochondria through autophagy. Scope of Review This review addresses a group of transcriptional signaling mechanisms that engage mitochondrial biogenesis, including energy-sensing and redox-regulated transcription factors and co-activators, after major inflammatory events. Major Conclusions Stimulation of the innate immune system by activation of toll-like receptors (TLR) generates pro-inflammatory mediators, such as tumor necrosis factor-α (TNF-α) and interleukin-1β, (IL-1β), necessary for optimal host defense, but which also contribute to mitochondrial damage through oxidative stress and other mechanisms. To protect its energy supply, host cells sense mitochondrial damage and initiate mitochondrial biogenesis under the control of an inducible transcriptional program that also activates anti-oxidant and anti-inflammatory gene expression. This multifunctional network not only increases cellular resistance to metabolic failure, oxidative stress, and cell death, but promotes immune tolerance as shown in the graphical abstract. General Significance The post-inflammatory induction of mitochondrial biogenesis supports metabolic function and cell viability while helping to control inflammation. In clinical settings, patients recovering from severe systemic infections may develop transient immune suppression, placing them at risk for recurrent infection, but there may be therapeutic opportunities to enhance mitochondrial quality control that would improve the resolution of life-threatening host responses to such infections. PMID:22265687

  20. 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. PMID:27166948

  1. 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 is restricted to, but conserved throughout, the protist phylum Euglenozoa. PMID:18393999

  2. Mitochondrial Biogenesis: A Therapeutic Target for Neurodevelopmental Disorders and Neurodegenerative Diseases

    PubMed Central

    Uittenbogaard, Martine; Chiaramello, Anne

    2014-01-01

    In the developing and mature brain, mitochondria act as central hubs for distinct but interwined pathways, necessary for neural development, survival, activity, connectivity and plasticity. In neurons, mitochondria assume diverse functions, such as energy production in the form of ATP, calcium buffering and generation of reactive oxygen species. Mitochondrial dysfunction contributes to a range of neurodevelopmental and neurodegenerative diseases, making mitochondria a potential target for pharmacological-based therapies. Pathogenesis associated with these diseases is accompanied by an increase in mitochondrial mass, a quantitative increase to overcome a qualitative deficiency due to mutated mitochondrial proteins that are either nuclear- or mitochondrial-encoded. This compensatory biological response is maladaptive, as it fails to sufficiently augment the bioenergetically functional mitochondrial mass and correct for the ATP deficit. Since regulation of neuronal mitochondrial biogenesis has been scantily investigated, our current understanding on the network of transcriptional regulators, co-activators and signaling regulators mainly derives from other cellular systems. The purpose of this review is to present the current state of our knowledge and understanding of the transcriptional and signaling cascades controlling neuronal mitochondrial biogenesis and the various therapeutic approaches to enhance the functional mitochondrial mass in the context of neurodevelopmental disorders and adult-onset neurodegenerative diseases. PMID:24606804

  3. 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.

  4. 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

  5. Mitochondrial localization unveils a novel role for GRK2 in organelle biogenesis

    PubMed Central

    Fusco, Anna; Santulli, Gaetano; Sorriento, Daniela; Cipolletta, Ersilia; Garbi, Corrado; Dorn, Gerald W.; Trimarco, Bruno; Feliciello, Antonio; Iaccarino, Guido

    2011-01-01

    Metabolic stimuli such as insulin and insulin like growth factor cause cellular accumulation of G protein Coupled Receptor Kinase 2 (GRK2), which in turn is able to induce insulin resistance. Here we show that in fibroblasts, GRK2 is able to increase ATP cellular content by enhancing mitochondrial biogenesis; also, it antagonizes ATP loss after hypoxia/reperfusion. Interestingly, GRK2 is able to localize in the mitochondrial outer membrane, possibly through one region within the RGS homology domain and one region within the catalytic domain. In vivo, GRK2 removal from the skeletal muscle results in reduced ATP production and impaired tolerance to ischemia. Our data show a novel sub-cellular localization of GRK2 in the mitochondria and an unexpected role in regulating mitochondrial biogenesis and ATP generation. PMID:21983013

  6. Regulation of SIRT1 in aging: Roles in mitochondrial function and biogenesis.

    PubMed

    Yuan, Yujia; Cruzat, Vinicius Fernandes; Newsholme, Philip; Cheng, Jingqiu; Chen, Younan; Lu, Yanrong

    2016-04-01

    Aging is a degenerative process associated with cumulative damage, which leads to cellular dysfunction, tissue failure, and disorders of body function. Silent information regulator-1, also known as sirtuin 1 (SIRT1), has been reported to be involved in the regulation of various important biological processes, including inflammation, mitochondrial biogenesis, as well as cell senescence and consequent aging. The level of SIRT1 is decreased in both transcriptional and postranscriptional conditions during aging, accompanied by attenuated mitochondrial biogenesis, an important component of aging-related diseases. Over the last decade, extensive studies have demonstrated that SIRT1 can activate several transcriptional factors, such as peroxisome proliferator activated receptor γ co-activator 1α (PGC-1α) and hypoxia-inducible factor 1α (HIF-1α) resulting in ameliorated mitochondria biogenesis and extended life span. In this review, we focus on the molecular regulation of SIRT1 and its role in mitochondrial biogenesis during in the context of aging and aging-related diseases. PMID:26923269

  7. 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

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

    SciTech Connect

    Zuo, Luning; Department of Cardiology, Yantaishan Hospital, Yantai, Shandong 264001 ; 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 HUVECs, which was mediated by PKA/CREB pathway.

  9. Exercise-Induced Urticaria

    MedlinePlus

    MENU Return to Web version Exercise-induced Urticaria Overview What is exercise-induced urticaria? Exercise-induced urticaria is a condition that causes hives and other allergic symptoms. It can occur during ...

  10. Mitochondrial Biogenesis: Regulation By Endogenous Gases during Inflammation and Organ Stress

    PubMed Central

    Suliman, Hagir B.; Piantadosi, Claude A.

    2014-01-01

    The influence of mitochondrial dysfunction on pathological states involving inflammatory and/or oxidative stress in tissues that do not show frank cellular apoptosis or necrosis has been rather difficult to unravel, and the literature is replete with contradictory information. Although such discrepancies have many potential causes related to the type of injurious agent, the severity and duration of the injury, and the particular cells and tissues and the functions involved, it is the successful induction of cellular adaptive responses that ultimately governs the resolution of mitochondrial dysfunction and survival of the cell. Much recent attention has been devoted to unraveling the signaling pathways that activate mitochondrial biogenesis and other processes involved in mitochondrial quality control (QC) during inflammatory and oxidative stress with an eye towards the development of novel targets for therapeutic mitigation of the resultant tissue damage. This review provides a brief overview of this emerging field with an emphasis on the role of signaling through the endogenous gases (NO, CO and H2S) and a redox-based approach that brings transparency to key factors that contribute to the resolution of mitochondrial dysfunction and the maintenance of cell vitality. We make the case that targeted stimulation of mitochondrial biogenesis could be a potentially valuable approach for the development of new therapies for the treatment of diseases for which mitochondrial damage is a major consideration. PMID:24606800

  11. Frataxin and Mitochondrial FeS Cluster Biogenesis*

    PubMed Central

    Stemmler, Timothy L.; Lesuisse, Emmanuel; Pain, Debkumar; Dancis, Andrew

    2010-01-01

    Friedreich ataxia is an inherited neurodegenerative disease caused by frataxin deficiency. Frataxin is a conserved mitochondrial protein that plays a role in FeS cluster assembly in mitochondria. FeS clusters are modular cofactors that perform essential functions throughout the cell. They are synthesized by a multistep and multisubunit mitochondrial machinery that includes the scaffold protein Isu for assembling a protein-bound FeS cluster intermediate. Frataxin interacts with Isu, iron, and the cysteine desulfurase Nfs1, which supplies sulfide, thus placing it at the center of mitochondrial FeS cluster biosynthesis. PMID:20522547

  12. Short Term Exercise Induces PGC-1α, Ameliorates Inflammation and Increases Mitochondrial Membrane Proteins but Fails to Increase Respiratory Enzymes in Aging Diabetic Hearts

    PubMed Central

    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. PMID:23936397

  13. 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. ► CoCl{sub 2} supplementation augmented endurance performance and aerobic respiration. ► It increased glucose uptake and metabolism in muscle. ► It enhanced mitochondrial biogenesis in red gastrocnemius muscle.

  14. Pyrroloquinoline Quinone Stimulates Mitochondrial Biogenesis through cAMP Response Element-binding Protein Phosphorylation and Increased PGC-1? Expression*

    PubMed Central

    Chowanadisai, Winyoo; Bauerly, Kathryn A.; Tchaparian, Eskouhie; Wong, Alice; Cortopassi, Gino A.; Rucker, Robert B.

    2010-01-01

    Bioactive compounds reported to stimulate mitochondrial biogenesis are linked to many health benefits such increased longevity, improved energy utilization, and protection from reactive oxygen species. Previously studies have shown that mice and rats fed diets lacking in pyrroloquinoline quinone (PQQ) have reduced mitochondrial content. Therefore, we hypothesized that PQQ can induce mitochondrial biogenesis in mouse hepatocytes. Exposure of mouse Hepa16 cells to 1030 ?m PQQ for 2448 h resulted in increased citrate synthase and cytochrome c oxidase activity, Mitotracker staining, mitochondrial DNA content, and cellular oxygen respiration. The induction of this process occurred through the activation of cAMP response element-binding protein (CREB) and peroxisome proliferator-activated receptor-? coactivator-1? (PGC-1?), a pathway known to regulate mitochondrial biogenesis. PQQ exposure stimulated phosphorylation of CREB at serine 133, activated the promoter of PGC-1?, and increased PGC-1? mRNA and protein expression. PQQ did not stimulate mitochondrial biogenesis after small interfering RNA-mediated reduction in either PGC-1? or CREB expression. Consistent with activation of the PGC-1? pathway, PQQ increased nuclear respiratory factor activation (NRF-1 and NRF-2) and Tfam, TFB1M, and TFB2M mRNA expression. Moreover, PQQ protected cells from mitochondrial inhibition by rotenone, 3-nitropropionic acid, antimycin A, and sodium azide. The ability of PQQ to stimulate mitochondrial biogenesis accounts in part for action of this compound and suggests that PQQ may be beneficial in diseases associated with mitochondrial dysfunction. PMID:19861415

  15. Thyroid Hormone Stimulation of Autophagy Is Essential for Mitochondrial Biogenesis and Activity in Skeletal Muscle.

    PubMed

    Lesmana, Ronny; Sinha, Rohit A; Singh, Brijesh K; Zhou, Jin; Ohba, Kenji; Wu, Yajun; Yau, Winifred Wy; Bay, Boon-Huat; Yen, Paul M

    2016-01-01

    Thyroid hormone (TH) and autophagy share similar functions in regulating skeletal muscle growth, regeneration, and differentiation. Although TH recently has been shown to increase autophagy in liver, the regulation and role of autophagy by this hormone in skeletal muscle is not known. Here, using both in vitro and in vivo models, we demonstrated that TH induces autophagy in a dose- and time-dependent manner in skeletal muscle. TH induction of autophagy involved reactive oxygen species (ROS) stimulation of 5'adenosine monophosphate-activated protein kinase (AMPK)-Mammalian target of rapamycin (mTOR)- Unc-51-like kinase 1 (Ulk1) signaling. TH also increased mRNA and protein expression of key autophagy genes, microtubule-associated protein light chain 3 (LC3), Sequestosome 1 (p62), and Ulk1, as well as genes that modulated autophagy and Forkhead box O (FOXO) 1/3a. TH increased mitochondrial protein synthesis and number as well as basal mitochondrial O2 consumption, ATP turnover, and maximal respiratory capacity. Surprisingly, mitochondrial activity and biogenesis were blunted when autophagy was blocked in muscle cells by Autophagy-related gene (Atg)5 short hairpin RNA (shRNA). Induction of ROS and 5'adenosine monophosphate-activated protein kinase (AMPK) by TH played a significant role in the up-regulation of Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PPARGC1A), the key regulator of mitochondrial synthesis. In summary, our findings showed that TH-mediated autophagy was essential for stimulation of mitochondrial biogenesis and activity in skeletal muscle. Moreover, autophagy and mitochondrial biogenesis were coupled in skeletal muscle via TH induction of mitochondrial activity and ROS generation. PMID:26562261

  16. Triiodothyronine induces lipid oxidation and mitochondrial biogenesis in rat Harderian gland.

    PubMed

    Santillo, A; Burrone, L; Falvo, S; Senese, R; Lanni, A; Chieffi Baccari, G

    2013-10-01

    The rat Harderian gland (HG) is an orbital gland producing a copious lipid secretion. Recent studies indicate that its secretory activity is regulated by thyroid hormones. In this study, we found that both isoforms of the thyroid hormone receptor (Trα (Thra) and Trβ (Thrb)) are expressed in rat HGs. Although Thra is expressed at a higher level, only Thrb is regulated by triiodothyronine (T3). Because T3 induces an increase in lipid metabolism in rat HGs, we investigated the effects of an animal's thyroid state on the expression levels of carnitine palmitoyltransferase-1A (Cpt1a) and carnitine palmitoyltransferase-1B (Cpt1b) and acyl-CoA oxidase (Acox1) (rate-limiting enzymes in mitochondrial and peroxisomal fatty acid oxidation respectively), as well as on the mitochondrial compartment, thereby correlating mitochondrial activity and biogenesis with morphological analysis. We found that hypothyroidism decreased the expression of Cpt1b and Acox1 mRNA, whereas the administration of T3 to hypothyroid rats increased transcript levels. Respiratory parameters and catalase protein levels provided further evidence that T3 modulates mitochondrial and peroxisomal activities. Furthermore, in hypothyroid rat HGs, the mitochondrial number and their total area decreased with respect to the controls, whereas the average area of the individual mitochondrion did not change. However, the average area of the individual mitochondrion was reduced by ∼50% in hypothyroid T3-treated HGs, and the mitochondrial number and the total area of the mitochondrial compartment increased. The mitochondrial morphometric data correlated well with the molecular results. Indeed, hypothyroid status did not modify the expression of mitochondrial biogenesis genes such as Ppargc1a, Nrf1 and Tfam, whereas T3 treatment increased the expression level of these genes. PMID:23873539

  17. 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

    2015-01-01

    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 contribute to its beneficial properties described in numerous other models of tissue injury. PMID:25569804

  18. 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

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

    PubMed Central

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

    2015-01-01

    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 contribute to its beneficial properties described in numerous other models of tissue injury. PMID:25569804

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

    PubMed

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

    2015-08-01

    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 biogenesis. PMID:26024684

  1. 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

  2. 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.

  3. 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

    2016-02-01

    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. PMID:26566717

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

    PubMed Central

    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

    ABSTRACT 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. PMID:26566717

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

    PubMed

    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

    2012-02-01

    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

  6. 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.-Cho, Y., Hazen, B. C., Gandra, P. G., Ward, S. R., Schenk, S., Russell, A. P., Kralli, A. Perm1 enhances mitochondrial biogenesis, oxidative capacity, and fatigue resistance in adult skeletal muscle. PMID:26481306

  7. 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. PMID:25582749

  8. 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

  9. Rev-erb-α modulates skeletal muscle oxidative capacity by regulating mitochondrial biogenesis and autophagy

    PubMed Central

    Woldt, Estelle; Sebti, Yasmine; Solt, Laura A.; Duhem, Christian; Lancel, Steve; Eeckhoute, Jérôme; Hesselink, Matthijs K.C.; Paquet, Charlotte; Delhaye, Stéphane; Shin, Youseung; Kamenecka, Theodore M.; Schaart, Gert; Lefebvre, Philippe; Nevière, Rémi; Burris, Thomas P.; Schrauwen, Patrick; Staels, Bart; Duez, Hélène

    2013-01-01

    The nuclear receptor Rev-erb-α modulates hepatic lipid and glucose metabolism, adipogenesis and the inflammatory response in macrophages. We show here that Rev-erb-α is highly expressed in oxidative skeletal muscle and plays a role in mitochondrial biogenesis and oxidative function, in gain- and loss-of function studies. Rev-erb-α-deficiency in skeletal muscle leads to reduced mitochondrial content and oxidative function, resulting in compromised exercise capacity. This phenotype was recapitulated in isolated fibers and in muscle cells upon Rev-erbα knock-down, while Rev-erb-α over-expression increased the number of mitochondria with improved respiratory capacity. Rev-erb-α-deficiency resulted in deactivation of the Stk11–Ampk–Sirt1–Ppargc1-α signaling pathway, whereas autophagy was up-regulated, resulting in both impaired mitochondrial biogenesis and increased clearance. Muscle over-expression or pharmacological activation of Rev-erb-α increased respiration and exercise capacity. This study identifies Rev-erb-α as a pharmacological target which improves muscle oxidative function by modulating gene networks controlling mitochondrial number and function. PMID:23852339

  10. Cyclovirobuxine D Attenuates Doxorubicin-Induced Cardiomyopathy by Suppression of Oxidative Damage and Mitochondrial Biogenesis Impairment

    PubMed Central

    Guo, Qian; Guo, Jiabin; Yang, Rong; Peng, Hui; Zhao, Jun; Li, Li; Peng, Shuangqing

    2015-01-01

    The clinical application of doxorubicin (DOX) is compromised by its cardiac toxic effect. Cyclovirobuxine D (CVB-D) is a steroid alkaloid extracted from a traditional Chinese medicine, Buxus microphylla. Our results showed that CVB-D pretreatment markedly attenuated DOX-induced cardiac contractile dysfunction and histological alterations. By using TUNEL assay and western blot analysis, we found that CVB-D pretreatment reduced DOX-induced apoptosis of myocardial cells and mitochondrial cytochrome c release to cytosol. CVB-D pretreatment ameliorated DOX-induced cardiac oxidative damage including lipid peroxidation and protein carbonylation and a decrease in the ratio of reduced glutathione (GSH) to oxidized glutathione (GSSG). Moreover, CVB-D was found to prevent DOX-induced mitochondrial biogenesis impairment as evidenced by preservation of peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) and nuclear respiratory factor 1 (NRF1), as well as mitochondrial DNA copy number. These findings demonstrate that CVB-D protects against DOX-induced cardiomyopathy, at least in part, by suppression of oxidative damage and mitochondrial biogenesis impairment. PMID:26075032

  11. 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 type2 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 carboxylase2, 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? co-activator-1?. 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 type2 diabetes. PMID:25261498

  12. β-Hydroxy-β-methylbutyrate, mitochondrial biogenesis, and skeletal muscle health.

    PubMed

    He, Xi; Duan, Yehui; Yao, Kang; Li, Fengna; Hou, Yongqing; Wu, Guoyao; Yin, Yulong

    2016-03-01

    The metabolic roles of mitochondria go far beyond serving exclusively as the major producer of ATP in tissues and cells. Evidence has shown that mitochondria may function as a key regulator of skeletal muscle fiber types and overall well-being. Maintaining skeletal muscle mitochondrial content and function is important for sustaining health throughout the lifespan. Of great importance, β-hydroxy-β-methylbutyrate (HMB, a metabolite of L-leucine) has been proposed to enhance the protein deposition and efficiency of mitochondrial biogenesis in skeletal muscle, as well as muscle strength in both exercise and clinical settings. Specifically, dietary supplementation with HMB increases the gene expression of peroxisome proliferator-activated receptor gamma co-activator 1-alpha (PGC-1α), which represents an upstream inducer of genes of mitochondrial metabolism, coordinates the expression of both nuclear- and mitochondrion-encoded genes in mitochondrial biogenesis. Additionally, PGC-1α plays a key role in the transformation of skeletal muscle fiber type, leading to a shift toward type I muscle fibers that are rich in mitochondria and have a high capacity for oxidative metabolism. As a nitrogen-free metabolite, HMB holds great promise to improve skeletal muscle mass and function, as well as whole-body health and well-being of animals and humans. PMID:26573541

  13. 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...

  14. Melatonin promotes adipogenesis and mitochondrial biogenesis in 3T3-L1 preadipocytes.

    PubMed

    Kato, Hisashi; Tanaka, Goki; Masuda, Shinya; Ogasawara, Junetsu; Sakurai, Takuya; Kizaki, Takako; Ohno, Hideki; Izawa, Tetsuya

    2015-09-01

    Melatonin is synthesized in the pineal gland, but elicits a wide range of physiological responses in peripheral target tissues. Recent advances suggest that melatonin controls adiposity, resulting in changes in body weight. The aim of this study was to investigate the effect of melatonin on adipogenesis and mitochondrial biogenesis in 3T3-L1 mouse embryo fibroblasts. Melatonin significantly increased the expression of peroxisome proliferator-activated receptor-γ (PPAR-γ), a master regulator of adipogenesis, and promoted differentiation into adipocytes. Melatonin-treated cells also formed smaller lipid droplets and abundantly expressed several molecules associated with lipolysis, including adipose triglyceride lipase, perilipin, and comparative gene identification-58. Moreover, the hormone promoted biogenesis of mitochondria, as indicated by fluorescent staining, elevated the citrate synthase activity, and upregulated the expression of PPAR-γ coactivator 1 α, nuclear respiratory factor-1, and transcription factor A. The expression of uncoupling protein 1 was also observable both at mRNA and at protein level in melatonin-treated cells. Finally, adiponectin secretion and the expression of adiponectin receptors were enhanced. These results suggest that melatonin promotes adipogenesis, lipolysis, mitochondrial biogenesis, and adiponectin secretion. Thus, melatonin has potential as an anti-obesity agent that may reverse obesity-related disorders. PMID:26123001

  15. 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. PMID:24084166

  16. High-fat diet-induced mitochondrial biogenesis is regulated by mitochondrial-derived reactive oxygen species activation of CaMKII.

    PubMed

    Jain, Swati S; Paglialunga, Sabina; Vigna, Chris; Ludzki, Alison; Herbst, Eric A; Lally, James S; Schrauwen, Patrick; Hoeks, Joris; Tupling, A Russ; Bonen, Arend; Holloway, Graham P

    2014-06-01

    Calcium/calmodulin-dependent protein kinase (CaMK) activation induces mitochondrial biogenesis in response to increasing cytosolic calcium concentrations. Calcium leak from the ryanodine receptor (RyR) is regulated by reactive oxygen species (ROS), which is increased with high-fat feeding. We examined whether ROS-induced CaMKII-mediated signaling induced skeletal muscle mitochondrial biogenesis in selected models of lipid oversupply. In obese Zucker rats and high-fat-fed rodents, in which muscle mitochondrial content was upregulated, CaMKII phosphorylation was increased independent of changes in calcium uptake because sarco(endo)plasmic reticulum Ca(2+)-ATPase (SERCA) protein expression or activity was not altered, implicating altered sarcoplasmic reticulum (SR) calcium leak in the activation of CaMKII. In support of this, we found that high-fat feeding increased mitochondrial ROS emission and S-nitrosylation of the RyR, whereas hydrogen peroxide induced SR calcium leak from the RyR and activation of CaMKII. Moreover, administration of a mitochondrial-specific antioxidant, SkQ, prevented high-fat diet-induced phosphorylation of CaMKII and the induction of mitochondrial biogenesis. Altogether, these data suggest that increased mitochondrial ROS emission is required for the induction of SR calcium leak, activation of CaMKII, and induction of mitochondrial biogenesis in response to excess lipid availability. PMID:24520120

  17. TNF-α downregulates eNOS expression and mitochondrial biogenesis in fat and muscle of obese rodents

    PubMed Central

    Valerio, Alessandra; Cardile, Annalisa; Cozzi, Valeria; Bracale, Renata; Tedesco, Laura; Pisconti, Addolorata; Palomba, Letizia; Cantoni, Orazio; Clementi, Emilio; Moncada, Salvador; Carruba, Michele O.; Nisoli, Enzo

    2006-01-01

    Obesity is associated with chronic low-grade inflammation. Thus, at metabolically relevant sites, including adipose tissue and muscle, there is abnormal production of proinflammatory cytokines such as TNF-α. Here we demonstrate that eNOS expression was reduced, with a concomitant reduction of mitochondrial biogenesis and function, in white and brown adipose tissue and in the soleus muscle of 3 different animal models of obesity. The genetic deletion of TNF receptor 1 in obese mice restored eNOS expression and mitochondrial biogenesis in fat and muscle; this was associated with less body weight gain than in obese wild-type controls. Furthermore, TNF-α downregulated eNOS expression and mitochondrial biogenesis in cultured white and brown adipocytes and muscle satellite cells of mice. The NO donors DETA-NO and SNAP prevented the reduction of mitochondrial biogenesis observed with TNF-α. Our findings demonstrate that TNF-α impairs mitochondrial biogenesis and function in different tissues of obese rodents by downregulating eNOS expression and suggest a novel pathophysiological process that sustains obesity. PMID:16981010

  18. Glucagon-Like Peptide-1 Increases Mitochondrial Biogenesis and Function in INS-1 Rat Insulinoma Cells

    PubMed Central

    Kang, Mi Yeon; Oh, Tae Jung

    2015-01-01

    Glucagon-like peptide-1 (GLP-1) is a gut-derived incretin hormone that increases glucose-stimulated insulin secretion in pancreatic β-cells. Since mitochondrial function is crucial to insulin secretion, we hypothesized that GLP-1 may increase mitochondrial biogenesis in pancreatic β-cells. We treated INS-1 rat insulinoma cells with GLP-1 or exendin-4 for 48 hours and measured mitochondrial mass and function. Both GLP-1 and exendin-4 increased mitochondrial mass by approximately 20%. The mitochondria/cytosol ratio was increased from 7.60±3.12% to 10.53±2.70% by exendin-4. In addition, GLP-1 increased the mitochondrial membrane potential and oxygen consumption. Proliferator-activated receptor-gamma coactivator 1α expression was increased approximately 2-fold by GLP-1 treatment. In conclusion, the present study presents evidence for a new mechanism of action by which GLP-1 improves pancreatic β-cell function via enhanced mitochondrial mass and performance. PMID:26194081

  19. 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

  20. PGC-1α mediates mitochondrial biogenesis and oxidative phosphorylation to promote metastasis

    PubMed Central

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

    2014-01-01

    Cancer cells can divert metabolites into anabolic pathways to support their rapid proliferation and to accumulate the cellular building blocks required for tumor growth. However, the specific bioenergetic profile of invasive and metastatic cancer cells is unknown. Here we report that migratory/invasive cancer cells specifically favor mitochondrial respiration and increased ATP production. Invasive cancer cells use transcription co-activator, PGC-1α to enhance oxidative phosphorylation, mitochondrial biogenesis and oxygen consumption rate. Clinical analysis of human invasive breast cancers revealed a strong correlation between PGC-1α expression in invasive cancer cells and formation of distant metastases. Silencing of PGC-1α in cancer cells suspended their invasive potential and attenuated metastasis without affecting proliferation, primary tumor growth or epithelial-to-mesenchymal (EMT) program. While inherent genetics of cancer cells determine the transcriptome framework required for invasion and metastasis, mitochondrial biogenesis and respiration induced by PGC-1α is also essential for functional motility of cancer cells and metastasis. PMID:25241037

  1. Recovery of Indicators of Mitochondrial Biogenesis, Oxidative Stress, and Aging With (-)-Epicatechin in Senile Mice.

    PubMed

    Moreno-Ulloa, Aldo; Nogueira, Leonardo; Rodriguez, Alonso; Barboza, Jonathan; Hogan, Michael C; Ceballos, Guillermo; Villarreal, Francisco; Ramirez-Sanchez, Israel

    2015-11-01

    There is evidence implicating oxidative stress (OS) as the cause of the deleterious effects of aging. In this study, we evaluated the capacity of the flavanol (-)-epicatechin (Epi) to reduce aging-induced OS and restore mitochondrial biogenesis, as well as, structural and functional endpoints in aged mice. Senile (S; 26-month-old) C57BL/6 male mice were randomly assigned to receive either water (vehicle) or 1mg/kg of Epi via oral gavage (twice daily) for 15 days. Young (Y; 6-month-old) mice were used as controls. In S brain, kidney, heart, and skeletal muscle (compared with Y animals) an increase in OS was observed as evidenced by increased protein-free carbonyls and decreased reduced glutathione levels as well as sirtuin 3, superoxide dismutase 2, catalase, thioredoxin and glutathione peroxidase protein levels. Well-recognized factors (eg, sirtuin 1) that regulate mitochondrial biogenesis and mitochondrial structure- and/or function-related endpoints (eg, mitofilin and citrate synthase) protein levels were also reduced in S organs. In contrast, the aging biomarker senescence-associated ?-galactosidase was increased in S compared with Y animals, and Epi administration reduced levels towards those observed in Y animals. Altogether, these data suggest that Epi is capable of shifting the biology of S mice towards that of Y animals. PMID:25143004

  2. 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 subunits. • It decreases the mtDNA copy number and mitochondrial content in rat brain. • It down-regulates the mRNA and protein levels of PGC-1α, NRF-1, NRF-2 and Tfam. • It also disturbs the mitochondrial or nuclear architecture of neurons. • Finally it also decreases mitochondrial number in HC and CS regions of rat brain.

  3. N-Acetyl-L-cysteine prevents exercise-induced intestinal lymphocyte apoptosis by maintaining intracellular glutathione levels and reducing mitochondrial membrane depolarization.

    PubMed

    Quadrilatero, J; Hoffman-Goetz, L

    2004-07-01

    Intense exercise leads to post-exercise lymphocytopenia and immunosuppression, possibly by triggering lymphocyte apoptosis. To test the role of oxidative stress on exercise-induced lymphocyte apoptosis, we administered the antioxidant N-acetyl--cysteine (NAC) and measured apoptosis in intestinal lymphocytes (IL) from exhaustively exercised animals. Eighty-seven female C57BL/6 mice were randomly assigned to receive NAC (1 g/kg) or saline 30 min prior to treadmill exercise for 90 min at 2degrees slope (30 min at 22 m min(-1), 30 min at 25 m min(-1), and 30 min at 28 m min(-1)) and sacrificed immediately (Imm) or 24 hours (24 h) after cessation of exercise. Control mice (nonexercised) were exposed to treadmill noise and vibration without running. Exercise increased IL phosphatidylserine externalization (p<0.001), mitochondrial membrane depolarization (p<0.05), and decreased intracellular glutathione concentrations (p<0.05) immediately following exercise in saline relative to nonexercised mice. At 24 h post-exercise, saline injected mice had fewer total (p<0.001) and CD3+ (p<0.005) IL compared to nonexercised animals. NAC injection in mice maintained intracellular glutathione levels, prevented phosphatidylserine externalization, mitochondrial membrane depolarization, and loss of IL immediately and 24 h after exercise. These data suggest that lymphocyte apoptosis precedes post-exercise lymphocytopenia and may be due to oxidative stress. PMID:15184067

  4. Regulation of PGC-1α, a nodal regulator of mitochondrial biogenesis1234

    PubMed Central

    Fernandez-Marcos, Pablo J; Auwerx, Johan

    2011-01-01

    Mechanisms responsible for energy management in the cell and in the whole organism require a complex network of transcription factors and cofactors. Peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) has emerged as a master regulator of mitochondrial biogenesis and function, thus becoming a crucial metabolic node. We present an overview of the mechanisms by which PGC-1α is regulated, including the transcriptional regulation of PGC-1α expression and the fine-tuning of its final activity via posttranslational modifications. PMID:21289221

  5. Mitochondrial Biogenesis Drives a Vicious Cycle of Metabolic Insufficiency and Mitochondrial DNA Deletion Mutation Accumulation in Aged Rat Skeletal Muscle Fibers

    PubMed Central

    Herbst, Allen; Johnson, Chad J.; Hynes, Kayla; McKenzie, Debbie; Aiken, Judd M.

    2013-01-01

    Aged muscles possess dysfunctional fibers that contain intracellular expansions of somatically derived mitochondrial DNA deletion mutations. At high abundance, these mutations disrupt the expression of mitochondrially-encoded protein subunits of the electron transport chain resulting in aerobic respiration deficient muscle fiber segments. These fiber segments atrophy and break contributing to the loss of muscle mass and function that occurs with age. By combining micro-dissection of individual muscle fibers with microarray analysis, we observed the response induced within these abnormal muscle fibers and detected an increase in many genes affecting metabolism and metabolic regulation. The transcriptional profile and subsequent protein validation suggested that a non-compensatory program of mitochondrial biogenesis was initiated. We hypothesized that this non-adaptive program of mitochondrial biogenesis was driving mtDNA deletion mutation accumulation. We tested this hypothesis by treating aged rats with ?-Guanidinopropionic acid, a compound that stimulates mitochondrial biogenesis. ?-Guanidinopropionic acid treatment increased muscle mitochondrial genome copy number and resulted in a 3.7 fold increase in the abundance of electron transport chain negative muscle fiber segments. We conclude that in electron transport system abnormal muscle fiber segments, a vicious cycle of metabolic insufficiency and non-compensatory mitochondrial biogenesis drive mtDNA deletion mutation accumulation. PMID:23516592

  6. Hypothalamic-pituitary-thyroid axis hormones stimulate mitochondrial function and biogenesis in human hair follicles.

    PubMed

    Vidali, Silvia; Knuever, Jana; Lerchner, Johannes; Giesen, Melanie; Bíró, Tamás; Klinger, Matthias; Kofler, Barbara; Funk, Wolfgang; Poeggeler, Burkhard; Paus, Ralf

    2014-01-01

    Thyroid hormones regulate mitochondrial function. As other hypothalamic-pituitary-thyroid (HPT) axis hormones, i.e., thyrotropin-releasing hormone (TRH) and thyrotropin (TSH), are expressed in human hair follicles (HFs) and regulate mitochondrial function in human epidermis, we investigated in organ-cultured human scalp HFs whether TRH (30 nM), TSH (10 mU ml(-1)), thyroxine (T4) (100 nM), and triiodothyronine (T3) (100 pM) alter intrafollicular mitochondrial energy metabolism. All HPT-axis members increased gene and protein expression of mitochondrial-encoded subunit 1 of cytochrome c oxidase (MTCO1), a subunit of respiratory chain complex IV, mitochondrial transcription factor A (TFAM), and Porin. All hormones also stimulated intrafollicular complex I/IV activity and mitochondrial biogenesis. The TSH effects on MTCO1, TFAM, and porin could be abolished by K1-70, a TSH-receptor antagonist, suggesting a TSH receptor-mediated action. Notably, as measured by calorimetry, T3 and TSH increased follicular heat production, whereas T3/T4 and TRH stimulated ATP production in cultured HF keratinocytes. HPT-axis hormones did not increase reactive oxygen species (ROS) production. Rather, T3 and T4 reduced ROS formation, and all tested HPT-axis hormones increased the transcription of ROS scavengers (catalase, superoxide dismutase 2) in HF keratinocytes. Thus, mitochondrial biology, energy metabolism, and redox state of human HFs are subject to profound (neuro-)endocrine regulation by HPT-axis hormones. The neuroendocrine control of mitochondrial biology in a complex human mini-organ revealed here may be therapeutically exploitable. PMID:23949722

  7. Biogenesis of Mitochondria in Germinating Peanut Cotyledons II. Changes in Cytochromes and Mitochondrial DNA 1

    PubMed Central

    Breidenbach, R. W.; Castelfranco, Paul; Criddle, R. S.

    1967-01-01

    Biogenesis of mitochondria occurs in the germinating cotyledons of peanuts. This process was demonstrated by measuring both constitutive and enzymatic properties of mitochondria as a function of germination time. Direct counting by phase contrast microscopy of sucrose density gradient preparations showed that the number of mitochondria increased markedly during germination. DNA with a buoyant density distinct from the major cellular DNA was associated with these mitochondrial preparations. During germination the amount of this DNA in mitochondrial pellets increased. This increase closely paralleled the increase in number of mitochondria. Succinoxidase and succinic dehydrogenase increased during germination. Both activities were confined to the mitochondrial fraction. The rate of increase of succinoxidase activity was significantly greater than the rate of increase of succinic dehydrogenase and both increased at least initially at a greater rate than the amount of mitochondrial DNA or numbers of mitochondria. The amounts of cytochromes present in mitochondrial preparations were measured spectrophotometrically. All of the cytochromes increased in amount during germination. The rate of increase of cytochrome a — a3 very close to the rate of increase in succinoxidase activity. PMID:16656611

  8. AMPK regulation of fatty acid metabolism and mitochondrial biogenesis: implications for obesity.

    PubMed

    O'Neill, Hayley M; Holloway, Graham P; Steinberg, Gregory R

    2013-02-25

    Skeletal muscle plays an important role in regulating whole-body energy expenditure given it is a major site for glucose and lipid oxidation. Obesity and type 2 diabetes are causally linked through their association with skeletal muscle insulin resistance, while conversely exercise is known to improve whole body glucose homeostasis simultaneously with muscle insulin sensitivity. Exercise activates skeletal muscle AMP-activated protein kinase (AMPK). AMPK plays a role in regulating exercise capacity, skeletal muscle mitochondrial content and contraction-stimulated glucose uptake. Skeletal muscle AMPK is also thought to be important for regulating fatty acid metabolism; however, direct genetic evidence in this area is currently lacking. This review will discuss the current paradigms regarding the influence of AMPK in regulating skeletal muscle fatty acid metabolism and mitochondrial biogenesis at rest and during exercise, and highlight the potential implications in the development of insulin resistance. PMID:22750049

  9. Mitochondrial dysfunction and biogenesis: do ICU patients die from mitochondrial failure?

    PubMed Central

    2011-01-01

    Mitochondrial functions include production of energy, activation of programmed cell death, and a number of cell specific tasks, e.g., cell signaling, control of Ca2+ metabolism, and synthesis of a number of important biomolecules. As proper mitochondrial function is critical for normal performance and survival of cells, mitochondrial dysfunction often leads to pathological conditions resulting in various human diseases. Recently mitochondrial dysfunction has been linked to multiple organ failure (MOF) often leading to the death of critical care patients. However, there are two main reasons why this insight did not generate an adequate resonance in clinical settings. First, most data regarding mitochondrial dysfunction in organs susceptible to failure in critical care diseases (liver, kidney, heart, lung, intestine, brain) were collected using animal models. Second, there is no clear therapeutic strategy how acquired mitochondrial dysfunction can be improved. Only the benefit of such therapies will confirm the critical role of mitochondrial dysfunction in clinical settings. Here we summarized data on mitochondrial dysfunction obtained in diverse experimental systems, which are related to conditions seen in intensive care unit (ICU) patients. Particular attention is given to mechanisms that cause cell death and organ dysfunction and to prospective therapeutic strategies, directed to recover mitochondrial function. Collectively the data discussed in this review suggest that appropriate diagnosis and specific treatment of mitochondrial dysfunction in ICU patients may significantly improve the clinical outcome. PMID:21942988

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

    PubMed Central

    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.

    2014-01-01

    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. 1H-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. PMID:25027327

  11. Flavan-3-ol fraction from cocoa powder promotes mitochondrial biogenesis in skeletal muscle in mice

    PubMed Central

    2014-01-01

    Background Numerous clinical studies have reported that ingestion of chocolate has reduced risk of metabolic syndrome. In order to elucidate the mechanism, we evaluated the influence of flavan-3-ols derived from cocoa powder on energy metabolism in mice using an indirect calorimetric method. Method The mice were divided into two groups, and administered either distilled water or 50 mg/kg of flavan-3-ol fraction for 2 weeks. At the end of the experimental period, animals were sacrificed after blood pressure and the mean respiratory exchange ratio (RER) over 24 hours were measured. Results The mean respiratory exchange ratio (RER) over 24 hours was reduced significantly in the flavan-3-ols group. The mean blood pressure was significantly decreased in flavan-3-ols treatment group compared with control group. The protein level of carnitine palmitoyltransferase 2 (CPT2) was increased significantly by flavan-3-ols in skeletal muscle, but not in liver. Uncoupling protein (UCP) 1 was increased significantly in brown adipose tissue by flavan-3-ols. The mitochondria copy number in gastrocnemius and soleus muscles and brown adipose tissue were increased significantly by administration of flavan-3-ol fraction. Conclusion These results suggest that flavan-3-ols enhances lipolysis and promotes mitochondrial biogenesis. We conclude that improvement of metabolic syndrome risk factors following ingestion of chocolate may be induced, in part, by the mitochondrial biogenesis-promoting effect of flavan-3-ols. PMID:24708519

  12. Mitochondrial biogenesis is required for the anchorage-independent survival and propagation of stem-like cancer cells

    PubMed Central

    Peiris-Pagès, Maria; Ozsvari, Bela; Smith, Duncan L.; Sanchez-Alvarez, Rosa; Martinez-Outschoorn, Ubaldo E.; Cappello, Anna Rita; Pezzi, Vincenzo; Lisanti, Michael P.; Sotgia, Federica

    2015-01-01

    Here, we show that new mitochondrial biogenesis is required for the anchorage independent survival and propagation of cancer stem-like cells (CSCs). More specifically, we used the drug XCT790 as an investigational tool, as it functions as a specific inhibitor of the ERRα-PGC1 signaling pathway, which governs mitochondrial biogenesis. Interestingly, our results directly demonstrate that XCT790 efficiently blocks both the survival and propagation of tumor initiating stem-like cells (TICs), using the MCF7 cell line as a model system. Mechanistically, we show that XCT790 suppresses the activity of several independent signaling pathways that are normally required for the survival of CSCs, such as Sonic hedgehog, TGFβ-SMAD, STAT3, and Wnt signaling. We also show that XCT790 markedly reduces oxidative mitochondrial metabolism (OXPHOS) and that XCT790-mediated inhibition of CSC propagation can be prevented or reversed by Acetyl-L-Carnitine (ALCAR), a mitochondrial fuel. Consistent with our findings, over-expression of ERRα significantly enhances the efficiency of mammosphere formation, which can be blocked by treatment with mitochondrial inhibitors. Similarly, mammosphere formation augmented by FOXM1, a downstream target of Wnt/β-catenin signaling, can also be blocked by treatment with three different classes of mitochondrial inhibitors (XCT790, oligomycin A, or doxycycline). In this context, our unbiased proteomics analysis reveals that FOXM1 drives the expression of >90 protein targets associated with mitochondrial biogenesis, glycolysis, the EMT and protein synthesis in MCF7 cells, processes which are characteristic of an anabolic CSC phenotype. Finally, doxycycline is an FDA-approved antibiotic, which is very well-tolerated in patients. As such, doxycycline could be re-purposed clinically as a ‘safe’ mitochondrial inhibitor, to target FOXM1 and mitochondrial biogenesis in CSCs, to prevent tumor recurrence and distant metastasis, thereby avoiding patient relapse. PMID:26087310

  13. Expression of nuclear-encoded genes involved in mitochondrial biogenesis and dynamics in experimentally denervated muscle.

    PubMed

    Wagatsuma, Akira; Kotake, Naoki; Mabuchi, Kunihiko; Yamada, Shigeru

    2011-09-01

    The abundance, morphology, and functional properties of mitochondria become altered in response to denervation. To gain insight into the regulation of this process, mitochondrial enzyme activities and gene expression involved in mitochondrial biogenesis and dynamics in mouse gastrocnemius muscle was investigated. Sciatic nerve transactions were performed on mice, and then gastrocnemius muscles were isolated at days 5 and 30 after surgery. Muscle weight was decreased significantly by 15% and 62% at days 5 and 30 after surgery, respectively. The activity of citrate synthase, a marker of oxidative enzyme, was reduced significantly by 31% and 53% at days 5 and 30, respectively. Enzyme histochemical analysis revealed that subsarcolemmal mitochondria were largely lost than intermyofibrillar mitochondria at day 5, and this trend was further progressed at day 30 after surgery. Expression levels of peroxisome proliferator-activated receptor, γ coactivator 1 (PGC-1)α, estrogen-related receptor α (ERRα), and mitofusin 2 were down-regulated throughout the experimental period, whereas those of PGC-1β, PRC, nuclear respiratory factor (NRF)-1, NRF-2, TFAM, and Lon protease were down-regulated at day 30 after surgery. These results suggest that PGC-1α, ERRα, and mitofusin 2 may be important factors in the process of denervation-induced mitochondrial adaptation. In addition, other PGC-1 family of transcriptional coactivators and DNA binding transcription factors may also contribute to mitochondrial adaptation after early response to denervation. PMID:21394548

  14. 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. PMID:26363853

  15. 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

  16. Experimental analysis of the rice mitochondrial proteome, its biogenesis, and heterogeneity.

    PubMed

    Huang, Shaobai; Taylor, Nicolas L; Narsai, Reena; Eubel, Holger; Whelan, James; Millar, A Harvey

    2009-02-01

    Mitochondria in rice (Oryza sativa) are vital in expanding our understanding of the cellular response to reoxygenation of tissues after anaerobiosis, the crossroads of carbon and nitrogen metabolism, and the role of respiratory energy generation in cytoplasmic male sterility. We have combined density gradient and surface charge purification techniques with proteomics to provide an in-depth proteome of rice shoot mitochondria covering both soluble and integral membrane proteins. Quantitative comparisons of mitochondria purified by density gradients and after further surface charge purification have been used to ensure that the proteins identified copurify with mitochondria and to remove contaminants from the analysis. This rigorous approach to defining a subcellular proteome has yielded 322 nonredundant rice proteins and highlighted contaminants in previously reported rice mitochondrial proteomes. Comparative analysis with the Arabidopsis (Arabidopsis thaliana) mitochondrial proteome reveals conservation of a broad range of known and unknown function proteins in plant mitochondria, with only approximately 20% not having a clear homolog in the Arabidopsis mitochondrial proteome. As in Arabidopsis, only approximately 60% of the rice mitochondrial proteome is predictable using current organelle-targeting prediction tools. Use of the rice protein data set to explore rice transcript data provided insights into rice mitochondrial biogenesis during seed germination, leaf development, and heterogeneity in the expression of nucleus-encoded mitochondrial components in different rice tissues. Highlights include the identification of components involved in thiamine synthesis, evidence for coexpressed and unregulated expression of specific components of protein complexes, a selective anther-enhanced subclass of the decarboxylating segment of the tricarboxylic acid cycle, the differential expression of DNA and RNA replication components, and enhanced expression of specific metabolic components in photosynthetic tissues. PMID:19010998

  17. Endothelial AMPK activation induces mitochondrial biogenesis and stress adaptation via eNOS-dependent mTORC1 signaling.

    PubMed

    Li, Chunying; Reif, Michaella M; Craige, Siobhan M; Kant, Shashi; Keaney, John F

    2016-05-01

    Metabolic stress sensors like AMP-activated protein kinase (AMPK) are known to confer stress adaptation and promote longevity in lower organisms. This study demonstrates that activating the metabolic stress sensor AMP-activated protein kinase (AMPK) in endothelial cells helps maintain normal cellular function by promoting mitochondrial biogenesis and stress adaptation. To better define the mechanisms whereby AMPK promotes endothelial stress resistance, we used 5-aminoimidazole-4-carboxamide riboside (AICAR) to chronically activate AMPK and observed stimulation of mitochondrial biogenesis in wild type mouse endothelium, but not in endothelium from endothelial nitric oxide synthase knockout (eNOS-null) mice. Interestingly, AICAR-enhanced mitochondrial biogenesis was blocked by pretreatment with the mammalian target of rapamycin complex 1 (mTORC1) inhibitor, rapamycin. Further, AICAR stimulated mTORC1 as determined by phosphorylation of its known downstream effectors in wild type, but not eNOS-null, endothelial cells. Together these data indicate that eNOS is needed to couple AMPK activation to mTORC1 and thus promote mitochondrial biogenesis and stress adaptation in the endothelium. These data suggest a novel mechanism for mTORC1 activation that is significant for investigations in vascular dysfunction. PMID:26989010

  18. Carvedilol promotes mitochondrial biogenesis by regulating the PGC-1/TFAM pathway in human umbilical vein endothelial cells (HUVECs).

    PubMed

    Yao, Kai; Zhang, Wayne W; Yao, Luyu; Yang, Shu; Nie, Wanpin; Huang, Feizhou

    2016-02-19

    Carvedilol, a third-generation and nonselective β-adrenoceptor antagonist, is a licensed drug for treating patients suffering from heart failure in clinics. It has been shown that Carvedilol protects cells against mitochondrial dysfunction. However, it's unknown whether Carvedilol affects mitochondrial biogenesis. In this study, we found that treatment with Carvedilol in HUVECs resulted in a significant increase of PGC-1α, NRF1, and TFAM. Notably, Carvedilol significantly increased mtDNA contents and the two mitochondrial proteins, cytochrome C and COX IV. In addition, MitoTracker Red staining results indicated that treatment with Carvedilol increased mitochondria mass. Mechanistically, we found that the effect of Carvedilol on the expression of PGC-1α is mediated by the PKA-CREB pathway. Importantly, our results revealed that stimulation of mitochondrial biogenesis by carvedilol resulted in functional gain of the mitochondria by showing increased oxygen consumption and mitochondrial respiratory rate. The increased expression of PGC-1α and mitochondrial biogenesis induced by Carvedilol might suggest a new mechanism of the therapeutic effects of Carvedilol in heart failure. PMID:26797282

  19. Nuclear Recruitment of Neuronal Nitric-oxide Synthase by α-Syntrophin Is Crucial for the Induction of Mitochondrial Biogenesis*

    PubMed Central

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

    2014-01-01

    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. PMID:24235139

  20. Promoting PGC-1α-driven mitochondrial biogenesis is detrimental in pressure-overloaded mouse hearts

    PubMed Central

    Karamanlidis, Georgios; Garcia-Menendez, Lorena; Kolwicz, Stephen C.; Lee, Chi Fung

    2014-01-01

    Mitochondrial dysfunction in animal models of heart failure is associated with downregulation of the peroxisome proliferator-activated receptor-γ coactivator (PGC)-1α pathway. To test whether PGC-1α is an appropriate therapeutic target for increasing mitochondrial biogenesis and improving function in heart failure, we used a transgenic (TG) mouse model of moderate overexpression of PGC-1α (∼3-fold) in the heart. TG mice had small increases in citrate synthase activity and mitochondria size in the heart without alterations in myocardial energetics or cardiac function at baseline. In vivo dobutamine stress increased fractional shortening in wild-type mice, but this increase was attenuated in TG mice, whereas ex vivo isolated perfused TG hearts demonstrated normal functional and energetic response to high workload challenge. When subjected to pressure overload by transverse aortic constriction (TAC), TG mice displayed a significantly greater acute mortality for both male and female mice; however, long-term survival up to 8 wk was similar between the two groups. TG mice also showed a greater decrease in fractional shortening and a greater increase in left ventricular chamber dimension in response to TAC. Mitochondrial gene expression and citrate synthase activity were mildly increased in TG mice compared with wild-type mice, and this difference was also maintained after TAC. Our data suggest that a moderate level of PGC-1α overexpression in the heart compromises acute survival and does not improve cardiac function during chronic pressure overload in mice. PMID:25172896

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

    PubMed Central

    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.—Corum, D. G., Tsichlis, P. N., Muise-Helmericks, R. C. AKT3 controls mitochondrial biogenesis and autophagy via regulation of the major nuclear export protein CRM-1. PMID:24081905

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

    PubMed

    O'Brien, Laura C; Keeney, Paula M; Bennett, James P

    2015-09-01

    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

  3. 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. PMID:26493151

  4. Branched-chain amino acids, mitochondrial biogenesis, and healthspan: an evolutionary perspective

    PubMed Central

    Valerio, Alessandra; D'Antona, Giuseppe; Nisoli, Enzo

    2011-01-01

    Malnutrition is common among older persons, with important consequences increasing frailty and morbidity and reducing health expectancy. On the contrary, calorie restriction (CR, a low-calorie dietary regimen with adequate nutrition) slows the progression of age-related diseases and extends the lifespan of many species. Identification of strategies mimicking key CR mechanisms – increased mitochondrial respiration and reduced production of oxygen radicals – is a hot topic in gerontology. Dietary supplementation with essential and/or branched chain amino acids (BCAAs) exerts a variety of beneficial effects in experimental animals and humans and has been recently demonstrated to support cardiac and skeletal muscle mitochondrial biogenesis, prevent oxidative damage, and enhance physical endurance in middle-aged mice, resulting in prolonged survival. Here we review recent studies addressing the possible role of BCAAs in energy metabolism and in the longevity of species ranging from unicellular organisms to mammals. We also summarize observations from human studies supporting the exciting hypothesis that dietary BCAA enriched mixture supplementation might be a health-promoting strategy in aged patients at risk. PMID:21566257

  5. Synergistic Effects of Cilostazol and Probucol on ER Stress-Induced Hepatic Steatosis via Heme Oxygenase-1-Dependent Activation of Mitochondrial Biogenesis

    PubMed Central

    Chen, Yingqing; Pandiri, Indira; Joe, Yeonsoo; Kim, Hyo Jeong; Kim, Seul-Ki; Park, Jeongmin; Ryu, Jinhyun; Cho, Gyeong Jae; Park, Jeong Woo; Ryter, Stefan W.; Chung, Hun Taeg

    2016-01-01

    The selective type-3 phosphodiesterase inhibitor cilostazol and the antihyperlipidemic agent probucol have antioxidative, anti-inflammatory, and antiatherogenic properties. Moreover, cilostazol and probucol can regulate mitochondrial biogenesis. However, the combinatorial effect of cilostazol and probucol on mitochondrial biogenesis remains unknown. Endoplasmic reticulum (ER) stress is a well-known causative factor of nonalcoholic fatty liver disease (NAFLD) which can impair mitochondrial function in hepatocytes. Here, we investigated the synergistic effects of cilostazol and probucol on mitochondrial biogenesis and ER stress-induced hepatic steatosis. A synergistic effect of cilostazol and probucol on HO-1 and mitochondrial biogenesis gene expression was found in human hepatocellular carcinoma cells (HepG2) and murine primary hepatocytes. Furthermore, in an animal model of ER stress involving tunicamycin, combinatorial treatment with cilostazol and probucol significantly increased the expression of HO-1 and mitochondrial biogenesis-related genes and proteins, whereas it downregulated serum ALT, eIF2 phosphorylation, and CHOP expression, as well as the lipogenesis-related genes SREBP-1c and FAS. Based on these results, we conclude that cilostazol and probucol exhibit a synergistic effect on the activation of mitochondrial biogenesis via upregulation of HO-1, which confers protection against ER stress-induced hepatic steatosis. PMID:27057275

  6. 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. PMID:23022608

  7. Monitoring of neuronal loss in the hippocampus of A?-injected rat: autophagy, mitophagy, and mitochondrial biogenesis stand against apoptosis.

    PubMed

    Shaerzadeh, Fatemeh; Motamedi, Fereshteh; Minai-Tehrani, Dariush; Khodagholi, Fariba

    2014-03-01

    In the present study, we tried to answer the following questions: which kind of defense pathways are activated after A? insult? How defense systems react against noxious effects of A? and whether they are able to deal against apoptosis or not? So, we traced some molecular pathways including autophagy, mitophagy, and mitochondrial biogenesis before reaching to the endpoint of apoptosis. Besides, we measured the function of mitochondria after injection of A? (1-42) in CA1 area of hippocampus as a model of Alzheimer's disease (AD). Based on our data, autophagy markers reached to their maximum level and returned to the control level as apoptotic markers started to increase. As a specialized form of autophagy, mitophagy markers followed the trend of autophagy markers. Whereas mitochondrial dynamic processes shifted toward fission, mitochondrial biogenesis was severely affected by A? and significantly decreased. Alongside suppression of mitochondrial biogenesis, activity of specific enzymes involved in antioxidant defense system, electron transport chain, and tricarboxylic acid cycle (TCA) decreased in response to the A?. Activity of antioxidant enzymes increased at first and then decreased significantly compared to the control. TCA enzymes aconitase and malate dehydrogenase activities reduced immediately while citrate synthase and fumarase activities did not change. Based on our finding, monitoring of the master molecules of intracellular cascades and determining their trends before the destructive function of A? could be the target of therapeutic issues for AD. PMID:24203394

  8. Exercise-Induced Changes in Caveolin-1, Depletion of Mitochondrial Cholesterol, and the Inhibition of Mitochondrial Swelling in Rat Skeletal Muscle but Not in the Liver

    PubMed Central

    Flis, Damian Jozef; Olek, Robert Antoni; Kaczor, Jan Jacek; Rodziewicz, Ewa; Halon, Malgorzata; Wozniak, Michal; Gabbianelli, Rosita; Ziolkowski, Wieslaw

    2016-01-01

    The reduction in cholesterol in mitochondria, observed after exercise, is related to the inhibition of mitochondrial swelling. Caveolin-1 (Cav-1) plays an essential role in the regulation of cellular cholesterol metabolism and is required by various signalling pathways. Therefore, the aim of this study was to investigate the effect of prolonged swimming on the mitochondrial Cav-1 concentration; additionally, we identified the results of these changes as they relate to the induction of changes in the mitochondrial swelling and cholesterol in rat skeletal muscle and liver. Male Wistar rats were divided into a sedentary control group and an exercise group. The exercised rats swam for 3 hours and were burdened with an additional 3% of their body weight. After the cessation of exercise, their quadriceps femoris muscles and livers were immediately removed for experimentation. The exercise protocol caused an increase in the Cav-1 concentration in crude muscle mitochondria; this was related to a reduction in the cholesterol level and an inhibition of mitochondrial swelling. There were no changes in rat livers, with the exception of increased markers of oxidative stress in mitochondria. These data indicate the possible role of Cav-1 in the adaptive change in the rat muscle mitochondria following exercise. PMID:26839631

  9. Exercise-Induced Changes in Caveolin-1, Depletion of Mitochondrial Cholesterol, and the Inhibition of Mitochondrial Swelling in Rat Skeletal Muscle but Not in the Liver.

    PubMed

    Flis, Damian Jozef; Olek, Robert Antoni; Kaczor, Jan Jacek; Rodziewicz, Ewa; Halon, Malgorzata; Antosiewicz, Jedrzej; Wozniak, Michal; Gabbianelli, Rosita; Ziolkowski, Wieslaw

    2016-01-01

    The reduction in cholesterol in mitochondria, observed after exercise, is related to the inhibition of mitochondrial swelling. Caveolin-1 (Cav-1) plays an essential role in the regulation of cellular cholesterol metabolism and is required by various signalling pathways. Therefore, the aim of this study was to investigate the effect of prolonged swimming on the mitochondrial Cav-1 concentration; additionally, we identified the results of these changes as they relate to the induction of changes in the mitochondrial swelling and cholesterol in rat skeletal muscle and liver. Male Wistar rats were divided into a sedentary control group and an exercise group. The exercised rats swam for 3 hours and were burdened with an additional 3% of their body weight. After the cessation of exercise, their quadriceps femoris muscles and livers were immediately removed for experimentation. The exercise protocol caused an increase in the Cav-1 concentration in crude muscle mitochondria; this was related to a reduction in the cholesterol level and an inhibition of mitochondrial swelling. There were no changes in rat livers, with the exception of increased markers of oxidative stress in mitochondria. These data indicate the possible role of Cav-1 in the adaptive change in the rat muscle mitochondria following exercise. PMID:26839631

  10. MITOPLD is a mitochondrial protein essential for nuage formation and piRNA biogenesis in the mouse germline.

    PubMed

    Watanabe, Toshiaki; Chuma, Shinichiro; Yamamoto, Yasuhiro; Kuramochi-Miyagawa, Satomi; Totoki, Yasushi; Toyoda, Atsushi; Hoki, Yuko; Fujiyama, Asao; Shibata, Tatsuhiro; Sado, Takashi; Noce, Toshiaki; Nakano, Toru; Nakatsuji, Norio; Lin, Haifan; Sasaki, Hiroyuki

    2011-03-15

    MITOPLD is a member of the phospholipase D superfamily proteins conserved among diverse species. Zucchini (Zuc), the Drosophila homolog of MITOPLD, has been implicated in primary biogenesis of Piwi-interacting RNAs (piRNAs). By contrast, MITOPLD has been shown to hydrolyze cardiolipin in the outer membrane of mitochondria to generate phosphatidic acid, which is a signaling molecule. To assess whether the mammalian MITOPLD is involved in piRNA biogenesis, we generated Mitopld mutant mice. The mice display meiotic arrest during spermatogenesis, demethylation and derepression of retrotransposons, and defects in primary piRNA biogenesis. Furthermore, in mutant germ cells, mitochondria and the components of the nuage, a perinuclear structure involved in piRNA biogenesis/function, are mislocalized to regions around the centrosome, suggesting that MITOPLD may be involved in microtubule-dependent localization of mitochondria and these proteins. Our results indicate a conserved role for MITOPLD/Zuc in the piRNA pathway and link mitochondrial membrane metabolism/signaling to small RNA biogenesis. PMID:21397847

  11. Impaired mitochondrial biogenesis contributes to depletion of functional mitochondria in chronic MPP+ toxicity: dual roles for ERK1/2

    PubMed Central

    Zhu, J H; Gusdon, A M; Cimen, H; Van Houten, B; Koc, E; Chu, C T

    2012-01-01

    The regulation of mitochondrial quality has emerged as a central issue in neurodegeneration, diabetes, and cancer. We utilized repeated low-dose applications of the complex I inhibitor 1-methyl-4-phenylpyridinium (MPP+) over 2 weeks to study cellular responses to chronic mitochondrial stress. Chronic MPP+ triggered depletion of functional mitochondria resulting in diminished capacities for aerobic respiration. Inhibiting autophagy/mitophagy only partially restored mitochondrial content. In contrast, inhibiting activation of extracellular signal-regulated protein kinases conferred complete cytoprotection with full restoration of mitochondrial functional and morphological parameters, enhancing spare respiratory capacity in MPP+ co-treated cells above that of control cells. Reversal of mitochondrial injury occurred when U0126 was added 1 week after MPP+, implicating enhanced repair mechanisms. Chronic MPP+ caused a >90% decrease in complex I subunits, along with decreases in complex III and IV subunits. Decreases in respiratory complex subunits were reversed by co-treatment with U0126, ERK1/2 RNAi or transfection of dominant-negative MEK1, but only partially restored by degradation inhibitors. Chronic MPP+ also suppressed the de novo synthesis of mitochondrial DNA-encoded proteins, accompanied by decreased expression of the mitochondrial transcription factor TFAM. U0126 completely reversed each of these deficits in mitochondrial translation and protein expression. These data indicate a key, limiting role for mitochondrial biogenesis in determining the outcome of injuries associated with elevated mitophagy. PMID:22622131

  12. Testosterone Plus Low-Intensity Physical Training in Late Life Improves Functional Performance, Skeletal Muscle Mitochondrial Biogenesis, and Mitochondrial Quality Control in Male Mice

    PubMed Central

    Guo, Wen; Wong, Siu; Li, Michelle; Liang, Wentao; Liesa, Marc; Serra, Carlo; Jasuja, Ravi; Bartke, Andrzej; Kirkland, James L.; Shirihai, Orian; Bhasin, Shalender

    2012-01-01

    Testosterone supplementation increases muscle mass in older men but has not been shown to consistently improve physical function and activity. It has been hypothesized that physical exercise is required to induce the adaptations necessary for translation of testosterone-induced muscle mass gain into functional improvements. However, the effects of testosterone plus low intensity physical exercise training (T/PT) on functional performance and bioenergetics are unknown. In this pilot study, we tested the hypothesis that combined administration of T/PT would improve functional performance and bioenergetics in male mice late in life more than low-intensity physical training alone. 28-month old male mice were randomized to receive T/PT or vehicle plus physical training (V/PT) for 2 months. Compare to V/PT control, administration of T/PT was associated with improvements in muscle mass, grip strength, spontaneous physical movements, and respiratory activity. These changes were correlated with increased mitochondrial DNA copy number and expression of markers for mitochondrial biogenesis. Mice receiving T/PT also displayed increased expression of key elements for mitochondrial quality control, including markers for mitochondrial fission-and-fusion and mitophagy. Concurrently, mice receiving T/PT also displayed increased expression of markers for reduced tissue oxidative damage and improved muscle quality. Conclusion: Testosterone administered with low-intensity physical training improves grip strength, spontaneous movements, and respiratory activity. These functional improvements were associated with increased muscle mitochondrial biogenesis and improved mitochondrial quality control. PMID:23240002

  13. Ketone bodies and two-compartment tumor metabolism: stromal ketone production fuels mitochondrial biogenesis in epithelial cancer cells.

    PubMed

    Martinez-Outschoorn, Ubaldo E; Lin, Zhao; Whitaker-Menezes, Diana; Howell, Anthony; Lisanti, Michael P; Sotgia, Federica

    2012-11-01

    We have previously suggested that ketone body metabolism is critical for tumor progression and metastasis. Here, using a co-culture system employing human breast cancer cells (MCF7) and hTERT-immortalized fibroblasts, we provide new evidence to directly support this hypothesis. More specifically, we show that the enzymes required for ketone body production are highly upregulated within cancer-associated fibroblasts. This appears to be mechanistically controlled by the stromal expression of caveolin-1 (Cav-1) and/or serum starvation. In addition, treatment with ketone bodies (such as 3-hydroxy-butyrate, and/or butanediol) is sufficient to drive mitochondrial biogenesis in human breast cancer cells. This observation was also validated by unbiased proteomic analysis. Interestingly, an MCT1 inhibitor was sufficient to block the onset of mitochondrial biogenesis in human breast cancer cells, suggesting a possible avenue for anticancer therapy. Finally, using human breast cancer tumor samples, we directly confirmed that the enzymes associated with ketone body production (HMGCS2, HMGCL and BDH1) were preferentially expressed in the tumor stroma. Conversely, enzymes associated with ketone re-utilization (ACAT1) and mitochondrial biogenesis (HSP60) were selectively associated with the epithelial tumor cell compartment. Our current findings are consistent with the "two-compartment tumor metabolism" model. Furthermore, they suggest that we should target ketone body metabolism as a new area for drug discovery, for the prevention and treatment of human cancers. PMID:23082721

  14. COA6 is a mitochondrial complex IV assembly factor critical for biogenesis of mtDNA-encoded COX2.

    PubMed

    Stroud, David A; Maher, Megan J; Lindau, Caroline; Vögtle, F-Nora; Frazier, Ann E; Surgenor, Elliot; Mountford, Hayley; Singh, Abeer P; Bonas, Matteo; Oeljeklaus, Silke; Warscheid, Bettina; Meisinger, Chris; Thorburn, David R; Ryan, Michael T

    2015-10-01

    Biogenesis of complex IV of the mitochondrial respiratory chain requires assembly factors for subunit maturation, co-factor attachment and stabilization of intermediate assemblies. A pathogenic mutation in COA6, leading to substitution of a conserved tryptophan for a cysteine residue, results in a loss of complex IV activity and cardiomyopathy. Here, we demonstrate that the complex IV defect correlates with a severe loss in complex IV assembly in patient heart but not fibroblasts. Complete loss of COA6 activity using gene editing in HEK293T cells resulted in a profound growth defect due to complex IV deficiency, caused by impaired biogenesis of the copper-bound mitochondrial DNA-encoded subunit COX2 and subsequent accumulation of complex IV assembly intermediates. We show that the pathogenic mutation in COA6 does not affect its import into mitochondria but impairs its maturation and stability. Furthermore, we show that COA6 has the capacity to bind copper and can associate with newly translated COX2 and the mitochondrial copper chaperone SCO1. Our data reveal that COA6 is intricately involved in the copper-dependent biogenesis of COX2. PMID:26160915

  15. Genome-Wide Screens in Saccharomyces cerevisiae Highlight a Role for Cardiolipin in Biogenesis of Mitochondrial Outer Membrane Multispan Proteins

    PubMed Central

    Sauerwald, Julia; Jores, Tobias; Eisenberg-Bord, Michal; Chuartzman, Silvia Gabriela

    2015-01-01

    A special group of mitochondrial outer membrane (MOM) proteins spans the membrane several times via multiple helical segments. Such multispan proteins are synthesized on cytosolic ribosomes before their targeting to mitochondria and insertion into the MOM. Previous work recognized the import receptor Tom70 and the mitochondrial import (MIM) complex, both residents of the MOM, as required for optimal biogenesis of these proteins. However, their involvement is not sufficient to explain either the entire import pathway or its regulation. To identify additional factors that are involved in the biogenesis of MOM multispan proteins, we performed complementary high-throughput visual and growth screens in Saccharomyces cerevisiae. Cardiolipin (CL) synthase (Crd1) appeared as a candidate in both screens. Our results indeed demonstrate lower steady-state levels of the multispan proteins Ugo1, Scm4, and Om14 in mitochondria from crd1Δ cells. Importantly, MOM single-span proteins were not affected by this mutation. Furthermore, organelles lacking Crd1 had a lower in vitro capacity to import newly synthesized Ugo1 and Scm4 molecules. Crd1, which is located in the mitochondrial inner membrane, condenses phosphatidylglycerol together with CDP-diacylglycerol to obtain de novo synthesized CL molecules. Hence, our findings suggest that CL is an important component in the biogenesis of MOM multispan proteins. PMID:26149385

  16. Mitochondrial DNA copy number and biogenesis in different tissues of early- and late-lactating dairy cows.

    PubMed

    Laubenthal, L; Hoelker, M; Frahm, J; Dänicke, S; Gerlach, K; Südekum, K-H; Sauerwein, H; Häussler, S

    2016-02-01

    Energy balance in dairy cows changes during the course of lactation due to alterations in voluntary feed intake and energy required for milk synthesis. To adapt to the demands of lactation, energy metabolism needs to be regulated and coordinated in key organs such as adipose tissue (AT), liver, and mammary gland. Mitochondria are the main sites of energy production in mammalian cells and their number varies depending on age, organ, and physiological condition. The copy number of the mitochondrial genome, the mitochondrial DNA (mtDNA), reflects the abundance of mitochondria within a cell and is regulated by transcriptional and translational factors. Environmental, physiological, and energetic conditions change during lactation and we thus hypothesized that these changes may influence the mtDNA copy number and the abundance of genes regulating mitochondrial biogenesis. Therefore, we aimed to provide an overview of mitochondrial biogenesis in liver, subcutaneous (sc)AT, mammary gland, and peripheral blood cells during early and late lactation in dairy cows. German Holstein cows (n=21) were fed according to their requirements, and biopsies from scAT, liver, mammary gland, and blood were collected in early and late lactation and assayed for relative mtDNA copy numbers and the mRNA abundance of genes regulating mitochondrial biogenesis, such as nuclear-respiratory factor 1 and 2 (NRF-1, NRF-2), mitochondrial transcription factor A (TFAM), and peroxisome proliferator-activated receptor-gamma coactivator 1-α (PGC-1α). The number of mtDNA copies increased from early to late lactation in all tissues, whereas that in peripheral blood cells was greater in early compared with late lactation. Moreover, mitochondrial activity enzymes (i.e., citrate synthase and cytochrome c oxidase) increased from early to late lactation in scAT. Comparing the number of mtDNA copies between tissues and blood in dairy cows, the highest mtDNA content was observed in liver. The mRNA abundance of genes related to mitochondrial biogenesis changed in a tissue-specific manner when comparing early versus late lactation. The mtDNA copy number was associated with transcriptional factors only in AT, suggesting nontranscriptional regulation of mtDNA in the other tissues. We detected strong correlations between peripheral blood mtDNA and tissue mtDNA content in early lactation. Peripheral blood forms an appropriate medium to display the cellular content of mtDNA copy numbers and consequently the cellular energy status of tissues during early lactation. PMID:26686730

  17. 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

  18. Rutin Increases Muscle Mitochondrial Biogenesis with AMPK Activation in High-Fat Diet-Induced Obese Rats

    PubMed Central

    Seo, Sangjin; Lee, Mak-Soon; Chang, Eugene; Shin, Yoonjin; Oh, Soojung; Kim, In-Hwan; Kim, Yangha

    2015-01-01

    Decreased mitochondrial number and dysfunction in skeletal muscle are associated with obesity and the progression of obesity-associated metabolic disorders. The specific aim of the current study was to investigate the effects of rutin on mitochondrial biogenesis in skeletal muscle of high-fat diet-induced obese rats. Supplementation with rutin reduced body weight and adipose tissue mass, despite equivalent energy intake (p < 0.05). Rutin significantly increased mitochondrial size and mitochondrial DNA (mtDNA) content as well as gene expression related to mitochondrial biogenesis, such as peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α), nuclear respiratory factor-1 (NRF-1), transcription factor A (Tfam), and nicotinamide adenine dinucleotide (NAD)-dependent deacetylase, sirtulin1 (SIRT1) in skeletal muscle (p < 0.05). Moreover, rutin consumption increased muscle adenosine monophosphate-activated protein kinase (AMPK) activity by 40% (p < 0.05). Taken together, these results suggested at least partial involvement of muscle mitochondria and AMPK activation in the rutin-mediated beneficial effect on obesity. PMID:26402699

  19. Regulation of mitochondrial respiratory chain biogenesis by estrogens/estrogen receptors and physiological, pathological and pharmacological implications.

    PubMed

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

    2009-10-01

    There has been increasing evidence pointing to the mitochondrial respiratory chain (MRC) as a novel and important target for the actions of 17beta-estradiol (E(2)) and estrogen receptors (ER) in a number of cell types and tissues that have high demands for mitochondrial energy metabolism. This novel E(2)-mediated mitochondrial pathway involves the cooperation of both nuclear and mitochondrial ERalpha and ERbeta 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, anti-cancer drug resistance in human breast cancer cells, neuroprotection 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 regimens for the prevention or treatment of a wide variety of medical complications based on E(2)/ER-mediated MRC biogenesis pathway. PMID:19559056

  20. Spatio-Temporal Dynamics of Yeast Mitochondrial Biogenesis: Transcriptional and Post-Transcriptional mRNA Oscillatory Modules

    PubMed Central

    Lelandais, Gaëlle; Saint-Georges, Yann; Geneix, Colette; Al-Shikhley, Liza; Dujardin, Geneviève; Jacq, Claude

    2009-01-01

    Examples of metabolic rhythms have recently emerged from studies of budding yeast. High density microarray analyses have produced a remarkably detailed picture of cycling gene expression that could be clustered according to metabolic functions. We developed a model-based approach for the decomposition of expression to analyze these data and to identify functional modules which, expressed sequentially and periodically, contribute to the complex and intricate mitochondrial architecture. This approach revealed that mitochondrial spatio-temporal modules are expressed during periodic spikes and specific cellular localizations, which cover the entire oscillatory period. For instance, assembly factors (32 genes) and translation regulators (47 genes) are expressed earlier than the components of the amino-acid synthesis pathways (31 genes). In addition, we could correlate the expression modules identified with particular post-transcriptional properties. Thus, mRNAs of modules expressed “early” are mostly translated in the vicinity of mitochondria under the control of the Puf3p mRNA-binding protein. This last spatio-temporal module concerns mostly mRNAs coding for basic elements of mitochondrial construction: assembly and regulatory factors. Prediction that unknown genes from this module code for important elements of mitochondrial biogenesis is supported by experimental evidence. More generally, these observations underscore the importance of post-transcriptional processes in mitochondrial biogenesis, highlighting close connections between nuclear transcription and cytoplasmic site-specific translation. PMID:19521515

  1. The mitochondrial proteins Atm1p and Nfs1p are essential for biogenesis of cytosolic Fe/S proteins.

    PubMed

    Kispal, G; Csere, P; Prohl, C; Lill, R

    1999-07-15

    Iron-sulfur (Fe/S) cluster-containing proteins catalyse a number of electron transfer and metabolic reactions. Little is known about the biogenesis of Fe/S clusters in the eukaryotic cell. Here, we demonstrate that mitochondria perform an essential role in the synthesis of both intra- and extra-mitochondrial Fe/S proteins. Nfs1p represents the yeast orthologue of the bacterial cysteine desulfurase NifS that initiates biogenesis by producing elemental sulfur. The matrix-localized protein is required for synthesis of both mitochondrial and cytosolic Fe/S proteins. The ATP-binding cassette (ABC) transporter Atm1p of the mitochondrial inner membrane performs an essential function only in the generation of cytosolic Fe/S proteins by mediating export of Fe/S cluster precursors synthesized by Nfs1p and other mitochondrial proteins. Assembly of cellular Fe/S clusters constitutes an indispensable biosynthetic task of mitochondria with potential relevance for an iron-storage disease and the control of cellular iron uptake. PMID:10406803

  2. Alterations in skeletal muscle indicators of mitochondrial structure and biogenesis in patients with type 2 diabetes and heart failure: effects of epicatechin rich cocoa.

    PubMed

    Taub, Pam R; Ramirez-Sanchez, Israel; Ciaraldi, Theodore P; Perkins, Guy; Murphy, Anne N; Naviaux, Robert; Hogan, Michael; Maisel, Alan S; Henry, Robert R; Ceballos, Guillermo; Villarreal, Francisco

    2012-02-01

    (-)-Epicatechin (Epi), a flavanol in cacao stimulates mitochondrial volume and cristae density and protein markers of skeletal muscle (SkM) mitochondrial biogenesis in mice. Type 2 diabetes mellitus (DM2) and heart failure (HF) are diseases associated with defects in SkM mitochondrial structure/function. A study was implemented to assess perturbations and to determine the effects of Epi-rich cocoa in SkM mitochondrial structure and mediators of biogenesis. Five patients with DM2 and stage II/III HF consumed dark chocolate and a beverage containing approximately 100 mg of Epi per day for 3 months. We assessed changes in protein and/or activity levels of oxidative phosphorylation proteins, porin, mitofilin, nNOS, nitric oxide, cGMP, SIRT1, PGC1α, Tfam, and mitochondria volume and cristae abundance by electron microscopy from SkM. Apparent major losses in normal mitochondria structure were observed before treatment. Epi-rich cocoa increased protein and/or activity of mediators of biogenesis and cristae abundance while not changing mitochondrial volume density. Epi-rich cocoa treatment improves SkM mitochondrial structure and in an orchestrated manner, increases molecular markers of mitochondrial biogenesis resulting in enhanced cristae density. Future controlled studies are warranted using Epi-rich cocoa (or pure Epi) to translate improved mitochondrial structure into enhanced cardiac and/or SkM muscle function. PMID:22376256

  3. 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.

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

    PubMed

    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

  5. 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

  6. 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

  7. Pyrroloquinoline quinone stimulates mitochondrial biogenesis through cAMP response element-binding protein phosphorylation and increased PGC-1alpha expression.

    PubMed

    Chowanadisai, Winyoo; Bauerly, Kathryn A; Tchaparian, Eskouhie; Wong, Alice; Cortopassi, Gino A; Rucker, Robert B

    2010-01-01

    Bioactive compounds reported to stimulate mitochondrial biogenesis are linked to many health benefits such increased longevity, improved energy utilization, and protection from reactive oxygen species. Previously studies have shown that mice and rats fed diets lacking in pyrroloquinoline quinone (PQQ) have reduced mitochondrial content. Therefore, we hypothesized that PQQ can induce mitochondrial biogenesis in mouse hepatocytes. Exposure of mouse Hepa1-6 cells to 10-30 microm PQQ for 24-48 h resulted in increased citrate synthase and cytochrome c oxidase activity, Mitotracker staining, mitochondrial DNA content, and cellular oxygen respiration. The induction of this process occurred through the activation of cAMP response element-binding protein (CREB) and peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha), a pathway known to regulate mitochondrial biogenesis. PQQ exposure stimulated phosphorylation of CREB at serine 133, activated the promoter of PGC-1alpha, and increased PGC-1alpha mRNA and protein expression. PQQ did not stimulate mitochondrial biogenesis after small interfering RNA-mediated reduction in either PGC-1alpha or CREB expression. Consistent with activation of the PGC-1alpha pathway, PQQ increased nuclear respiratory factor activation (NRF-1 and NRF-2) and Tfam, TFB1M, and TFB2M mRNA expression. Moreover, PQQ protected cells from mitochondrial inhibition by rotenone, 3-nitropropionic acid, antimycin A, and sodium azide. The ability of PQQ to stimulate mitochondrial biogenesis accounts in part for action of this compound and suggests that PQQ may be beneficial in diseases associated with mitochondrial dysfunction. PMID:19861415

  8. Resistance exercise enhances the molecular signaling of mitochondrial biogenesis induced by endurance exercise in human skeletal muscle.

    PubMed

    Wang, Li; Mascher, Henrik; Psilander, Niklas; Blomstrand, Eva; Sahlin, Kent

    2011-11-01

    Combining endurance and strength training (concurrent training) may change the adaptation compared with single mode training. However, the site of interaction and the mechanisms are unclear. We have investigated the hypothesis that molecular signaling of mitochondrial biogenesis after endurance exercise is impaired by resistance exercise. Ten healthy subjects performed either only endurance exercise (E; 1-h cycling at ?65% of maximal oxygen uptake), or endurance exercise followed by resistance exercise (ER; 1-h cycling + 6 sets of leg press at 70-80% of 1 repetition maximum) in a randomized cross-over design. Muscle biopsies were obtained before and after exercise (1 and 3 h postcycling). The mRNA of genes related to mitochondrial biogenesis [(peroxisome proliferator-activated receptor-? coactivator-1 (PGC-1)?, PGC-1-related coactivator (PRC)] related coactivator) and substrate regulation (pyruvate dehydrogenase kinase-4) increased after both E and ER, but the mRNA levels were about twofold higher after ER (P < 0.01). Phosphorylation of proteins involved in the signaling cascade of protein synthesis [mammalian target of rapamycin (mTOR), ribosomal S6 kinase 1, and eukaryotic elongation factor 2] was altered after ER but not after E. Moreover, ER induced a larger increase in mRNA of genes associated with positive mTOR signaling (cMyc and Rheb). Phosphorylation of AMP-activated protein kinase, acetyl-CoA carboxylase, and Akt increased similarly at 1 h postcycling (P < 0.01) after both types of exercise. Contrary to our hypothesis, the results demonstrate that ER, performed after E, amplifies the adaptive signaling response of mitochondrial biogenesis compared with single-mode endurance exercise. The mechanism may relate to a cross talk between signaling pathways mediated by mTOR. The results suggest that concurrent training may be beneficial for the adaptation of muscle oxidative capacity. PMID:21836044

  9. Time-course effect of high-glucose-induced reactive oxygen species on mitochondrial biogenesis and function in human renal mesangial cells.

    PubMed

    Al-Kafaji, Ghada; Sabry, Mohamed Abdalla; Skrypnyk, Cristina

    2016-01-01

    The present study investigated the time-course effect of high-glucose-induced reactive oxygen species (ROS) on mitochondrial biogenesis and function in human renal mesangial cells and the effect of direct inhibition of ROS on mitochondria. The cells were cultured for 1, 4, and 7 days in normal glucose or high glucose in the presence and absence of Mn(III)tetrakis(4-benzoic acid)porphyrin chloride (MnTBAP) or catalase. Mitochondrial ROS production was assessed by confocal microscope. mtDNA copy number and peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α), nuclear respiratory factors 1 (NRF-1), and mitochondrial transcription factor A (TFAM) transcripts were analyzed by real-time PCR. PGC-1α, NRF-1, and TFAM proteins were analyzed by Western blotting. Mitochondrial function was determined by assessing mitochondrial membrane potential and adenosine triphosphate (ATP) levels. High glucose induced significant increases in mitochondrial superoxide and hydrogen peroxide (H2 O2 ) at day 1, which remained significantly elevated at days 4 and 7. The copy number of mtDNA and expression of PGC-1α, NRF-1, and TFAM were significantly increased at 1 day in high glucose but were significantly decreased at 4 and 7 days. A progressive decrease in mitochondrial membrane potential was observed at 1, 4, and 7 days in high glucose, and this was associated with decreased ATP levels. Treatment of cells with MnTBAP or catalase during high-glucose incubation attenuated ROS production and reversed the alterations in mitochondrial biogenesis and function. Increased mitochondrial biogenesis in human renal mesangial cells may be an early adaptive response to high-glucose-induced ROS, and prolonged ROS production induced by chronic high glucose decreased mitochondrial biogenesis and impaired mitochondrial function. Protection of mitochondria from high-glucose-induced ROS may provide a potential approach to retard the development and progression of diabetic nephropathy. PMID:26251331

  10. Roux-en-Y Gastric Bypass Acutely Decreases Protein Carbonylation and Increases Expression of Mitochondrial Biogenesis Genes in Subcutaneous Adipose Tissue

    PubMed Central

    Jahansouz, Cyrus; Serrot, Federico J.; Frohnert, Brigitte I.; Foncea, Rocio E.; Dorman, Robert B.; Slusarek, Bridget; Leslie, Daniel B.; Bernlohr, David A.; Ikramuddin, Sayeed

    2015-01-01

    Background Mitochondrial dysfunction in adipose tissue has been implicated as a pathogenic step in the development of type 2 diabetes mellitus (T2DM). In adipose tissue, chronic nutrient overload results in mitochondria driven increased reactive oxygen species (ROS) leading to carbonylation of proteins that impair mitochondrial function and downregulation of key genes linked to mitochondrial biogenesis. In patients with T2DM, Roux-en-Y gastric bypass (RYGB) surgery leads to improvements in glycemic profile prior to significant weight loss. Consequently, we hypothesized that improved glycemia early after RYGB would be paralleled by decreased protein carbonylation and increased expression of genes related to mitochondrial biogenesis in adipose tissue. Methods To evaluate this hypothesis, 16 obese individuals were studied before and 7–8 days following RYGB and adjustable gastric banding (AGB). Subcutaneous adipose tissue was obtained pre- and post-bariatric surgery as well as from eight healthy, non-obese individual controls. Results Prior to surgery, adipose tissue expression of PGC1α, NRF1, Cyt C, and eNOS (but not Tfam) showed significantly lower expression in the obese bariatric surgery group when compared to lean controls (p<0.05). Following RYGB, but not after AGB, patients showed significant decrease in HOMA-IR, reduction in adipose protein carbonylation, and increased expression of genes linked to mitochondrial biogenesis. Conclusions These results suggest that rapid reduction in protein carbonylation and increased mitochondrial biogenesis may explain postoperative metabolic improvements following RYGB. PMID:25975200

  11. Decreased Levels of Proapoptotic Factors and Increased Key Regulators of Mitochondrial Biogenesis Constitute New Potential Beneficial Features of Long-lived Growth Hormone Receptor GeneDisrupted 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 longevitydecreased 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 interventionscalorie 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

  12. MitBASE pilot: a database on nuclear genes involved in mitochondrial biogenesis and its regulation in Saccharomyces cerevisiae.

    PubMed

    de Pinto, B; Malladi, S B; Altamura, N

    1999-01-01

    In the framework of the EU BIOTECH PROGRAM and within the 'MITBASE: a comprehensive and integrated database on mtDNA' project, we have prepared a pilot database (MitBASE Pilot) on nuclear genes involved in mitochondrial biogenesis and its regulation in Saccharomyces cerevisiae. MitBASE Pilot includes nuclear genes encoding mitochondrial proteins as well as nuclear genes encoding products which are localised in other sub-cellular compartments but nevertheless interact with mitochondrial functions. Genes have been classified on the basis of the mitochondrial process in which they participate and the mitochondrial phenotype of the gene knockout. The structure of the MitBASE Pilot database has been conceived for a flexible organisation of the information. An intuitive visual query system has been developed which allows users to select information in different combinations, both in the query and the output format, according to their needs. MitBASE Pilot is a relational database, is maintained at the EMBL-European Bioinformatics Institute (EBI) and is available at the World Wide Web site http://www3.ebi.ac. uk/Research/Mitbase/mitbiog.pl PMID:9847161

  13. 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:25673772

  14. Puf3p, a Pumilio family RNA binding protein, localizes to mitochondria and regulates mitochondrial biogenesis and motility in budding yeast

    PubMed Central

    García-Rodríguez, Luis J.; Gay, Anna Card; Pon, Liza A.

    2007-01-01

    Puf3p binds preferentially to messenger RNAs (mRNAs) for nuclear-encoded mitochondrial proteins. We find that Puf3p localizes to the cytosolic face of the mitochondrial outer membrane. Overexpression of PUF3 results in reduced mitochondrial respiratory activity and reduced levels of Pet123p, a protein encoded by a Puf3p-binding mRNA. Puf3p levels are reduced during the diauxic shift and growth on a nonfermentable carbon source, conditions that stimulate mitochondrial biogenesis. These findings support a role for Puf3p in mitochondrial biogenesis through effects on mRNA interactions. In addition, Puf3p links the mitochore, a complex required for mitochondrial–cytoskeletal interactions, to the Arp2/3 complex, the force generator for actin-dependent, bud-directed mitochondrial movement. Puf3p, the mitochore, and the Arp2/3 complex coimmunoprecipitate and have two-hybrid interactions. Moreover, deletion of PUF3 results in reduced interaction between the mitochore and the Arp2/3 complex and defects in mitochondrial morphology and motility similar to those observed in Arp2/3 complex mutants. Thus, Puf3p is a mitochondrial protein that contributes to the biogenesis and motility of the organelle. PMID:17210948

  15. 4-Hydroxyisoleucine improves insulin resistance by promoting mitochondrial biogenesis and act through AMPK and Akt dependent pathway.

    PubMed

    Rawat, Arun Kumar; Korthikunta, Venkateswarlu; Gautam, Sudeep; Pal, Savita; Tadigoppula, Narender; Tamrakar, Akhilesh Kumar; Srivastava, Arvind Kumar

    2014-12-01

    4-Hydroxyisoleucine (4-HIL) is an unusual amino acid isolated from fenugreek seeds (Trigonella foenum graecum L). Various studies have shown that it acts as an antidiabetic agent yet its mechanism of action is not clear. We therefore investigated the effect 4-HIL on the high fructose diet fed streptozotocin induced diabetic rats and L6 myotubes. 4-HIL (50 mg/kg) has improved blood lipid profile, glucose tolerance and insulin sensitivity in a diabetic rat model. It has increased the glucose uptake in L6 myotubes in AMPK-dependent manner and upregulated the expression of genes (PGC-1?, PGC-1?, CPT 1 and CPT 2), which have role in mitochondrial biogenesis and energy metabolism in the liver, skeletal muscles as well as in L6 myotubes. Interestingly, it also increased the AMPK and Akt expression along with their phosphorylated forms in the liver and muscle tissues of treated animals. Altogether we concluded that 4-HIL acts to improve insulin resistance by promoting mitochondrial biogenesis in high fructose diet fed STZ induced diabetic rats. PMID:25454462

  16. 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 mitochondrial response.

  17. The deacetylase enzyme SIRT1 is not associated with oxidative capacity in rat heart and skeletal muscle and its overexpression reduces mitochondrial biogenesis.

    PubMed

    Gurd, Brendon J; Yoshida, Yuko; Lally, James; Holloway, Graham P; Bonen, Arend

    2009-04-15

    Deacetylation of PGC-1alpha by SIRT1 is thought to be an important step in increasing PGC-1alpha transcriptional activity, since in muscle cell lines SIRT1 induces PGC-1alpha protein expression and mitochondrial biogenesis. We examined the relationship between SIRT1 protein and activity, PGC-1alpha and markers of mitochondrial density, (a) across a range of metabolically heterogeneous skeletal muscles and the heart, and when mitochondrial biogenesis was stimulated by (b) chronic muscle stimulation (7 days) and (c) AICAR administration (5 days), and finally, (d) we also examined the effects of SIRT1 overexpression on mitochondrial biogenesis and PGC-1alpha. SIRT1 protein and activity were correlated (r = 0.97). There were negative correlations between SIRT1 protein and PGC-1alpha (r = -0.95), COX IV (r = -0.94) and citrate synthase (r = -0.97). Chronic muscle stimulation and AICAR upregulated PGC-1alpha protein (22-159%) and oxidative capacity (COX IV, 20-69%); in each instance SIRT1 protein was downregulated by 20-40%, while SIRT1 intrinsic activity was increased. SIRT1 overexpression in rodent muscle increased SIRT1 protein (+240%) and doubled SIRT1 activity, but PGC-1alpha (-25%), mtTFA (-14%) and COX IV (-10%) proteins were downregulated. Taken altogether these experiments are not consistent with the notion that SIRT1 protein plays an obligatory regulatory role in the process of PGC-1alpha-mediated mitochondrial biogenesis in mammalian muscle. PMID:19237425

  18. Long-term high-fat-diet feeding induces skeletal muscle mitochondrial biogenesis in rats in a sex-dependent and muscle-type specific manner

    PubMed Central

    2012-01-01

    Background Mitochondrial dysfunction is thought to play a crucial role in the etiology of insulin resistance, in which skeletal muscle is the main tissue contributor. Sex differences in skeletal muscle insulin and antioxidant responses to high-fat-diet (HFD) feeding have been described. The aim of this study was to elucidate whether there is a sex dimorphism in the effects of HFD feeding on skeletal muscle mitochondrial biogenesis and on the adiponectin signaling pathway, as well as the influence of the muscle type (oxidative or glycolytic). Methods Gastrocnemius and soleus muscles of male and female Wistar rats of 2 months of age fed with a high-fat-diet (HFD) or a low fat diet for 26 weeks were used. Mitochondrial biogenesis and oxidative damage markers, oxidative capacity and antioxidant defences were analyzed. Serum insulin sensitivity parameters and the levels of proteins involved in adiponectin signaling pathway were also determined. Results HFD feeding induced mitochondrial biogenesis in both sexes, but to a higher degree in male rats. Although HFD female rats showed greater antioxidant protection and maintained a better insulin sensitivity profile than their male counterparts, both sexes showed an impaired response to adiponectin, which was more evident in gastrocnemius muscle. Conclusions We conclude that HFD rats may induce skeletal muscle mitochondrial biogenesis as an attempt to compensate the deleterious consequences of adiponectin and insulin resistance on oxidative metabolism, and that the effects of HFD feeding are sex-dependent and muscle-type specific. PMID:22353542

  19. Mitochondrial DNA (mtDNA) Biogenesis: Visualization and Duel Incorporation of BrdU and EdU Into Newly Synthesized mtDNA In Vitro

    PubMed Central

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

    2010-01-01

    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. (J Histochem Cytochem 58:207–218, 2010) PMID:19875847

  20. 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. PMID:19875847

  1. 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.; Department of Heart Disease, Haukeland University Hospital ; 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.

  2. Exercise-Induced Neuroprotection of Hippocampus in APP/PS1 Transgenic Mice via Upregulation of Mitochondrial 8-Oxoguanine DNA Glycosylase

    PubMed Central

    Kang, Weimin; Jiang, Ning; Wang, Xun; Zhang, Yong; Ji, Li Li

    2014-01-01

    Improving mitochondrial function has been proposed as a reasonable therapeutic strategy to reduce amyloid-β (Aβ) load and to modify the progression of Alzheimer's disease (AD). However, the relationship between mitochondrial adaptation and brain neuroprotection caused by physical exercise in AD is poorly understood. This study was undertaken to investigate the effects of long-term treadmill exercise on mitochondrial 8-oxoguanine DNA glycosylase-1 (OGG1) level, mtDNA oxidative damage, and mitochondrial function in the hippocampus of APP/PS1 transgenic mouse model of AD. In the present study, twenty weeks of treadmill training significantly improved the cognitive function and reduced the expression of Aβ-42 in APP/PS1 transgenic (Tg) mice. Training also ameliorated mitochondrial respiratory function by increasing the complexes I, and IV and ATP synthase activities, whereas it attenuated ROS generation and mtDNA oxidative damage in Tg mice. Furthermore, the impaired mitochondrial antioxidant enzymes and mitochondrial OGG1 activities seen in Tg mice were restored with training. Acetylation level of mitochondrial OGG1 and MnSOD was markedly suppressed in Tg mice after exercise training, in parallel with increased level of SIRT3. These findings suggest that exercise training could increase mtDNA repair capacity in the mouse hippocampus, which in turn would result in protection against AD-related mitochondrial dysfunction and phenotypic deterioration. PMID:25538817

  3. Exercise-induced neuroprotection of hippocampus in APP/PS1 transgenic mice via upregulation of mitochondrial 8-oxoguanine DNA glycosylase.

    PubMed

    Bo, Hai; Kang, Weimin; Jiang, Ning; Wang, Xun; Zhang, Yong; Ji, Li Li

    2014-01-01

    Improving mitochondrial function has been proposed as a reasonable therapeutic strategy to reduce amyloid-β (Aβ) load and to modify the progression of Alzheimer's disease (AD). However, the relationship between mitochondrial adaptation and brain neuroprotection caused by physical exercise in AD is poorly understood. This study was undertaken to investigate the effects of long-term treadmill exercise on mitochondrial 8-oxoguanine DNA glycosylase-1 (OGG1) level, mtDNA oxidative damage, and mitochondrial function in the hippocampus of APP/PS1 transgenic mouse model of AD. In the present study, twenty weeks of treadmill training significantly improved the cognitive function and reduced the expression of Aβ-42 in APP/PS1 transgenic (Tg) mice. Training also ameliorated mitochondrial respiratory function by increasing the complexes I, and IV and ATP synthase activities, whereas it attenuated ROS generation and mtDNA oxidative damage in Tg mice. Furthermore, the impaired mitochondrial antioxidant enzymes and mitochondrial OGG1 activities seen in Tg mice were restored with training. Acetylation level of mitochondrial OGG1 and MnSOD was markedly suppressed in Tg mice after exercise training, in parallel with increased level of SIRT3. These findings suggest that exercise training could increase mtDNA repair capacity in the mouse hippocampus, which in turn would result in protection against AD-related mitochondrial dysfunction and phenotypic deterioration. PMID:25538817

  4. Nicotinamide phosphoribosyltransferase is required for the calorie restriction-mediated improvements in oxidative stress, mitochondrial biogenesis, and metabolic adaptation.

    PubMed

    Song, Jie; Ke, Sen-Fang; Zhou, Can-Can; Zhang, Sai-Long; Guan, Yun-Feng; Xu, Tian-Ying; Sheng, Chun-Quan; Wang, Pei; Miao, Chao-Yu

    2014-01-01

    Calorie restriction (CR) is one of the most reproducible treatments for weight loss and slowing aging. However, how CR induces these metabolic alterations is not fully understood. In this work, we studied whether nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme for nicotinamide adenine dinucleotide biosynthesis, plays a role in CR-induced beneficial metabolic effects using a specific inhibitor of NAMPT (FK866). CR upregulated NAMPT mRNA and protein levels in rat skeletal muscle and white adipose tissue. Inhibition of NAMPT activity by FK866 in rats did not affect the SIRT1 upregulation by CR but suppressed the CR-induced SIRT1 activity and deacetylation of Forkhead box protein O1/peroxisome proliferator-activated receptor γ coactivator-1α. Inhibition of NAMPT activity by FK866 also attenuated the CR-induced SIRT3 activity, evidenced by deacetylation of superoxide dismutase-2. Furthermore, FK866 not only weakened the CR-induced decrease of oxidative stress (dichlorofluorescin signal, superoxide , and malondialdehyde levels), but also greatly attenuated the CR-induced improvements of antioxidative activity (total superoxide dismutase, glutathione, and glutathione/oxidized glutathione ratio) and mitochondrial biogenesis (mRNA levels of nuclear respiratory factor 1, cytochrome c oxidase IV, peroxisome proliferator-activated receptor-γ coactivator-1α, and transcription factor A, mitochondrial and citrate synthase activity). At last, FK866 blocked the CR-induced insulin sensitizing, Akt signaling activation, and endothelial nitric oxide synthase phosphorylation. Collectively, our data provide the first evidence that the CR-induced beneficial effects in oxidative stress, mitochondrial biogenesis, and metabolic adaptation require NAMPT. PMID:23946338

  5. 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

  6. Lipoamide Acts as an Indirect Antioxidant by Simultaneously Stimulating Mitochondrial Biogenesis and Phase II Antioxidant Enzyme Systems in ARPE-19 Cells

    PubMed Central

    Zhao, Lin; Liu, Zhongbo; Jia, Haiqun; Feng, Zhihui; Liu, Jiankang; Li, Xuesen

    2015-01-01

    In our previous study, we found that pretreatment with lipoamide (LM) more effectively than alpha-lipoic acid (LA) protected retinal pigment epithelial (RPE) cells from the acrolein-induced damage. However, the reasons and mechanisms for the greater effect of LM than LA are unclear. We hypothesize that LM, rather than the more direct antioxidant LA, may act more as an indirect antioxidant. In the present study, we treated ARPE-19 cells with LA and LM and compared their effects on activation of mitochondrial biogenesis and induction of phase II enzyme systems. It is found that LM is more effective than LA on increasing mitochondrial biogenesis and inducing the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and its translocation to the nucleus, leading to an increase in expression or activity of phase II antioxidant enzymes (NQO-1, GST, GCL, catalase and Cu/Zn SOD). Further study demonstrated that mitochondrial biogenesis and phase II enzyme induction are closely coupled via energy requirements. These results suggest that LM, compared with the direct antioxidant LA, plays its protective effect on oxidative damage more as an indirect antioxidant to simultaneously stimulate mitochondrial biogenesis and induction of phase II antioxidant enzymes. PMID:26030919

  7. Lipoamide Acts as an Indirect Antioxidant by Simultaneously Stimulating Mitochondrial Biogenesis and Phase II Antioxidant Enzyme Systems in ARPE-19 Cells.

    PubMed

    Zhao, Lin; Liu, Zhongbo; Jia, Haiqun; Feng, Zhihui; Liu, Jiankang; Li, Xuesen

    2015-01-01

    In our previous study, we found that pretreatment with lipoamide (LM) more effectively than alpha-lipoic acid (LA) protected retinal pigment epithelial (RPE) cells from the acrolein-induced damage. However, the reasons and mechanisms for the greater effect of LM than LA are unclear. We hypothesize that LM, rather than the more direct antioxidant LA, may act more as an indirect antioxidant. In the present study, we treated ARPE-19 cells with LA and LM and compared their effects on activation of mitochondrial biogenesis and induction of phase II enzyme systems. It is found that LM is more effective than LA on increasing mitochondrial biogenesis and inducing the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and its translocation to the nucleus, leading to an increase in expression or activity of phase II antioxidant enzymes (NQO-1, GST, GCL, catalase and Cu/Zn SOD). Further study demonstrated that mitochondrial biogenesis and phase II enzyme induction are closely coupled via energy requirements. These results suggest that LM, compared with the direct antioxidant LA, plays its protective effect on oxidative damage more as an indirect antioxidant to simultaneously stimulate mitochondrial biogenesis and induction of phase II antioxidant enzymes. PMID:26030919

  8. Mitogen-activated protein kinase kinases promote mitochondrial biogenesis in part through inducing peroxisome proliferator-activated receptor γ coactivator-1β expression.

    PubMed

    Gao, Minghui; Wang, Junjian; Lu, Na; Fang, Fang; Liu, Jinsong; Wong, Chi-Wai

    2011-06-01

    Growth factor activates mitogen-activated protein kinase kinases to promote cell growth. Mitochondrial biogenesis is an integral part of cell growth. How growth factor regulates mitochondrial biogenesis is not fully understood. In this study, we found that mitochondrial mass was specifically reduced upon serum starvation and induced upon re-feeding with serum. Using mitogen-activated protein kinase kinases inhibitor U0126, we found that the mRNA expression levels of ATP synthase, cytochrome-C, mitochondrial transcription factor A, and mitofusin 2 were reduced. Since the transcriptional levels of these genes are under the control of peroxisome proliferator-activated receptor γ coactivator-1α and -1β (PGC-1α and PGC-1β), we examined and found that only the mRNA and protein levels of PGC-1β were suppressed. Importantly, over-expression of PGC-1β partially reversed the reduction of mitochondrial mass upon U0126 treatment. Thus, we conclude that mitogen-activated protein kinase kinases direct mitochondrial biogenesis through selectively inducing PGC-1β expression. PMID:21458501

  9. Assessment of Newly Synthesized Mitochondrial DNA Using BrdU Labeling in Primary Neurons from Alzheimer’s Disease Mice: Implications for Impaired Mitochondrial Biogenesis and Synaptic Damage

    PubMed Central

    Calkins, Marcus J.; Reddy, P. Hemachandra

    2011-01-01

    The purpose our study was to assess mitochondrial biogenesis and distribution in murine primary neurons. Using 5-bromo-2-deoxyuridie (BrdU) incorporation and primary neurons, we studied the mitochondrial biogenesis and mitochondrial distribution in hippocampal neurons from amyloid beta precursor protein (AβPP) transgenic mice and wild-type (WT) neurons treated with oxidative stressors, rotenone and H2O2. We found that after 20 hr of labeling, BrdU incorporation was specific to porin-positive mitochondria. The proportion of mitochondrial area that labeled with BrdU was 40.3 ± 6.3% at 20 hr. The number of mitochondria with newly synthesized DNA was higher in AβPP neuronal cell bodies than in the cell bodies of WT neurons (AβPP, 45.23 ± 2.67 BrdU-positive/cell body; WT, 32.92 ± 2.49 BrdU-positive/cell body; p = 0.005). In neurites, the number of BrdU-positive mitochondria decreased in AβPP cultures compared to WT neurons (AβPP, 0.105 ± 0.008 BrdU-positive/μm neurite; WT, 0.220 ± 0.036 BrdU-positive−/−μm neurite; p = 0.010). Further, BrdU in the cell body increased when neurons were treated with low doses of H2O2 (49.6 ± 2.7 BrdU-positive/cell body, p = 0.0002 compared to untreated cells), while the neurites showed decreased BrdU staining (0.122 ± 0.010 BrdU-positive/μm neurite, p = 0.005 compared to the untreated). BrdU labeling was increased in the cell body under rotenone treatment. Additionally, under rotenone treatment, the content of BrdU labeling decreased in neurites. These findings suggest that Aβ and mitochondrial toxins enhance mitochondrial fragmentation in cell body, and may cause impaired axonal transport of mitochondria leading to synaptic degeneration. PMID:21549836

  10. Assessment of newly synthesized mitochondrial DNA using BrdU labeling in primary neurons from Alzheimer's disease mice: Implications for impaired mitochondrial biogenesis and synaptic damage.

    PubMed

    Calkins, Marcus J; Reddy, P Hemachandra

    2011-09-01

    The purpose of our study was to assess mitochondrial biogenesis and distribution in murine primary neurons. Using 5-bromo-2-deoxyuridine (BrdU) incorporation and primary neurons, we studied the mitochondrial biogenesis and mitochondrial distribution in hippocampal neurons from amyloid beta precursor protein (AβPP) transgenic mice and wild-type (WT) neurons treated with oxidative stressors, rotenone and H(2)O(2). We found that after 20h of labeling, BrdU incorporation was specific to porin-positive mitochondria. The proportion of mitochondrial area labeled with BrdU was 40.3±6.3% at 20h. The number of mitochondria with newly synthesized DNA was higher in AβPP neuronal cell bodies than in the cell bodies of WT neurons (AβPP, 45.23±2.67 BrdU-positive/cell body; WT, 32.92±2.49 BrdU-positive/cell body; p=0.005). In neurites, the number of BrdU-positive mitochondria decreased in AβPP cultures compared to WT neurons (AβPP, 0.105±0.008 BrdU-positive/μm neurite; WT, 0.220±0.036 BrdU-positive/μm neurite; p=0.010). Further, BrdU in the cell body increased when neurons were treated with low doses of H(2)O(2) (49.6±2.7 BrdU-positive/cell body, p=0.0002 compared to untreated cells), while the neurites showed decreased BrdU staining (0.122±0.010 BrdU-positive/μm neurite, p=0.005 compared to the untreated). BrdU labeling was increased in the cell body under rotenone treatment. Additionally, under rotenone treatment, the content of BrdU labeling decreased in neurites. These findings suggest that Aβ and mitochondrial toxins enhance mitochondrial fragmentation in the cell body, and may cause impaired axonal transport of mitochondria leading to synaptic degeneration. PMID:21549836

  11. 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-?-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-?-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

  12. High fat diet-induced liver steatosis promotes an increase in liver mitochondrial biogenesis in response to hypoxia.

    PubMed

    Carabelli, Julieta; Burgueño, Adriana L; Rosselli, Maria Soledad; Gianotti, Tomas Fernández; Lago, Nestor R; Pirola, Carlos J; Sookoian, Silvia

    2011-06-01

    Mitochondrial DNA (mtDNA) copy number plays a key role in the pathophysiology of metabolic syndrome-related phenotypes, but its role in non-alcoholic fatty liver disease (NAFLD) is not well understood. We evaluated the molecular mechanisms that may be involved in the regulation of liver mtDNA content in a high-fat-induced rat model of NAFLD. In particular, we tested the hypothesis that liver mtDNA copy number is associated with liver expression of HIF-1α. Rats were given either standard chow diet (SCD, n = 10) or high-fat diet (HFD, n = 15) for 20 weeks. Subsequently, mtDNA quantification using nuclear DNA (nDNA) as a reference was carried out using real time quantitative PCR. HFD induced a significant increase in liver mtDNA/nDNA ratio, which significantly correlated with the liver triglyceride content (R: 0.29, P < 0.05). The liver mtDNA/nDNA ratio significantly correlated with the hepatic expression of HIF-1α mRNA (R: 0.37, P < 0.001); liver HIF-1α mRNA was significantly higher in the HFD group. In addition, liver cytochrome c oxidase subunit IV isoform 1 (COX4I1) mRNA expression was also positively correlated with liver mtDNA content. The hepatic expression of mRNA of transcriptional factors that regulate mitochondrial biogenesis, including peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α) and PGC-1β, nuclear respiratory factor-1 (NRF-1), peroxisome proliferator-activated receptor δ and Tfam, was not associated with the liver mtDNA content. Neither hepatocyte apoptosis nor oxidative stress was involved in the HIF-1α-mediated increase in mtDNA copy number. In conclusion, we found that HFD promotes an increase in liver mitochondrial biogenesis in response to hypoxia via HIF-1α, probably to enhance the mitochondrial function as well as to accommodate the metabolic load. PMID:20629985

  13. High fat diet-induced liver steatosis promotes an increase in liver mitochondrial biogenesis in response to hypoxia

    PubMed Central

    Carabelli, Julieta; Burgueño, Adriana L; Rosselli, Maria Soledad; Gianotti, Tomas Fernández; Lago, Nestor R; Pirola, Carlos J; Sookoian, Silvia

    2011-01-01

    Abstract Mitochondrial DNA (mtDNA) copy number plays a key role in the pathophysiology of metabolic syndrome-related phenotypes, but its role in non-alcoholic fatty liver disease (NAFLD) is not well understood. We evaluated the molecular mechanisms that may be involved in the regulation of liver mtDNA content in a high-fat-induced rat model of NAFLD. In particular, we tested the hypothesis that liver mtDNA copy number is associated with liver expression of HIF-1α. Rats were given either standard chow diet (SCD, n= 10) or high-fat diet (HFD, n= 15) for 20 weeks. Subsequently, mtDNA quantification using nuclear DNA (nDNA) as a reference was carried out using real time quantitative PCR. HFD induced a significant increase in liver mtDNA/nDNA ratio, which significantly correlated with the liver triglyceride content (R: 0.29, P < 0.05). The liver mtDNA/nDNA ratio significantly correlated with the hepatic expression of HIF-1α mRNA (R: 0.37, P < 0.001); liver HIF-1α mRNA was significantly higher in the HFD group. In addition, liver cytochrome c oxidase subunit IV isoform 1 (COX4I1) mRNA expression was also positively correlated with liver mtDNA content. The hepatic expression of mRNA of transcriptional factors that regulate mitochondrial biogenesis, including peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α) and PGC-1β, nuclear respiratory factor-1 (NRF-1), peroxisome proliferator-activated receptor δ and Tfam, was not associated with the liver mtDNA content. Neither hepatocyte apoptosis nor oxidative stress was involved in the HIF-1α-mediated increase in mtDNA copy number. In conclusion, we found that HFD promotes an increase in liver mitochondrial biogenesis in response to hypoxia via HIF-1α, probably to enhance the mitochondrial function as well as to accommodate the metabolic load. PMID:20629985

  14. Inhibition of akt phosphorylation diminishes mitochondrial biogenesis regulators, tricarboxylic acid cycle activity and exacerbates recognition memory deficit in rat model of Alzheimer's disease.

    PubMed

    Shaerzadeh, Fatemeh; Motamedi, Fereshteh; Khodagholi, Fariba

    2014-11-01

    3-Methyladenine (3-MA), as a PI3K inhibitor, is widely used for inhibition of autophagy. Inhibition of PI3K class I leads to inhibition of Akt phosphorylation, a central molecule involved in diverse arrays of intracellular cascades in nervous system. Accordingly, in the present study, we aimed to determine the alterations of specific mitochondrial biogenesis markers and mitochondrial function in 3-MA-injected rats following amyloid beta (A?) insult. Our data revealed that inhibition of Akt phosphorylation downregulates master regulator of mitochondrial biogenesis, peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1?). Our data also showed that decrease in PGC-1? level presumably is due to decrease in the phosphorylation of cAMP-response element binding and AMP-activated kinase, two upstream activators of PGC-1?. As a consequence, the level of some mitochondrial biogenesis factors including nuclear respiratory factor-1, mitochondrial transcription factor A, and Cytochrome c decreased significantly. Also, activities of tricarboxylic acid cycle (TCA) enzymes such as Aconitase, a-ketoglutarate dehydrogenase, and malate dehydrogenase reduced in the presence of 3-MA with or without A? insult. Decrease in mitochondrial biogenesis factors and TCA enzyme activity in the rats receiving 3-MA and A? were more compared to the rats that received either alone; indicating the additive destructive effects of these two agents. In agreement with our molecular results, data obtained from behavioral test (using novel objective recognition test) indicated that inhibition of Akt phosphorylation with or without A? injection impaired novel recognition (non-spatial) memory. Our results suggest that 3-MA amplified deleterious effects of A? by targeting central molecule Akt. PMID:25135709

  15. 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

    PubMed Central

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

    2012-01-01

    The fundamental question of how and which neuronal specific transcription factors tailor mitochondrial 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. PMID:22814253

  16. Elevated Mitochondrial Oxidative Stress Impairs Metabolic Adaptations to Exercise in Skeletal Muscle

    PubMed Central

    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. PMID:24324727

  17. 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. PMID:24324727

  18. Phosphatase and Tensin Homolog Deleted on Chromosome 10 (PTEN) Signaling Regulates Mitochondrial Biogenesis and Respiration via Estrogen-related Receptor α (ERRα)*

    PubMed Central

    Li, Yang; He, Lina; Zeng, Ni; Sahu, Divya; Cadenas, Enrique; Shearn, Colin; Li, Wei; Stiles, Bangyan L.

    2013-01-01

    Mitochondrial abnormalities are associated with cancer development, yet how oncogenic signals affect mitochondrial functions has not been fully understood. In this study, we investigate the relationship between mitochondrial alterations and PI3K/protein kinase B (AKT) signaling activation using hepatocytes and liver tissues as our experimental models. We show here that liver-specific deletion of Pten, which leads to activation of PI3K/AKT, is associated with elevated oxidative stress, increased mitochondrial mass, and augmented respiration accompanied by enhanced glycolysis. Consistent with these observations, estrogen-related receptor α (ERRα), an orphan nuclear receptor known for its role in mitochondrial biogenesis, is up-regulated in the absence of phosphatase and tensin homolog deleted on chromosome 10 (PTEN). Our pharmacological and genetic studies show that PI3K/AKT activity regulates the expression of ERRα and mitochondrial biogenesis/respiration. Furthermore, cAMP-response element-binding protein, as a downstream target of AKT, plays a role in the regulation of ERRα, independent of PKA signaling. ERRα regulates reactive oxygen species production, and ERRα knockdown attenuates proliferation and colony-forming potential in Pten-null hepatocytes. Finally, analysis of clinical datasets from liver tissues showed a negative correlation between expressions of ERRα and PTEN in patients with liver cancer. Therefore, this study has established a previously unrecognized link between a growth signal and mitochondrial metabolism. PMID:23836899

  19. 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

  20. Acute exercise induces tumour suppressor protein p53 translocation to the mitochondria and promotes a p53–Tfam–mitochondrial DNA complex in skeletal muscle

    PubMed Central

    Saleem, Ayesha; Hood, David A

    2013-01-01

    The major tumour suppressor protein p53 plays an important role in maintaining mitochondrial content and function in skeletal muscle. p53 has been shown to reside in the mitochondria complexed with mitochondrial DNA (mtDNA); however, the physiological repercussions of mitochondrial p53 remain unknown. We endeavoured to elucidate whether an acute bout of endurance exercise could mediate an increase in mitochondrial p53 levels. C57Bl6 mice (n= 6 per group) were randomly assigned to sedentary, acute exercise (AE, 15 m min−1 for 90 min) or acute exercise + 3 h recovery (AER) groups. Exercise concomitantly increased the mRNA content of nuclear-encoded (PGC-1α, Tfam, NRF-1, COX-IV, citrate synthase) and mtDNA-encoded (COX-I) genes in the AE group, and further by ∼5-fold in the AER group. Nuclear p53 protein levels were reduced in the AE and AER groups, while in contrast, the abundance of p53 was drastically enhanced by ∼2.4-fold and ∼3.9-fold in subsarcolemmal and intermyofibrillar mitochondria, respectively, in the AER conditions. Within the mitochondria, the interaction of p53 with mtDNA at the D-loop and with Tfam was elevated by ∼4.6-fold and ∼3.6-fold, respectively, in the AER group. In the absence of p53, the enhanced COX-I mRNA content observed with AE and AER was abrogated. This study is the first to indicate that endurance exercise can signal to localize p53 to the mitochondria where it may serve to positively modulate the activity of the mitochondrial transcription factor Tfam. Our findings help us understand the mechanisms underlying the effects of exercise as a therapeutic intervention designed to trigger the pro-metabolic functions of p53. PMID:23690562

  1. Agonism of the 5-hydroxytryptamine 1F receptor promotes mitochondrial biogenesis and recovery from acute kidney injury.

    PubMed

    Garrett, Sara M; Whitaker, Ryan M; Beeson, Craig C; Schnellmann, Rick G

    2014-08-01

    Many acute and chronic conditions, such as acute kidney injury, chronic kidney disease, heart failure, and liver disease, involve mitochondrial dysfunction. Although we have provided evidence that drug-induced stimulation of mitochondrial biogenesis (MB) accelerates mitochondrial and cellular repair, leading to recovery of organ function, only a limited number of chemicals have been identified that induce MB. The goal of this study was to assess the role of the 5-hydroxytryptamine 1F (5-HT1F) receptor in MB. Immunoblot and quantitative polymerase chain reaction analyses revealed 5-HT1F receptor expression in renal proximal tubule cells (RPTC). A MB screening assay demonstrated that two selective 5-HT1F receptor agonists, LY334370 (4-fluoro-N-[3-(1-methyl-4-piperidinyl)-1H-indol-5-yl]benzamide) and LY344864 (N-[(3R)-3-(dimethylamino)-2,3,4,9-tetrahydro-1H-carbazol-6-yl]-4-fluorobenzamide; 1-100 nM) increased carbonylcyanide-p-trifluoromethoxyphenylhydrazone-uncoupled oxygen consumption in RPTC, and validation studies confirmed both agonists increased mitochondrial proteins [e.g., ATP synthase ?, cytochrome c oxidase 1 (Cox1), and NADH dehydrogenase (ubiquinone) 1? subcomplex subunit 8 (NDUFB8)] in vitro. Small interfering RNA knockdown of the 5-HT1F receptor blocked agonist-induced MB. Furthermore, LY344864 increased peroxisome proliferator-activated receptor coactivator 1-?, Cox1, and NDUFB8 transcript levels and mitochondrial DNA (mtDNA) copy number in murine renal cortex, heart, and liver. Finally, LY344864 accelerated recovery of renal function, as indicated by decreased blood urea nitrogen and kidney injury molecule 1 and increased mtDNA copy number following ischemia/reperfusion-induced acute kidney injury (AKI). In summary, these studies reveal that the 5-HT1F receptor is linked to MB, 5-HT1F receptor agonism promotes MB in vitro and in vivo, and 5-HT1F receptor agonism promotes recovery from AKI injury. Induction of MB through 5-HT1F receptor agonism represents a new target and approach to treat mitochondrial organ dysfunction. PMID:24849926

  2. Agonism of the 5-Hydroxytryptamine 1F Receptor Promotes Mitochondrial Biogenesis and Recovery from Acute Kidney Injury

    PubMed Central

    Garrett, Sara M.; Whitaker, Ryan M.; Beeson, Craig C.

    2014-01-01

    Many acute and chronic conditions, such as acute kidney injury, chronic kidney disease, heart failure, and liver disease, involve mitochondrial dysfunction. Although we have provided evidence that drug-induced stimulation of mitochondrial biogenesis (MB) accelerates mitochondrial and cellular repair, leading to recovery of organ function, only a limited number of chemicals have been identified that induce MB. The goal of this study was to assess the role of the 5-hydroxytryptamine 1F (5-HT1F) receptor in MB. Immunoblot and quantitative polymerase chain reaction analyses revealed 5-HT1F receptor expression in renal proximal tubule cells (RPTC). A MB screening assay demonstrated that two selective 5-HT1F receptor agonists, LY334370 (4-fluoro-N-[3-(1-methyl-4-piperidinyl)-1H-indol-5-yl]benzamide) and LY344864 (N-[(3R)-3-(dimethylamino)-2,3,4,9-tetrahydro-1H-carbazol-6-yl]-4-fluorobenzamide; 1100 nM) increased carbonylcyanide-p-trifluoromethoxyphenylhydrazoneuncoupled oxygen consumption in RPTC, and validation studies confirmed both agonists increased mitochondrial proteins [e.g., ATP synthase ?, cytochrome c oxidase 1 (Cox1), and NADH dehydrogenase (ubiquinone) 1? subcomplex subunit 8 (NDUFB8)] in vitro. Small interfering RNA knockdown of the 5-HT1F receptor blocked agonist-induced MB. Furthermore, LY344864 increased peroxisome proliferatoractivated receptor coactivator 1-?, Cox1, and NDUFB8 transcript levels and mitochondrial DNA (mtDNA) copy number in murine renal cortex, heart, and liver. Finally, LY344864 accelerated recovery of renal function, as indicated by decreased blood urea nitrogen and kidney injury molecule 1 and increased mtDNA copy number following ischemia/reperfusion-induced acute kidney injury (AKI). In summary, these studies reveal that the 5-HT1F receptor is linked to MB, 5-HT1F receptor agonism promotes MB in vitro and in vivo, and 5-HT1F receptor agonism promotes recovery from AKI injury. Induction of MB through 5-HT1F receptor agonism represents a new target and approach to treat mitochondrial organ dysfunction. PMID:24849926

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

    PubMed Central

    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. PMID:26230519

  4. The deacetylase enzyme SIRT1 is not associated with oxidative capacity in rat heart and skeletal muscle and its overexpression reduces mitochondrial biogenesis

    PubMed Central

    Gurd, Brendon J; Yoshida, Yuko; Lally, James; Holloway, Graham P; Bonen, Arend

    2009-01-01

    Deacetylation of PGC-1α by SIRT1 is thought to be an important step in increasing PGC-1α transcriptional activity, since in muscle cell lines SIRT1 induces PGC-1α protein expression and mitochondrial biogenesis. We examined the relationship between SIRT1 protein and activity, PGC-1α and markers of mitochondrial density, (a) across a range of metabolically heterogeneous skeletal muscles and the heart, and when mitochondrial biogenesis was stimulated by (b) chronic muscle stimulation (7 days) and (c) AICAR administration (5 days), and finally, (d) we also examined the effects of SIRT1 overexpression on mitochondrial biogenesis and PGC-1α. SIRT1 protein and activity were correlated (r= 0.97). There were negative correlations between SIRT1 protein and PGC-1α (r=−0.95), COX IV (r=−0.94) and citrate synthase (r=−0.97). Chronic muscle stimulation and AICAR upregulated PGC-1α protein (22–159%) and oxidative capacity (COX IV, 20–69%); in each instance SIRT1 protein was downregulated by 20–40%, while SIRT1 intrinsic activity was increased. SIRT1 overexpression in rodent muscle increased SIRT1 protein (+240%) and doubled SIRT1 activity, but PGC-1α (−25%), mtTFA (−14%) and COX IV (−10%) proteins were downregulated. Taken altogether these experiments are not consistent with the notion that SIRT1 protein plays an obligatory regulatory role in the process of PGC-1α-mediated mitochondrial biogenesis in mammalian muscle. PMID:19237425

  5. Exercise-induced anaphylaxis.

    PubMed

    Sheffer, A L; Austen, K F

    1980-08-01

    Sixteen patients were seen because of possibly life-threatening exercise-associated symptoms similar to anaphylactic reactions. Asthma attacks, cholinergic urticaria and angioedema, and cardiac arrythmias are recognized as exertion-related phenomena in predisposed patients but are distinct from the syndrome described here. A syndrome characterized by the exertion-related onset of cutaneous pruritus and warmth, the development of generalized urticaria, and the appearance of such additional manifestations as collapse in 12 patients, gastrointestinal tract symptoms in five patients, and upper respiratory distress in 10 patients has been designated exercise-induced anaphylaxis, because of the striking similarity of this symptom complex to the anaphylactic syndrome elicited by ingestion or injection of a foreign antigenic substance. There is a family history of atopic desease for 11 patients and cold urticaria for two others and a personal history of atopy in six. The size of the wheals, the failure to develop an attack with a warm bath or shower or a fever, and the prominence of syncope rule against the diagnosis of conventional cholinergic urticaria. There is no history or evidence of an encounter with an environmental source of antigen during the exercise period. PMID:7400473

  6. Exercise-induced asthma.

    PubMed

    Mahler, D A

    1993-05-01

    Bronchoconstriction associated with exercise can occur in nearly all individuals with asthma and in 35-40% of those with allergic rhinitis/hay fever symptoms. This represents approximately 12-15% of the population. Exercise-induced asthma (EIA) is a clinical syndrome characterized by transient airflow obstruction typically 5-15 min after cessation of physical exertion. Symptoms may include chest tightness, breathlessness, coughing, and/or wheezing. Some individuals may experience delayed bronchoconstriction (late phase response) 6-10 h after completing exercise. Approximately 40-50% of those with asthma exhibit a "refractory period", i.e., diminished bronchoconstriction to exercise performed within 2 h. The pathophysiology of EIA is related to thermal events within the intrathoracic airways. Alterations in the temperature of the airways and/or osmolarity in the epithelial lining fluid cause release of mediators in the airways and the development of bronchoconstriction. Although EIA can be strongly suspected by an appropriate history, pulmonary function testing is necessary to make a specific diagnosis. Measurement of lung function is an important first diagnostic test. If there is no evidence of airflow obstruction at rest, then either bronchoprovocation testing or exercise challenge testing is indicated. Nonpharmacologic therapy includes "warm-up" exercise prior to training or competition to induce a "refractory period" and to prevent/reduce bronchoconstriction. An inhaled beta 2-adrenergic agonist, e.g., albuterol, is usually effective for preventing/treating EIA. Cromolyn sodium is an alternative class of medication that inhibits both the early and late phase responses. Other bronchodilator agents are available if combination therapy with an inhaled beta 2-adrenergic agonist and cromolyn sodium is not effective.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:8492682

  7. Low-molecular-weight polyphenols protect kidney damage through suppressing NF-κB and modulating mitochondrial biogenesis in diabetic db/db mice.

    PubMed

    Liu, Hung-Wen; Wei, Chu-Chun; Chang, Sue-Joan

    2016-04-20

    Hyperglycemia, increased inflammatory responses, and dysregulation of mitochondrial function accompanied by type 2 diabetes may eventually lead to kidney damage. We examined the protective effects of oligonol, a low-molecular-weight polyphenol derived from lychee fruit and green tea, on kidney damage in diabetic db/db mice. Dietary oligonol supplementation lowered glucose and insulin levels and improved oral glucose tolerance. Oligonol attenuated serum resistin and IL-6 levels and reduced glomerular hypertrophy and mesangial matrix expansion caused by diabetes. Oligonol reduced activation of nuclear factor-kappa B (NF-κB) and p38 mitogen-activated protein kinase. Suppressed renal oxidative stress by oligonol was associated with stimulated sirtuin1 expression and restored AMP-activated kinase protein α activity, mitochondrial DNA copy number, and mitochondrial biogenesis associated genes including nuclear respiratory factor 1 and mitochondrial transcription factor A. In conclusion, oligonol reduced fasting glucose level, improved insulin sensitivity, suppressed inflammatory responses, and upregulated metabolic regulators involved in mitochondrial biogenesis, thereby leading to protection against diabetes-induced kidney damage. PMID:26960417

  8. Sam50 Functions in Mitochondrial Intermembrane Space Bridging and Biogenesis of Respiratory Complexes

    PubMed Central

    Ott, Christine; Ross, Katharina; Straub, Sebastian; Thiede, Bernd; Götz, Monika; Goosmann, Christian; Krischke, Markus; Mueller, Martin J.; Krohne, Georg

    2012-01-01

    Mitochondria possess an outer membrane (OMM) and an inner membrane (IMM), which folds into invaginations called cristae. Lipid composition, membrane potential, and proteins in the IMM influence organization of cristae. Here we show an essential role of the OMM protein Sam50 in the maintenance of the structure of cristae. Sam50 is a part of the sorting and assembly machinery (SAM) necessary for the assembly of β-barrel proteins in the OMM. We provide evidence that the SAM components exist in a large protein complex together with the IMM proteins mitofilin and CHCHD3, which we term the mitochondrial intermembrane space bridging (MIB) complex. Interactions between OMM and IMM components of the MIB complex are crucial for the preservation of cristae. After destabilization of the MIB complex, we observed deficiency in the assembly of respiratory chain complexes. Long-term depletion of Sam50 influences the amounts of proteins from all large respiratory complexes that contain mitochondrially encoded subunits, pointing to a connection between the structural integrity of cristae, assembly of respiratory complexes, and/or the maintenance of mitochondrial DNA (mtDNA). PMID:22252321

  9. 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

  10. The CDP-Ethanolamine Pathway Regulates Skeletal Muscle Diacylglycerol Content and Mitochondrial Biogenesis without Altering Insulin Sensitivity.

    PubMed

    Selathurai, Ahrathy; Kowalski, Greg M; Burch, Micah L; Sepulveda, Patricio; Risis, Steve; Lee-Young, Robert S; Lamon, Severine; Meikle, Peter J; Genders, Amanda J; McGee, Sean L; Watt, Matthew J; Russell, Aaron P; Frank, Matthew; Jackowski, Suzanne; Febbraio, Mark A; Bruce, Clinton R

    2015-05-01

    Accumulation of diacylglycerol (DG) in muscle is thought to cause insulin resistance. DG is a precursor for phospholipids, thus phospholipid synthesis could be involved in regulating muscle DG. Little is known about the interaction between phospholipid and DG in muscle; therefore, we examined whether disrupting muscle phospholipid synthesis, specifically phosphatidylethanolamine (PtdEtn), would influence muscle DG content and insulin sensitivity. Muscle PtdEtn synthesis was disrupted by deleting CTP:phosphoethanolamine cytidylyltransferase (ECT), the rate-limiting enzyme in the CDP-ethanolamine pathway, a major route for PtdEtn production. WhilePtdEtn was reduced in muscle-specific ECT knockout mice, intramyocellular and membrane-associated DG was markedly increased. Importantly, however, this was not associated with insulin resistance. Unexpectedly, mitochondrial biogenesis and muscle oxidative capacity were increased in muscle-specific ECT knockout mice and were accompanied by enhanced exercise performance. These findings highlight the importance of the CDP-ethanolamine pathway in regulating muscle DG content and challenge the DG-induced insulin resistance hypothesis. PMID:25955207

  11. Short-Chain Fatty Acid Acetate Stimulates Adipogenesis and Mitochondrial Biogenesis via GPR43 in Brown Adipocytes.

    PubMed

    Hu, Jiamiao; Kyrou, Ioannis; Tan, Bee K; Dimitriadis, Georgios K; Ramanjaneya, Manjunath; Tripathi, Gyanendra; Patel, Vanlata; James, Sean; Kawan, Mohamed; Chen, Jing; Randeva, Harpal S

    2016-05-01

    Short-chain fatty acids play crucial roles in a range of physiological functions. However, the effects of short-chain fatty acids on brown adipose tissue have not been fully investigated. We examined the role of acetate, a short-chain fatty acid formed by fermentation in the gut, in the regulation of brown adipocyte metabolism. Our results show that acetate up-regulates adipocyte protein 2, peroxisomal proliferator-activated receptor-γ coactivator-1α, and uncoupling protein-1 expression and affects the morphological changes of brown adipocytes during adipogenesis. Moreover, an increase in mitochondrial biogenesis was observed after acetate treatment. Acetate also elicited the activation of ERK and cAMP response element-binding protein, and these responses were sensitive to G(i/o)-type G protein inactivator, Gβγ-subunit inhibitor, phospholipase C inhibitor, and MAPK kinase inhibitor, indicating a role for the G(i/o)βγ/phospholipase C/protein kinase C/MAPK kinase signaling pathway in these responses. These effects of acetate were mimicked by treatment with 4-chloro-α-(1-methylethyl)-N-2-thiazolylbenzeneacetamide, a synthetic G protein-coupled receptor 43 (GPR43) agonist and were impaired in GPR43 knockdown cells. Taken together, our results indicate that acetate may have important physiological roles in brown adipocytes through the activation of GPR43. PMID:26990063

  12. 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. PMID:26700734

  13. Hydroxytyrosol protects against oxidative damage by simultaneous activation of mitochondrial biogenesis and phase II detoxifying enzyme systems in retinal pigment epithelial cells.

    PubMed

    Zhu, Lu; Liu, Zhongbo; Feng, Zhihui; Hao, Jiejie; Shen, Weili; Li, Xuesen; Sun, Lijuan; Sharman, Edward; Wang, Ying; Wertz, Karin; Weber, Peter; Shi, Xianglin; Liu, Jiankang

    2010-11-01

    Studies in this laboratory have previously shown that hydroxytyrosol, the major antioxidant polyphenol in olives, protects ARPE-19 human retinal pigment epithelial cells from oxidative damage induced by acrolein, an environmental toxin and endogenous end product of lipid oxidation, that occurs at increased levels in age-related macular degeneration lesions. A proposed mechanism for this is that protection by hydroxytyrosol against oxidative stress is conferred by the simultaneous activation of two critically important pathways, viz., induction of phase II detoxifying enzymes and stimulation of mitochondrial biogenesis. Cultured ARPE-19 cells were pretreated with hydroxytyrosol and challenged with acrolein. The protective effects of hydroxytyrosol on key factors of mitochondrial biogenesis and phase II detoxifying enzyme systems were examined. Hydroxytyrosol treatment simultaneously protected against acrolein-induced inhibition of nuclear factor-E2-related factor 2 (Nrf2) and peroxisome proliferator-activated receptor coactivator 1 alpha (PPARGC1?) in ARPE-19 cells. The activation of Nrf2 led to activation of phase II detoxifying enzymes, including ?-glutamyl-cysteinyl-ligase, NADPH (nicotinamide adenine dinucleotide phosphate)-quinone-oxidoreductase 1, heme-oxygenase-1, superoxide dismutase, peroxiredoxin and thioredoxin as well as other antioxidant enzymes, while the activation of PPARGC1? led to increased protein expression of mitochondrial transcription factor A, uncoupling protein 2 and mitochondrial complexes. These results suggest that hydroxytyrosol is a potent inducer of phase II detoxifying enzymes and an enhancer of mitochondrial biogenesis. Dietary supplementation of hydroxytyrosol may contribute to eye health by preventing the degeneration of retinal pigment epithelial cells induced by oxidative stress. PMID:20149621

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

    PubMed Central

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

    2016-01-01

    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 diet in utero and 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 number P < 0.05; transcription factor A, mitochondrial expression P < 0.05), increased mitochondrial antioxidant defenses [manganese superoxide dismutase (MnSOD) P < 0.05; copper/zinc superoxide dismutase P < 0.05; glutathione peroxidase 4 P < 0.01] and increased lipoxygenase expression (arachidonate 12-lipoxygenase P < 0.05; arachidonate 15-lipoxygenase P < 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. PMID:26700734

  15. Mitochondria in exercise-induced oxidative stress.

    PubMed

    Di Meo, S; Venditti, P

    2001-01-01

    In recent years it has been suggested that reactive oxygen species (ROS) are involved in the damage to muscle and other tissues induced by acute exercise. Despite the small availability of direct evidence for ROS production during exercise, there is an abundance of literature providing indirect support that oxidative stress occurs during exercise. The electron transport associated with the mitochondrial respiratory chain is considered the major process leading to ROS production at rest and during exercise. It is widely assumed that during exercise the increased electron flow through the mitochondrial electron transport chain leads to an increased rate of ROS production. On the other hand, results obtained by in vitro experiments indicate that mitochondrial ROS production is lower in state 3 (ADP-stimulated) than in state 4 (basal) respiration. It is possible, however, that factors, such as temperature, that are modified in vivo during intense physical activity induce changes (uncoupling associated with loss of cytochrome oxidase activity) leading to increased ROS production. The mitochondrial respiratory chain could also be a potential source of ROS in tissues, such as liver, kidney and nonworking muscles, that during exercise undergo partial ischemia because of reduced blood supply. Sufficient oxygen is available to interact with the increasingly reduced respiratory chain and enhance the ROS generation. At the cessation of exercise, blood flow to hypoxic tissues resumes leading to their reoxygenation. This mimics the ischemia-reperfusion phenomenon, which is known to cause excessive production of free radicals. Apart from a theoretical rise in ROS, there is little evidence that exercise-induced oxidative stress is due to its increased mitochondrial generation. On the other hand, if mitochondrial production of ROS supplies a remarkable contribution to exercise-induced oxidative stress, mitochondria should be a primary target of oxidative damage. Unfortunately, there are controversial reports concerning the exercise effects on structural and functional characteristics of mitochondria. However, the isolation of mitochondrial fractions by differential centrifugation has shown that the amount of damaged mitochondria, recovered in the lightest fraction, is remarkably increased by long-lasting exercise. PMID:11223645

  16. Biogenesis of the preprotein translocase of the outer mitochondrial membrane: protein kinase A phosphorylates the precursor of Tom40 and impairs its import

    PubMed Central

    Rao, Sanjana; Schmidt, Oliver; Harbauer, Angelika B.; Schönfisch, Birgit; Guiard, Bernard; Pfanner, Nikolaus; Meisinger, Chris

    2012-01-01

    The preprotein translocase of the outer mitochondrial membrane (TOM) functions as the main entry gate for the import of nuclear-encoded proteins into mitochondria. The major subunits of the TOM complex are the three receptors Tom20, Tom22, and Tom70 and the central channel-forming protein Tom40. Cytosolic kinases have been shown to regulate the biogenesis and activity of the Tom receptors. Casein kinase 2 stimulates the biogenesis of Tom22 and Tom20, whereas protein kinase A (PKA) impairs the receptor function of Tom70. Here we report that PKA exerts an inhibitory effect on the biogenesis of the β-barrel protein Tom40. Tom40 is synthesized as precursor on cytosolic ribosomes and subsequently imported into mitochondria. We show that PKA phosphorylates the precursor of Tom40. The phosphorylated Tom40 precursor is impaired in import into mitochondria, whereas the nonphosphorylated precursor is efficiently imported. We conclude that PKA plays a dual role in the regulation of the TOM complex. Phosphorylation by PKA not only impairs the receptor activity of Tom70, but it also inhibits the biogenesis of the channel protein Tom40. PMID:22419819

  17. Role of cAMP-responsive element-binding protein (CREB)-regulated transcription coactivator 3 (CRTC3) in the initiation of mitochondrial biogenesis and stress response in liver cells.

    PubMed

    Than, Tin Aung; Lou, Huan; Ji, Cheng; Win, Sanda; Kaplowitz, Neil

    2011-06-24

    Peroxisome proliferator-activated receptor α, coactivator 1α (PGC-1α) is the master regulator of mitochondrial biogenesis. PGC-1α expression is under the control of the transcription factor, cAMP-responsive element-binding protein (CREB). In searching for candidate transcription factors that mediate mitochondrial stress-initiated mitochondria-to-nucleus signaling in the regulation of mitochondrial biogenesis, we assessed the effect of silencing CREB-regulated transcription co-activators (CRTC). CRTC isoforms are co-activators of CREB-regulated transcription by a CREB phosphorylation-independent pathway. Using cultured HepG2 cells and primary mouse hepatocytes, we determined that mitochondrial stress imposed by the complex I inhibitor rotenone elicited mitochondrial biogenesis, which was dependent on an induction of PGC-1α, which was inhibited by silencing PGC-1α. PGC-1α induction in response to rotenone was inhibited by silencing the expression of CRTC3, which blocked downstream mitochondria biogenesis. In contrast, silencing CRTC2 did not affect the induction of this pathway in response to rotenone. Thus, CRTC3 plays a selective role in mitochondrial biogenesis in response to rotenone. PMID:21536665

  18. Effects of Nitric Oxide Synthase Inhibition on Fiber-Type Composition, Mitochondrial Biogenesis, and SIRT1 Expression in Rat Skeletal Muscle.

    PubMed

    Suwa, Masataka; Nakano, Hiroshi; Radak, Zsolt; Kumagai, Shuzo

    2015-09-01

    It was hypothesized that nitric oxide synthases (NOS) regulated SIRT1 expression and lead to a corresponding changes of contractile and metabolic properties in skeletal muscle. The purpose of the present study was to investigate the influence of long-term inhibition of nitric oxide synthases (NOS) on the fiber-type composition, metabolic regulators such as and silent information regulator of transcription 1 (SIRT1) and peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α), and components of mitochondrial biogenesis in the soleus and plantaris muscles of rats. Rats were assigned to two groups: control and NOS inhibitor (N (ω)-nitro-L-arginine methyl ester hydrochloride (L-NAME), ingested for 8 weeks in drinking water)-treated groups. The percentage of Type I fibers in the L-NAME group was significantly lower than that in the control group, and the percentage of Type IIA fibers was concomitantly higher in soleus muscle. In plantaris muscle, muscle fiber composition was not altered by L-NAME treatment. L-NAME treatment decreased the cytochrome C protein expression and activity of mitochondrial oxidative enzymes in the plantaris muscle but not in soleus muscle. NOS inhibition reduced the SIRT1 protein expression level in both the soleus and plantaris muscles, whereas it did not affect the PGC-1α protein expression. L-NAME treatment also reduced the glucose transporter 4 protein expression in both muscles. These results suggest that NOS plays a role in maintaining SIRT1 protein expression, muscle fiber composition and components of mitochondrial biogenesis in skeletal muscle. Key pointsNOS inhibition by L-NAME treatment decreased the SIRT1 protein expression in skeletal muscle.NOS inhibition induced the Type I to Type IIA fiber type transformation in soleus muscle.NOS inhibition reduced the components of mitochondrial biogenesis and glucose metabolism in skeletal muscle. PMID:26336341

  19. Decreased endothelial nitric oxide synthase expression and function contribute to impaired mitochondrial biogenesis and oxidative stress in fetal lambs with persistent pulmonary hypertension.

    PubMed

    Afolayan, Adeleye J; Eis, Annie; Alexander, Maxwell; Michalkiewicz, Teresa; Teng, Ru-Jeng; Lakshminrusimha, Satyan; Konduri, Girija G

    2016-01-01

    Impaired vasodilation in persistent pulmonary hypertension of the newborn (PPHN) is characterized by mitochondrial dysfunction. We investigated the hypothesis that a decreased endothelial nitric oxide synthase level leads to impaired mitochondrial biogenesis and function in a lamb model of PPHN induced by prenatal ductus arteriosus constriction. We ventilated PPHN lambs with 100% O2 alone or with inhaled nitric oxide (iNO). We treated pulmonary artery endothelial cells (PAECs) from normal and PPHN lambs with detaNONOate, an NO donor. We observed decreased mitochondrial (mt) DNA copy number, electron transport chain (ETC) complex subunit levels, and ATP levels in PAECs and lung tissue of PPHN fetal lambs at baseline compared with gestation matched controls. Phosphorylation of AMP-activated kinase (AMPK) and levels of peroxisome proliferator-activated receptor-γ coactivator 1-α (PGC-1α) and sirtuin-1, which facilitate mitochondrial biogenesis, were decreased in PPHN. Ventilation with 100% O2 was associated with larger decreases in ETC subunits in the lungs of PPHN lambs compared with unventilated PPHN lambs. iNO administration, which facilitated weaning of FiO2 , partly restored mtDNA copy number, ETC subunit levels, and ATP levels. DetaNONOate increased eNOS phosphorylation and its interaction with heat shock protein 90 (HSP90); increased levels of superoxide dismutase 2 (SOD2) mRNA, protein, and activity; and decreased the mitochondrial superoxide levels in PPHN-PAECs. Knockdown of eNOS decreased ETC protein levels in control PAECs. We conclude that ventilation with 100% O2 amplifies oxidative stress and mitochondrial dysfunction in PPHN, which are partly improved by iNO and weaning of oxygen. PMID:26519208

  20. Mitochondrial biogenesis during fungal spore germination: respiration and cytochrome c oxidase in Neurospora crassa.

    PubMed Central

    Stade, S; Brambl, R

    1981-01-01

    The germination of conidiospores of wild-type Neurospora crassa was found to be dependent upon the function of the cytochrome-mediated electron transport pathway. The cyanide-insensitive alternate oxidase did not contribute significantly to the respiration of these germinating spores. The dormant spores contained all of the cytochrome components and a catalytically active cytochrome c oxidase required for the activity of the standard respiratory pathway, and these preserved components were responsible for the accelerating rates of oxygen uptake which began immediately upon suspension of the spores in an incubation medium. Mitochondria of the dormant spores contained all of the subunit peptides of the functional cytochrome c oxidase; nevertheless, de novo synthesis of these subunits began at low rates in the first stages of germination. Reactivation of the respiratory system of germinating N. crassa spores seems not to be dependent initially upon the function of either the mitochondrial or cytoplasmic protein-synthesizing systems. The respiratory activity of spores of three mutant cytochrome c oxidase-deficient strains of N. crassa also was found to depend upon the function of the cytochrome electron transport pathway; the dormant and germinating spores of these strains contained a catalytically active cytochrome c oxidase. Cytochrome c oxidase may be present in the dormant and germinating spores of these strains as the result of a developmental-phase-specific synthesis of and requirement for the enzyme. PMID:6268605

  1. Tumor necrosis factor-α impairs adiponectin signalling, mitochondrial biogenesis, and myogenesis in primary human myotubes cultures.

    PubMed

    Sente, Tahnee; Van Berendoncks, An M; Fransen, Erik; Vrints, Christiaan J; Hoymans, Vicky Y

    2016-05-01

    Skeletal muscle metabolic changes are common in patients with chronic heart failure (HF). Previously, we demonstrated a functional skeletal muscle adiponectin resistance in HF patients with reduced left ventricular ejection fraction (HFrEF). We aimed to examine the impact of adiponectin receptor 1 (AdipoR1) deficiency and TNF-α treatment on adiponectin signaling, proliferative capacity, myogenic differentiation, and mitochondrial biogenesis in primary human skeletal muscle cells. Primary cultures of myoblasts and myotubes were initiated from the musculus vastus lateralis of 10 HFrEF patients (left ventricular ejection fraction; 31.30 ± 2.89%) and 10 age- and gender-matched healthy controls. Healthy control cultures were transfected with siAdipoR1 and/or exposed to TNF-α (10 ng/ml; 72 h). Primary cultures from HFrEF patients preserved the features of adiponectin resistance in vivo. AdipoR1 mRNA was negatively correlated with time to reach maximal cell index (r = -0.7319, P = 0.003). SiRNA-mediated AdipoR1 silencing reduced pAMPK (P < 0.01), AMPK activation (P = 0.046), and myoblast proliferation rate (xCELLigence Real-Time Cellular Analysis; P < 0.0001). Moreover, TNF-α decreased the mRNA expression of genes involved in glucose (APPL1, P = 0.0002; AMPK, P = 0.021), lipid (PPARα, P = 0.025; ACADM, P = 0.003), and mitochondrial (FOXO3, P = 0.018) metabolism, impaired myogenesis (MyoD1, P = 0.053; myogenin, P = 0.048) and polarized cytokine secretion toward a growth-promoting phenotype (IL-10, IL-1β, IFN-γ, P < 0.05 for all; Meso Scale Discovery Technology). Major features of adiponectin resistance are retained in primary cultures from the skeletal muscle of HFrEF patients. In addition, our results suggest that an increased inflammatory constitution contributes to adiponectin resistance and confers alterations in skeletal muscle differentiation, growth, and function. PMID:26921438

  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. Epigenetic Modifications of the PGC-1α Promoter during Exercise Induced Expression in Mice

    PubMed Central

    Lochmann, Timothy L.; Thomas, Ravindar R.; Bennett, James P.; Taylor, Shirley M.

    2015-01-01

    The transcriptional coactivator, PGC-1α, is known for its role in mitochondrial biogenesis. Although originally thought to exist as a single protein isoform, recent studies have identified additional promoters which produce multiple mRNA transcripts. One of these promoters (promoter B), approximately 13.7kb upstream of the canonical PGC-1α promoter (promoter A), yields alternative transcripts present at levels much lower than the canonical PGC-1α mRNA transcript. In skeletal muscle, exercise resulted in a substantial, rapid increase of mRNA of these alternative PGC-1α transcripts. Although the β2-adrenergic receptor was identified as a signaling pathway that activates transcription from PGC-1α promoter B, it is not yet known what molecular changes occur to facilitate PGC-1α promoter B activation following exercise. We sought to determine whether epigenetic modifications were involved in this exercise response in mouse skeletal muscle. We found that DNA hydroxymethylation correlated to increased basal mRNA levels from PGC-1α promoter A, but that DNA methylation appeared to play no role in the exercise-induced activation of PGC-1α promoter B. The level of the activating histone mark H3K4me3 increased with exercise 2–4 fold across PGC-1α promoter B, but remained unaltered past the canonical PGC-1α transcriptional start site. Together, these data show that epigenetic modifications partially explain exercise-induced changes in the skeletal muscle mRNA levels of PGC-1α isoforms. PMID:26053857

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

    PubMed

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

    2015-09-01

    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 V˙O2peak. 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

  5. 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

  6. Overexpression of human selenoprotein H in neuronal cells enhances mitochondrial biogenesis and function through activation of protein kinase A, protein kinase B, and cyclic adenosine monophosphate response element-binding protein pathway

    PubMed Central

    Mehta, Suresh L.; Mendelev, Natalia; Kumari, Santosh; Li, P. Andy

    2013-01-01

    Mitochondrial biogenesis is activated by nuclear encoded transcription co-activator peroxisome proliferator–activated receptor γ coactivator-1α (PGC-1α), which is regulated by several upstream factors including protein kinase A and Akt/protein kinase B. We have previously shown that selenoprotein H enhances the levels of nuclear regulators for mitochondrial biogenesis, increases mitochondrial mass and improves mitochondrial respiratory rate, under physiological condition. Furthermore, overexpression of selenoprotein H protects neuronal HT22 cells from ultraviolet B irradiation-induced cell damage by lowering reactive oxygen species production, and inhibiting activation of caspase-3 and -9, as well as p53. The objective of this study is to identify the cell signaling pathways by which selenoprotein H initiates mitochondrial biogenesis. We first confirmed our previous observation that selenoprotein H transfected HT22 cells increased the protein levels of nuclear-encoded mitochondrial biogenesis factors, peroxisome proliferator–activated receptor γ coactivator-1α, nuclear respiratory factor 1 and mitochondrial.transcription factor A, We then observed that total and phosphorylation of protein kinase A, Akt/protein kinase B and cyclic adenosine monophosphate response element-binding protein (CREB) were significantly increased in selenoprotein H transfected cells compared to vector transfected HT22 cells. To verify whether the observed stimulating effects on mitochondrial biogenesis pathways are caused by selenoprotein H and mediated through CREB, we knocked down selenoprotein H mRNA level using siRNA and inhibited CREB with napthol AS-E phosphate in selenoprotein H transfected cells and repeated the measurements of the aforementioned biomarkers. Our results revealed that silencing of selenoprotein H not only decreased the protein levels of PGC-1α, nuclear respiratory factor 1 and mitochondrial transcription factor A, but also decreased the total and phosphorylation levels of protein kinase A, protein kinase B, and CREB. Similarly, CREB inhibition reduced CREB activation and PGC-1α protein levels in selenoprotein H transfected cells. Moreover, selenoprotein H transfection increased the activity of mitochondrial complexes and prevented the ultraviolet B induced fall of mitochondrial membrane potential. We conclude that the effects of selenoprotein H on mitochondrial biogenesis and mitochondrial function are probably mediated through protein kinase A- CREB- PGC-1α and Akt/proetin kinase B- CREB- PGC-1α pathways. PMID:23220172

  7. Familial exercise-induced anaphylaxis.

    PubMed

    Longley, S; Panush, R S

    1987-04-01

    We identified two siblings with exercise-induced anaphylaxis who share the HLA haplotype A3-B8-DR3 with their atopic father. The index case, a 16-year-old female, noted initial episodes at age 13. Intense pruritus, urticaria, facial edema, choking sensation, nausea, hypothermia, and collapse followed vigorous running but not swimming, cycling, racquetball, solar exposure, or cold exposure. Neither antihistamine, antiserotonin, anticholinergic nor epinephrine therapy was entirely effective or protective; only modification of running prevented episodes. Three similar episodes were noted at age 15 years by a brother who, now age 25, relates a 4-year history of seasonal rhinitis and exercise-related urticaria without anaphylactoid reaction. The remainder of the family (father, 47; mother, 46; brother, 22 years) does not have exercise intolerance. The father has allergic rhinitis; his nephew suffers exercise-induced urticaria without collapse. HLA typing revealed the father to be A1-B8-DR3, A3-B8-DR3; the symptomatic daughter to be A3-B8-DR3, A30-B5-DR8; and the symptomatic son to be A3-B8-DR3, A30-B5-DR8. The asymptomatic mother was A30-B5-DR8, A2-B7-DR5 and the asymptomatic son A1-B8-DR3, A30-B5-DR8. We describe exercise-induced anaphylaxis in a unique familial setting, perhaps linked to the HLA haplotype A3-B8-DR3. PMID:3471098

  8. Exercise-induced leukocyte apoptosis.

    PubMed

    Krüger, Karsten; Mooren, Frank C

    2014-01-01

    Physical exercise is well known to affect leukocyte numbers and function. While regular exercise training has been shown to enhance specific immune functions, acute bouts of intensive exercise often lead to a pro-inflammatory response accompanied by a transient lymphocytopenia and neutrophilia. It can be assumed, that lymphocytopenia can be attributed at least partially to an enhanced lymphocyte apoptosis. In contrast, regulation of neutrophil apoptosis after exercise remains controversial since studies demonstrated both an up-regulation as well as a down-regulation of cell death. However, these discrepancies may be due to differences in exercise protocols, subjects' fitness levels, and to different methodological approaches. Two major signalling pathways of exercise induced apoptosis have been identified. First the external receptor mediated pathway using death receptors, and second the internal, oxidative-mediated pathway which encompasses the mitochondria. Potential apoptosis modulating mediators are reactive oxygen species (ROS), glucocorticoids and cytokines which are part of the systemic inflammatory response evoked after acute intensive exercise. Finally, the physiological impact and clinical relevance of leukocyte apoptosis will be discussed. On the one hand, exercise-induced apoptosis might be a mechanism to remove activated and potentially autoreactive immune cells. On the other hand, apoptosis might be a regulatory mechanism which is necessary for tissue reorganization and adaptational training processes. PMID:24974724

  9. Maternal stress predicts altered biogenesis and the profile of mitochondrial proteins in the frontal cortex and hippocampus of adult offspring rats.

    PubMed

    Głombik, Katarzyna; Stachowicz, Aneta; Ślusarczyk, Joanna; Trojan, Ewa; Budziszewska, Bogusława; Suski, Maciej; Kubera, Marta; Lasoń, Władysław; Wędzony, Krzysztof; Olszanecki, Rafał; Basta-Kaim, Agnieszka

    2015-10-01

    Currently, much attention is focused on the influence of mitochondrial disturbances at the onset of depression. The goal of this study was to investigate the impact of prenatal stress (an animal model of depression) on the mitochondrial biogenesis proteins and mitoproteome profile in the frontal cortex and hippocampus of adult 3-month-old male rats following a prenatal stress procedure. Our results show that rats that were exposed to prenatal stress stimuli displayed depression-like behaviors based on the sucrose preference and elevated plus maze tests. It has been found that the level of the PGC-1α protein was reduced in the frontal cortex and hippocampus of the adult offspring after the prenatal stress procedure. Moreover, in the frontal cortex, the level of the pro-apoptotic protein Bax was up-regulated. Two-dimensional electrophoresis coupled with mass spectrometry showed the statistically significant down-regulation of the mitochondrial ribosomal protein L12 (Mrpl12) and mitochondrial NADH dehydrogenase [ubiquinone] flavoprotein 2 (NDUFV2) as well as the up-regulation of the Tubulin Polymerization Promoting Proteins (Tppp/p25) in the frontal cortex. In contrast, in the hippocampus, the mitochondrial pyruvate dehydrogenase E1 component subunit beta, the voltage-dependent anion-selective channel protein 2 (VDAC2), and the GTP-binding nuclear protein RAN (RAN) were down-regulated and the expression of phosphatidylethanolamine-binding protein 1 (PEBP-1) was enhanced. These findings provide new evidence that stress during pregnancy may lead not only to behavioral deficits, but also to disturbances in the brain mitoproteome profile in adult rat offspring. PMID:26143539

  10. PPR2263, a DYW-Subgroup Pentatricopeptide Repeat Protein, Is Required for Mitochondrial nad5 and cob Transcript Editing, Mitochondrion Biogenesis, and Maize Growth[C][W

    PubMed Central

    Sosso, Davide; Mbelo, Sylvie; Vernoud, Vanessa; Gendrot, Ghislaine; Dedieu, Annick; Chambrier, Pierre; Dauzat, Myriam; Heurtevin, Laure; Guyon, Virginie; Takenaka, Mizuki; Rogowsky, Peter M.

    2012-01-01

    RNA editing plays an important role in organelle gene expression in various organisms, including flowering plants, changing the nucleotide information at precise sites. Here, we present evidence that the maize (Zea mays) nuclear gene Pentatricopeptide repeat 2263 (PPR2263) encoding a DYW domain–containing PPR protein is required for RNA editing in the mitochondrial NADH dehydrogenase5 (nad5) and cytochrome b (cob) transcripts at the nad5-1550 and cob-908 sites, respectively. Its putative ortholog, MITOCHONDRIAL EDITING FACTOR29, fulfills the same role in Arabidopsis thaliana. Both the maize and the Arabidopsis proteins show preferential localization to mitochondria but are also detected in chloroplasts. In maize, the corresponding ppr2263 mutation causes growth defects in kernels and seedlings. Embryo and endosperm growth are reduced, leading to the production of small but viable kernels. Mutant plants have narrower and shorter leaves, exhibit a strong delay in flowering time, and generally do not reach sexual maturity. Whereas mutant chloroplasts do not have major defects, mutant mitochondria lack complex III and are characterized by a compromised ultrastructure, increased transcript levels, and the induction of alternative oxidase. The results suggest that mitochondrial RNA editing at the cob-908 site is necessary for mitochondrion biogenesis, cell division, and plant growth in maize. PMID:22319053

  11. OM2, a Novel Oligomannuronate-Chromium(III) Complex, Promotes Mitochondrial Biogenesis and Lipid Metabolism in 3T3-L1 Adipocytes via the AMPK-PGC1α Pathway

    PubMed Central

    Hao, Jiejie; Hao, Cui; Zhang, Lijuan; Liu, Xin; Zhou, Xiaolin; Dun, Yunlou; Li, Haihua; Li, Guangsheng; Zhao, Xiaoliang; An, Yuanyuan; Liu, Jiankang; Yu, Guangli

    2015-01-01

    Background In our previous studies, we prepared novel oligomannuronate-chromium(III) complexes (OM2, OM4) from marine alginate, and found that these compounds sensitize insulin action better than oligomannuronate(OM), chromium, and metformin in C2C12 skeletal muscle cells. In the present study, we studied their effects on mitochondrial biogenesis, lipid metabolism, and the underlying molecular mechanisms in differentiated 3T3-L1 adipocytes. Methodology/Principal Findings We firstly used the pGL3-PGC1α and pGL3-ATGL promoter plasmids to compare their effects on PGC1α and ATGL transcription activities. Then mitochondrial biogenesis was quantified by transmission electron microscopy and MitoTracker staining. Mitochondrial oxygen consumption and fatty acid oxidation were measured by an oxygen biosensor system and ³H-labelled water scintillation. The mitochondrial DNA and mRNA involved in mitochondrial biogenesis and lipid oxidation were evaluated by real-time PCR. AMPK together with other protein expression levels were measured by western blotting. The inhibitor compound C and siRNA of PGC1α were used to inhibit the OM2-induced AMPK-PGC1α signaling pathway. And we found that OM2 stimulated AMPK-PGC1α pathway in the 3T3-L1 adipocytes, which were correlated with induced mitochondrial biogenesis, improved mitochondrial function, and reduced lipid accumulation by enhanced fatty acid β-oxidation and augmented ATGL protein expression. Conclusions/Significance Our data indicated that the marine oligosaccharide-derived OM2 might represent a novel class of molecules that could be useful for type 2 diabetes prevention and treatment by up-regulating AMPK-PGC1α signaling pathway. PMID:26176781

  12. Food related, exercise induced anaphylaxis.

    PubMed Central

    Caffarelli, C; Terzi, V; Perrone, F; Cavagni, G

    1996-01-01

    Four children under 12 years of age with food dependent, exercise induced anaphylaxis (EIAn) were investigated. These children and five controls performed exercise challenges when fasting and one hour after a meal without food suspected to predispose to the reaction. Patients then performed exercise tests after intake of each suspected food. Three out of 15 food-exercise combination challenges were positive, but no reactions were provoked after exercise without prior intake of suspected foods. Patients underwent skin prick tests to foods and serum total and specific IgE antibodies were measured. Skin prick test results were positive and RAST results were positive in two of three instances. In case 3, food-exercise combination challenges did not provoke any clinical reaction. The diagnosis of food dependent EIAn should be considered in young children with EIAn of unknown origin. PMID:8869196

  13. Mutant huntingtin's interaction with mitochondrial protein Drp1 impairs mitochondrial biogenesis and causes defective axonal transport and synaptic degeneration in Huntington's disease.

    PubMed

    Shirendeb, Ulziibat P; Calkins, Marcus J; Manczak, Maria; Anekonda, Vishwanath; Dufour, Brett; McBride, Jodi L; Mao, Peizhong; Reddy, P Hemachandra

    2012-01-15

    The purpose of this study was to investigate the link between mutant huntingtin (Htt) and neuronal damage in relation to mitochondria in Huntington's disease (HD). In an earlier study, we determined the relationship between mutant Htt and mitochondrial dynamics/synaptic viability in HD patients. We found mitochondrial loss, abnormal mitochondrial dynamics and mutant Htt association with mitochondria in HD patients. In the current study, we sought to expand on our previous findings and further elucidate the relationship between mutant Htt and mitochondrial and synaptic deficiencies. We hypothesized that mutant Htt, in association with mitochondria, alters mitochondrial dynamics, leading to mitochondrial fragmentation and defective axonal transport of mitochondria in HD neurons. In this study, using postmortem HD brains and primary neurons from transgenic BACHD mice, we identified mutant Htt interaction with the mitochondrial protein Drp1 and factors that cause abnormal mitochondrial dynamics, including GTPase Drp1 enzymatic activity. Further, using primary neurons from BACHD mice, for the first time, we studied axonal transport of mitochondria and synaptic degeneration. We also investigated the effect of mutant Htt aggregates and oligomers in synaptic and mitochondrial deficiencies in postmortem HD brains and primary neurons from BACHD mice. We found that mutant Htt interacts with Drp1, elevates GTPase Drp1 enzymatic activity, increases abnormal mitochondrial dynamics and results in defective anterograde mitochondrial movement and synaptic deficiencies. These observations support our hypothesis and provide data that can be utilized to develop therapeutic targets that are capable of inhibiting mutant Htt interaction with Drp1, decreasing mitochondrial fragmentation, enhancing axonal transport of mitochondria and protecting synapses from toxic insults caused by mutant Htt. PMID:21997870

  14. Dual Location of the Mitochondrial Preprotein Transporters B14.7 and Tim23-2 in Complex I and the TIM17:23 Complex in Arabidopsis Links Mitochondrial Activity and Biogenesis[C][W][OA

    PubMed Central

    Wang, Yan; Carrie, Chris; Giraud, Estelle; Elhafez, Dina; Narsai, Reena; Duncan, Owen; Whelan, James; Murcha, Monika W.

    2012-01-01

    Interactions between the respiratory chain and protein import complexes have been previously reported in Saccharomyces cerevisiae, but the biological significance of such interactions remains unknown. Characterization of two mitochondrial preprotein and amino acid transport proteins from Arabidopsis thaliana, NADH dehydrogenase B14.7 like (B14.7 [encoded by At2g42210]) and Translocase of the inner membrane subunit 23-2 (Tim23-2 [encoded by At1g72750]), revealed both proteins are present in respiratory chain complex I and the Translocase of the Inner Membrane 17:23. Whereas depletion of B14.7 by T-DNA insertion is lethal, Tim23-2 can be depleted without lethality. Subtle overexpression of Tim23-2 results in a severe delayed growth phenotype and revealed an unexpected, inverse correlation between the abundance of Tim23-2 and the abundance of respiratory complex I. This newly discovered relationship between protein import and respiratory function was confirmed through the investigation of independent complex I knockout mutants, which were found to have correspondingly increased levels of Tim23-2. This increase in Tim23-2 was also associated with delayed growth phenotypes, increased abundance of other import components, and an increased capacity for mitochondrial protein import. Analysis of the Tim23-2–overexpressing plants through global quantitation of transcript abundance and in-organelle protein synthesis assays revealed widespread alterations in transcript abundance of genes encoding mitochondrial proteins and altered rates of mitochondrial protein translation, indicating a pivotal relationship between the machinery of mitochondrial biogenesis and mitochondrial function. PMID:22730406

  15. Methyl-Arginine Profile of Brain from Aged PINK1-KO+A53T-SNCA Mice Suggests Altered Mitochondrial Biogenesis

    PubMed Central

    Auburger, Georg; Gispert, Suzana

    2016-01-01

    Hereditary Parkinson's disease can be triggered by an autosomal dominant overdose of alpha-Synuclein (SNCA) or the autosomal recessive deficiency of PINK1. We recently showed that the combination of PINK1-knockout with overexpression of A53T-SNCA in double mutant (DM) mice potentiates phenotypes and reduces survival. Now we studied brain hemispheres of DM mice at age of 18 months in a hypothesis-free approach, employing a quantitative label-free global proteomic mass spectrometry scan of posttranslational modifications focusing on methyl-arginine. The strongest effects were documented for the adhesion modulator CMAS, the mRNA decapping/deadenylation factor PATL1, and the synaptic plasticity mediator CRTC1/TORC1. In addition, an intriguing effect was observed for the splicing factor PSF/SFPQ, known to interact with the dopaminergic differentiation factor NURR1 as well as with DJ-1, the protein responsible for the autosomal recessive PARK7 variant of PD. CRTC1, PSF, and DJ-1 are modulators of PGC1alpha and of mitochondrial biogenesis. This pathway was further stressed by dysregulations of oxygen sensor EGLN3 and of nuclear TMPO. PSF and TMPO cooperate with dopaminergic differentiation factors LMX1B and NURR1. Further dysregulations concerned PRR18, TRIO, HNRNPA1, DMWD, WAVE1, ILDR2, DBNDD1, and NFM. Thus, we report selective novel endogenous stress responses in brain, which highlight early dysregulations of mitochondrial homeostasis and midbrain vulnerability. PMID:27034888

  16. 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

  17. Biogenesis of Porin of the Outer Mitochondrial Membrane Involves an Import Pathway via Receptors and the General Import Pore of the Tom Complex

    PubMed Central

    Krimmer, Thomas; Rapaport, Doron; Ryan, Michael T.; Meisinger, Chris; Kassenbrock, C. Kenneth; Blachly-Dyson, Elizabeth; Forte, Michael; Douglas, Michael G.; Neupert, Walter; Nargang, Frank E.; Pfanner, Nikolaus

    2001-01-01

    Porin, also termed the voltage-dependent anion channel, is the most abundant protein of the mitochondrial outer membrane. The process of import and assembly of the protein is known to be dependent on the surface receptor Tom20, but the requirement for other mitochondrial proteins remains controversial. We have used mitochondria from Neurospora crassa and Saccharomyces cerevisiae to analyze the import pathway of porin. Import of porin into isolated mitochondria in which the outer membrane has been opened is inhibited despite similar levels of Tom20 as in intact mitochondria. A matrix-destined precursor and the porin precursor compete for the same translocation sites in both normal mitochondria and mitochondria whose surface receptors have been removed, suggesting that both precursors utilize the general import pore. Using an assay established to monitor the assembly of in vitro–imported porin into preexisting porin complexes we have shown that besides Tom20, the biogenesis of porin depends on the central receptor Tom22, as well as Tom5 and Tom7 of the general import pore complex (translocase of the outer mitochondrial membrane [TOM] core complex). The characterization of two new mutant alleles of the essential pore protein Tom40 demonstrates that the import of porin also requires a functional Tom40. Moreover, the porin precursor can be cross-linked to Tom20, Tom22, and Tom40 on its import pathway. We conclude that import of porin does not proceed through the action of Tom20 alone, but requires an intact outer membrane and involves at least four more subunits of the TOM machinery, including the general import pore. PMID:11266446

  18. Human C4orf14 interacts with the mitochondrial nucleoid and is involved in the biogenesis of the small mitochondrial ribosomal subunit.

    PubMed

    He, J; Cooper, H M; Reyes, A; Di Re, M; Kazak, L; Wood, S R; Mao, C C; Fearnley, I M; Walker, J E; Holt, I J

    2012-07-01

    The bacterial homologue of C4orf14, YqeH, has been linked to assembly of the small ribosomal subunit. Here, recombinant C4orf14 isolated from human cells, co-purified with the small, 28S subunit of the mitochondrial ribosome and the endogenous protein co-fractionated with the 28S subunit in sucrose gradients. Gene silencing of C4orf14 specifically affected components of the small subunit, leading to decreased protein synthesis in the organelle. The GTPase of C4orf14 was critical to its interaction with the 28S subunit, as was GTP. Therefore, we propose that C4orf14, with bound GTP, binds to components of the 28S subunit facilitating its assembly, and GTP hydrolysis acts as the release mechanism. C4orf14 was also found to be associated with human mitochondrial nucleoids, and C4orf14 gene silencing caused mitochondrial DNA depletion. In vitro C4orf14 is capable of binding to DNA. The association of C4orf14 with mitochondrial translation factors and the mitochondrial nucleoid suggests that the 28S subunit is assembled at the mitochondrial nucleoid, enabling the direct transfer of messenger RNA from the nucleoid to the ribosome in the organelle. PMID:22447445

  19. Exercise-induced arterial hypoxemia.

    PubMed

    Dempsey, J A; Wagner, P D

    1999-12-01

    Exercise-induced arterial hypoxemia (EIAH) at or near sea level is now recognized to occur in a significant number of fit, healthy subjects of both genders and of varying ages. Our review aims to define EIAH and to critically analyze what we currently understand, and do not understand, about its underlying mechanisms and its consequences to exercise performance. Based on the effects on maximal O(2) uptake of preventing EIAH, we suggest that mild EIAH be defined as an arterial O(2) saturation of 93-95% (or 3-4% 25-30 Torr) and inadequate compensatory hyperventilation (arterial PCO(2) >35 Torr) commonly contribute to EIAH, as do acid- and temperature-induced shifts in O(2) dissociation at any given arterial PO(2). In turn, expiratory flow limitation presents a significant mechanical constraint to exercise hyperpnea, whereas ventilation-perfusion ratio maldistribution and diffusion limitation contribute about equally to the excessive A-a DO(2). Exactly how diffusion limitation is incurred or how ventilation-perfusion ratio becomes maldistributed with heavy exercise remains unknown and controversial. Hypotheses linked to extravascular lung water accumulation or inflammatory changes in the "silent" zone of the lung's peripheral airways are in the early stages of exploration. Indirect evidence suggests that an inadequate hyperventilatory response is attributable to feedback inhibition triggered by mechanical constraints and/or reduced sensitivity to existing stimuli; but these mechanisms cannot be verified without a sensitive measure of central neural respiratory motor output. Finally, EIAH has detrimental effects on maximal O(2) uptake, but we have not yet determined the cause or even precisely identified which organ system, involved directly or indirectly with O(2) transport to muscle, is responsible for this limitation. PMID:10601141

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

    PubMed Central

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

    2010-01-01

    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 ± 0.4 years, ml kg−1 min−1) performed six training sessions over 2 weeks. Each session consisted of 8–12 × 60 s intervals at ∼100% of peak power output elicited during a ramp peak test (355 ± 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 γ co-activator 1α (PGC-1α) was ∼25% higher after training (P < 0.05), but total PGC-1α protein content remained unchanged. Total SIRT1 content, a proposed activator of PGC-1α and mitochondrial biogenesis, was increased by ∼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-1α, and Tfam may be involved in coordinating mitochondrial adaptations in response to HIT in human skeletal muscle. PMID:20100740

  1. Roles for the lipid-signaling enzyme MitoPLD in mitochondrial dynamics, piRNA biogenesis, and spermatogenesis.

    PubMed

    Gao, Qun; Frohman, Michael A

    2012-01-01

    Phospholipase D (PLD), a superfamily of signaling enzymes that most commonly generate the lipid second messenger Phosphatidic Acid (PA), is found in diverse organisms from bacteria to man and functions in multiple cellular pathways. A fascinating member of the family, MitoPLD, is anchored to the mitochondrial surface and has two reported roles. In the first role, MitoPLD-generated PA regulates mitochondrial shape through facilitating mitochondrial fusion. In the second role, MitoPLD performs a critical function in a pathway that creates a specialized form of RNAi required by developing spermatocytes to suppress transposon mobilization during meiosis. This spermatocyte-specific RNAi, known as piRNA, is generated in the nuage, an electron-dense accumulation of RNA templates and processing proteins that localize adjacent to mitochondria in a structure also called intermitochondrial cement. In this review, we summarize recent findings on these roles for MitoPLD functions, highlighting directions that need to be pursued to define the underlying mechanisms. PMID:22281006

  2. Purple sweet potato color attenuates domoic acid-induced cognitive deficits by promoting estrogen receptor-α-mediated mitochondrial biogenesis signaling in mice.

    PubMed

    Lu, Jun; Wu, Dong-mei; Zheng, Yuan-lin; Hu, Bin; Cheng, Wei; Zhang, Zi-feng

    2012-02-01

    Recent findings suggest that endoplasmic reticulum stress may be involved in the pathogenesis of domoic acid-induced neurodegeneration. Purple sweet potato color, a class of naturally occurring anthocyanins, has beneficial health and biological effects. Recent studies have also shown that anthocyanins have estrogenic activity and can enhance estrogen receptor-α expression. In this study, we evaluated the effect of purple sweet potato color on cognitive deficits induced by hippocampal mitochondrial dysfunction in domoic acid-treated mice and explored the potential mechanisms underlying this effect. Our results showed that the oral administration of purple sweet potato color to domoic acid-treated mice significantly improved their behavioral performance in a step-through passive avoidance task and a Morris water maze task. These improvements were mediated, at least in part, by a stimulation of estrogen receptor-α-mediated mitochondrial biogenesis signaling and by decreases in the expression of p47phox and gp91phox. Decreases in reactive oxygen species and protein carbonylation were also observed, along with a blockade of the endoplasmic reticulum stress pathway. Furthermore, purple sweet potato color significantly suppressed endoplasmic reticulum stress-induced apoptosis, which prevented neuron loss and restored the expression of memory-related proteins. However, knockdown of estrogen receptor-α using short hairpin RNA only partially blocked the neuroprotective effects of purple sweet potato color in the hippocampus of mice cotreated with purple sweet potato color and domoic acid, indicating that purple sweet potato color acts through multiple pathways. These results suggest that purple sweet potato color could be a possible candidate for the prevention and treatment of cognitive deficits in excitotoxic and other brain disorders. PMID:22178976

  3. The Signal Transducer and Activator of Transcription 1 (STAT1) Inhibits Mitochondrial Biogenesis in Liver and Fatty Acid Oxidation in Adipocytes

    PubMed Central

    Sisler, Jennifer D.; Morgan, Magdalena; Raje, Vidisha; Grande, Rebecca C.; Derecka, Marta; Meier, Jeremy; Cantwell, Marc; Szczepanek, Karol; Korzun, William J.; Lesnefsky, Edward J.; Harris, Thurl E.; Croniger, Colleen M.; Larner, Andrew C.

    2015-01-01

    The transcription factor STAT1 plays a central role in orchestrating responses to various pathogens by activating the transcription of nuclear-encoded genes that mediate the antiviral, the antigrowth, and immune surveillance effects of interferons and other cytokines. In addition to regulating gene expression, we report that STAT1-/- mice display increased energy expenditure and paradoxically decreased release of triglycerides from white adipose tissue (WAT). Liver mitochondria from STAT1-/- mice show both defects in coupling of the electron transport chain (ETC) and increased numbers of mitochondria. Consistent with elevated numbers of mitochondria, STAT1-/- mice expressed increased amounts of PGC1α, a master regulator of mitochondrial biogenesis. STAT1 binds to the PGC1α promoter in fed mice but not in fasted animals, suggesting that STAT1 inhibited transcription of PGC1α. Since STAT1-/- mice utilized more lipids we examined white adipose tissue (WAT) stores. Contrary to expectations, fasted STAT1-/- mice did not lose lipid from WAT. β-adrenergic stimulation of glycerol release from isolated STAT1-/- WAT was decreased, while activation of hormone sensitive lipase was not changed. These findings suggest that STAT1-/- adipose tissue does not release glycerol and that free fatty acids (FFA) re-esterify back to triglycerides, thus maintaining fat mass in fasted STAT1-/- mice. PMID:26689548

  4. Platycodon grandiflorum A. De Candolle Ethanolic Extract Inhibits Adipogenic Regulators in 3T3-L1 Cells and Induces Mitochondrial Biogenesis in Primary Brown Preadipocytes.

    PubMed

    Kim, Hye-Lin; Park, Jinbong; Park, Hyewon; Jung, Yunu; Youn, Dong-Hyun; Kang, JongWook; Jeong, Mi-Young; Um, Jae-Young

    2015-09-01

    This study was designed to evaluate the effects of Platycodon grandiflorum A. DC. ethanolic extract (PG) on obesity in brown/white preadipocytes. The effect of PG on the differentiation and mitochondrial biogenesis of brown adipocytes is still not examined. An in vivo study showed that PG induced weight loss in mice with high-fat-diet-induced obesity. PG successfully suppressed the differentiation of 3T3-L1 cells by down-regulating cellular induction of the peroxisome proliferators activated receptor γ (PPARγ), CCAAT enhancer binding protein α (C/EBPα), lipin-1, and adiponectin but increasing expression of silent mating type information regulation 2 homologue 1 (SIRT1) and the phosphorylation of AMP-activated protein kinase α (AMPKα). The effect of PG on the adipogenic factors was compared with that of its bioactive compound platycodin D. In addition, PG increased expressions of mitochondria-related genes, including uncoupling protein 1 (UCP1), peroxisome proliferator activated receptor-coactivator 1 α (PGC1α), PR domain containing 16 (PRDM16), SIRT3, nuclear respiratory factor (NRF), and cytochrome C (CytC) in primary brown adipocytes. These results indicate that PG stimulates the differentiation of brown adipocytes through modulation of mitochondria-related genes and could offer clinical benefits as a supplement to treat obesity. PMID:26244589

  5. The airway microvasculature and exercise induced asthma.

    PubMed Central

    Anderson, S D; Daviskas, E

    1992-01-01

    It has been proposed that exercise induced asthma is a result of "rapid expansion of the blood volume of peribronchial plexi" (McFadden ER, Lancet 1990;335:880-3). This hypothesis proposes that the development of exercise induced asthma depends on the thermal gradient in the airways at the end of hyperpnoea. The events that result in exercise induced asthma are vasoconstriction and airway cooling followed by reactive hyperaemia. We agree that the airway microcirculation has the potential for contributing to the pathophysiology of exercise induced asthma. We do, however, question whether reactive hyperaemia, in response to airway cooling, is the mechanism whereby hyperpnoea provokes airways obstruction in asthmatic patients. Further, we question whether vasoconstriction accompanies dry air breathing and whether an abnormal temperature gradient and rapid rewarming of the airways are prerequisites for exercise induced asthma. From published experiments we conclude that dry air breathing is associated with vasodilation and increase in airway blood flow rather than vasoconstriction and a decrease in blood flow to the airways. We propose that the stimulus for the increase in airway blood flow is an increase in osmolarity of the airway submucosa. This osmotic change is caused by the movement of water to the airway lumen in response to evaporative water loss during hyperpnoea. The increase in airway blood flow may occur directly or indirectly by the osmotic release of mediators. Exercise induced asthma is most likely to be due to the contraction of bronchial smooth muscle caused by the same mediators. Whether it is enhanced or inhibited by alterations in airway blood flow is not yet established in man. PMID:1440473

  6. Uteroplacental insufficiency leads to hypertension, but not glucose intolerance or impaired skeletal muscle mitochondrial biogenesis, in 12-month-old rats.

    PubMed

    Tran, Melanie; Young, Margaret E; Jefferies, Andrew J; Hryciw, Deanne H; Ward, Michelle M; Fletcher, Erica L; Wlodek, Mary E; Wadley, Glenn D

    2015-09-01

    Growth restriction impacts on offspring development and increases their risk of disease in adulthood which is exacerbated with "second hits." The aim of this study was to investigate if blood pressure, glucose tolerance, and skeletal muscle mitochondrial biogenesis were altered in 12-month-old male and female offspring with prenatal or postnatal growth restriction. Bilateral uterine vessel ligation induced uteroplacental insufficiency and growth restriction in offspring (Restricted). A sham surgery was also performed during pregnancy (Control) and some litters from sham mothers had their litter size reduced (Reduced litter), which restricted postnatal growth. Growth-restricted females only developed hypertension at 12 months, which was not observed in males. In Restricted females only homeostasis model assessment for insulin resistance was decreased, indicating enhanced hepatic insulin sensitivity, which was not observed in males. Plasma leptin was increased only in the Reduced males at 12 months compared to Control and Restricted males, which was not observed in females. Compared to Controls, leptin, ghrelin, and adiponectin were unaltered in the Restricted males and females, suggesting that at 12 months of age the reduction in body weight in the Restricted offspring is not a consequence of circulating adipokines. Skeletal muscle PGC-1α levels were unaltered in 12-month-old male and female rats, which indicate improvements in lean muscle mass by 12 months of age. In summary, sex strongly impacts the cardiometabolic effects of growth restriction in 12-month-old rats and it is females who are at particular risk of developing long-term hypertension following growth restriction. PMID:26416974

  7. Assessment of mitochondrial biogenesis and mTORC1 signaling during chronic rapamycin feeding in male and female mice.

    PubMed

    Drake, Joshua C; Peelor, Frederick F; Biela, Laurie M; Watkins, Molly K; Miller, Richard A; Hamilton, Karyn L; Miller, Benjamin F

    2013-12-01

    Chronic inhibition of the protein synthesis regulator mTORC1 through rapamycin extends life span in mice, with longer extension in females than in males. Whether rapamycin treatment inhibits protein synthesis or whether it does so differently between sexes has not been examined. UM-HET3 mice were fed a control or rapamycin-supplemented (Rap) diet for 12 weeks. Protein synthesis in mixed, cytosolic (cyto), and mitochondrial (mito) fractions and DNA synthesis and mTORC1 signaling were determined in skeletal muscle, heart, and liver. In both sexes, mito protein synthesis was maintained in skeletal muscle from Rap despite decreases in mixed and cyto fractions, DNA synthesis, and rpS6 phosphorylation. In the heart, no change in protein synthesis occurred despite the decreased DNA synthesis. In the heart and liver, Rap males were more sensitive to mTORC1 inhibition than Rap females. In conclusion, we show changes in protein synthesis and mTORC1 signaling that differ by sex and tissue. PMID:23657975

  8. Mitochondrial biogenesis during fungal spore germination. Purification, properties and biosynthesis of cytochrome c oxidase from Botryodiplodia theobromae.

    PubMed

    Josephson, M; Brambl, R

    1980-01-01

    1. Cytochrome c oxidase (ferrocytochrome c:oxygen oxidoreductase, EC 1.9.3.1) was purified from the mycelial fungus Botryodiplodia theobromae by sodium cholate and ammonium sulfate solubilization, ammonium sulfate fractionation, and DEAE-cellulose chromatography. The purified enzyme contained 6--7 nmol heme a/mg of protein. The specific activity of the purified enzyme was 2.1--2.3 . 10(3) k (min-1) per mg of protein with 15 mumol ferrocytochrome c and at pH 5.9 and optimal phosphate and Tween 80 concentrations (65 mM and 0.1%, respectively). The Km for ferrocytochrome c was determined to be 1.2--1.3 . 10(-5) M, while at infinite substrate concentration the enzyme catalyzed the oxidation of about 60 mumole of ferrocytochrome c/min per mg of protein. Sedimentation behavior and kinetic evidence suggest that the purified enzyme exists as aggregates of the single molecule. The purified B. theobromae cytochrome c oxidase with its 428 nm Soret absorption maximum may be similar if not identical to oxygenated forms of the enzyme from other fungal species. 2. The purified enzyme was shown by sodium dodecyl sulfate polyacrylamide gel electrophoresis to consist of seven polypeptides with the following respective molecular weights: I, 41 000; II, 28 000; III, 19 000; IV, 14 800; V, 12 800; VI, 11 500; and VII, 9300. Biosynthesis studies showed that the three highest molecular weight polypeptides of the enzyme were synthesized on mitochondrial ribosomes, and the four smaller polypeptides were products of cytoplasmic ribosomes. PMID:6243487

  9. Exercise-induced muscle damage in humans.

    PubMed

    Clarkson, Priscilla M; Hubal, Monica J

    2002-11-01

    Exercise-induced muscle injury in humans frequently occurs after unaccustomed exercise, particularly if the exercise involves a large amount of eccentric (muscle lengthening) contractions. Direct measures of exercise-induced muscle damage include cellular and subcellular disturbances, particularly Z-line streaming. Several indirectly assessed markers of muscle damage after exercise include increases in T2 signal intensity via magnetic resonance imaging techniques, prolonged decreases in force production measured during both voluntary and electrically stimulated contractions (particularly at low stimulation frequencies), increases in inflammatory markers both within the injured muscle and in the blood, increased appearance of muscle proteins in the blood, and muscular soreness. Although the exact mechanisms to explain these changes have not been delineated, the initial injury is ascribed to mechanical disruption of the fiber, and subsequent damage is linked to inflammatory processes and to changes in excitation-contraction coupling within the muscle. Performance of one bout of eccentric exercise induces an adaptation such that the muscle is less vulnerable to a subsequent bout of eccentric exercise. Although several theories have been proposed to explain this "repeated bout effect," including altered motor unit recruitment, an increase in sarcomeres in series, a blunted inflammatory response, and a reduction in stress-susceptible fibers, there is no general agreement as to its cause. In addition, there is controversy concerning the presence of sex differences in the response of muscle to damage-inducing exercise. In contrast to the animal literature, which clearly shows that females experience less damage than males, research using human studies suggests that there is either no difference between men and women or that women are more prone to exercise-induced muscle damage than are men. PMID:12409811

  10. Mechanisms of Exercise-Induced Cardioprotection

    PubMed Central

    Smuder, Ashley J.; Kavazis, Andreas N.; Quindry, John C.

    2014-01-01

    Myocardial ischemia-reperfusion (IR) injury can cause ventricular cell death and is a major pathological event leading to morbidity and mortality in those with coronary artery disease. Interestingly, as few as five bouts of exercise on consecutive days can rapidly produce a cardiac phenotype that resists IR-induced myocardial injury. This review summarizes the development of exercise-induced cardioprotection and the mechanisms responsible for this important adaptive response. PMID:24382869

  11. 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

  12. Role of mitochondria in exercise-induced oxidative stress in skeletal muscle from hyperthyroid rats.

    PubMed

    Venditti, P; Bari, A; Di Stefano, L; Di Meo, S

    2007-07-01

    Previous study showed that exercise induces higher oxidative damage and respiratory capacity reduction in hyperthyroid than in euthyroid skeletal muscle. Because impaired cell function can result from mitochondrial dysfunction, we evaluated the changes induced by exercise in oxygen consumption of skeletal muscle mitochondria from euthyroid and hyperthyroid rats. The mitochondrial function was related with indices of oxidative damage and nitric oxide production, scavenger levels and mitochondrial ROS production rates. Our results show that exercise increased state 4 and decreased state 3 respiration, and the highest changes happened in hyperthyroid preparations. This was consistent with the observation that oxidative damage and NO(*) derivative content were increased by T(3) administration and exercise, reaching the highest levels in hyperthyroid exercised rats. Our results also indicate that the high mitochondrial oxidative damage induced by T(3) and exercise is due to enhanced ROS production, which is dependent on increases in mitochondrial content and reduction degree, respectively, of autoxidizable electron carriers. PMID:17395147

  13. 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

  14. Endurance exercise rescues progeroid aging and induces systemic mitochondrial rejuvenation in mtDNA mutator mice.

    PubMed

    Safdar, Adeel; Bourgeois, Jacqueline M; Ogborn, Daniel I; Little, Jonathan P; Hettinga, Bart P; Akhtar, Mahmood; Thompson, James E; Melov, Simon; Mocellin, Nicholas J; Kujoth, Gregory C; Prolla, Tomas A; Tarnopolsky, Mark A

    2011-03-01

    A causal role for mitochondrial DNA (mtDNA) mutagenesis in mammalian aging is supported by recent studies demonstrating that the mtDNA mutator mouse, harboring a defect in the proofreading-exonuclease activity of mitochondrial polymerase gamma, exhibits accelerated aging phenotypes characteristic of human aging, systemic mitochondrial dysfunction, multisystem pathology, and reduced lifespan. Epidemiologic studies in humans have demonstrated that endurance training reduces the risk of chronic diseases and extends life expectancy. Whether endurance exercise can attenuate the cumulative systemic decline observed in aging remains elusive. Here we show that 5 mo of endurance exercise induced systemic mitochondrial biogenesis, prevented mtDNA depletion and mutations, increased mitochondrial oxidative capacity and respiratory chain assembly, restored mitochondrial morphology, and blunted pathological levels of apoptosis in multiple tissues of mtDNA mutator mice. These adaptations conferred complete phenotypic protection, reduced multisystem pathology, and prevented premature mortality in these mice. The systemic mitochondrial rejuvenation through endurance exercise promises to be an effective therapeutic approach to mitigating mitochondrial dysfunction in aging and related comorbidities. PMID:21368114

  15. Update on exercise-induced pulmonary hemorrhage.

    PubMed

    Sullivan, Stacey; Hinchcliff, Kenneth

    2015-04-01

    Exercise-induced pulmonary hemorrhage (EIPH) is an important disease of horses that perform high-intensity athletic activity. EIPH is an ongoing concern for the racing industry because of its high prevalence; potential impact on performance; welfare concerns; and use of prophylactic medications, such as furosemide, on race day. During the last 10 years, significant progress has been made in understanding the pathogenesis and risk factors for EIPH and the impact of the disease on performance and career. This article summarizes the most recent advances in EIPH. PMID:25770069

  16. 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

    2014-05-01

    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. PMID:24806687

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

    PubMed

    Picklo, Matthew J; Thyfault, John P

    2015-04-01

    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

  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. Exercise-induced anaphylaxis: A clinical view

    PubMed Central

    2012-01-01

    Exercise-induced anaphylaxis (EIA) is a distinct form of physical allergy. The development of anaphylaxis during exertion often requires the concomitant exposure to triggering factors such as intake of foods (food dependent exercise-induced anaphylaxis) or drugs prior to exercise, extreme environmental conditions. EIA is a rare, but serious disorder, which is often undetected or inadequately treated. This article summarizes current evidences on pathophysiology, diagnosis and management. We reviewed recent advances in factors triggering the release of mediators from mast cells which seems to play a pathogenetic role. A correct diagnosis is essential to avoid unnecessary restricted diet, to allow physical activity in subjects with EIA dependent from triggering factors such as food, and to manage attacks. An algorithm for diagnosing EIA based on medical history, IgE tests and exercise challenge test has been provided. In the long-term management of EIA, there is a need for educating patients and care-givers to avoid exposure to precipitating factors and to recognize and treat episodes. Future researches on existing questions are discussed. PMID:22980517

  20. Exercise-induced airways constriction 1

    PubMed Central

    Simonsson, Bo G.; Skoogh, B-E.; Ekström-Jodal, B.

    1972-01-01

    Airway conductance was measured in a body plethysmograph at different lung volumes before and after graded exercise. In 14 out of 19 patients, mostly asthmatics, airway conductance fell significantly after exercise. These subjects also showed other signs of an increased bronchial reactivity to different stimuli, including forced breathing, hyperventilation, and cold air, but they had no exogenous allergy. The exercise-induced bronchoconstriction could be blocked by atropine in six of the nine patients tested. Exercise-induced bronchoconstriction in patients with clinical and physiological evidence of increased airway reactivity thus seems to be primarily mediated via a vagal reflex, probably from hyperresponsive airway mechanoreceptors reacting to increased ventilatory flow or lung distension. No relation was found between PaCO2 or pH and the severity of airways constriction. Cromoglycic acid failed to block the exercise reaction in five of the six hyperreactive patients tested. In addition to or following the vagal reflex a disturbed relation between beta and alpha receptors in bronchial muscles or a release of humoral spasmogens may contribute to the progression of post-exercise airways constriction. PMID:4624586

  1. Exercise-induced anaphylaxis and antileukotriene montelukast.

    PubMed

    Gajbhiye, Sapna; Agrawal, Rajendra Prasad; Atal, Shubham; Tiwari, Vikalp; Phadnis, Pradeep

    2015-01-01

    We report a rare case of exercise-induced anaphylaxis (EIA), occurring exclusively with exercise, without any other associated trigger, detected in the prodromal phase, and prevented from additional anaphylaxis episodes by treatment with cetirizine and 10 mg daily of antileukotriene montelukast to date. EIA is a syndrome in which patients experience a spectrum of the symptoms of anaphylaxis ranging from mild cutaneous signs to severe systemic manifestations such as hypotension, syncope, and even death after increased physical activity. Many people have triggers, such as, a variety of foods, various medications, alcohol, cold weather, humidity, and seasonal and hormonal changes along with exercise that cause the symptoms. Typically, either exercise or the specific trigger alone will rarely cause symptoms. It is differentiated from cholinergic urticaria by the absence of response to passive body warming and emotional stress. PMID:26312002

  2. Exercise-induced anaphylaxis and antileukotriene montelukast

    PubMed Central

    Gajbhiye, Sapna; Agrawal, Rajendra Prasad; Atal, Shubham; Tiwari, Vikalp; Phadnis, Pradeep

    2015-01-01

    We report a rare case of exercise-induced anaphylaxis (EIA), occurring exclusively with exercise, without any other associated trigger, detected in the prodromal phase, and prevented from additional anaphylaxis episodes by treatment with cetirizine and 10 mg daily of antileukotriene montelukast to date. EIA is a syndrome in which patients experience a spectrum of the symptoms of anaphylaxis ranging from mild cutaneous signs to severe systemic manifestations such as hypotension, syncope, and even death after increased physical activity. Many people have triggers, such as, a variety of foods, various medications, alcohol, cold weather, humidity, and seasonal and hormonal changes along with exercise that cause the symptoms. Typically, either exercise or the specific trigger alone will rarely cause symptoms. It is differentiated from cholinergic urticaria by the absence of response to passive body warming and emotional stress. PMID:26312002

  3. Nutritional Support for Exercise-Induced Injuries.

    PubMed

    Tipton, Kevin D

    2015-11-01

    Nutrition is one method to counter the negative impact of an exercise-induced injury. Deficiencies of energy, protein and other nutrients should be avoided. Claims for the effectiveness of many other nutrients following injuries are rampant, but the evidence is equivocal. The results of an exercise-induced injury may vary widely depending on the nature of the injury and severity. Injuries typically result in cessation, or at least a reduction, in participation in sport and decreased physical activity. Limb immobility may be necessary with some injuries, contributing to reduced activity and training. Following an injury, an inflammatory response is initiated and while excess inflammation may be harmful, given the importance of the inflammatory process for wound healing, attempting to drastically reduce inflammation may not be ideal for optimal recovery. Injuries severe enough for immobilization of a limb result in loss of muscle mass and reduced muscle strength and function. Loss of muscle results from reductions in basal muscle protein synthesis and the resistance of muscle to anabolic stimulation. Energy balance is critical. Higher protein intakes (2-2.5 g/kg/day) seem to be warranted during immobilization. At the very least, care should be taken not to reduce the absolute amount of protein intake when energy intake is reduced. There is promising, albeit preliminary, evidence for the use of omega-3 fatty acids and creatine to counter muscle loss and enhance hypertrophy, respectively. The overriding nutritional recommendation for injured exercisers should be to consume a well-balanced diet based on whole, minimally processed foods or ingredients made from whole foods. The diet composition should be carefully assessed and changes considered as the injury heals and activity patterns change. PMID:26553492

  4. 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

  5. Exercise induced compartment syndrome in a professional footballer.

    PubMed

    Cetinus, E; Uzel, M; Bilgiç, E; Karaoguz, A; Herdem, M

    2004-04-01

    Recurrent pain in the lower leg caused by exercise is a common problem in athletes. The main causes are exercise induced compartment syndrome, periostitis of the tibia, stress fracture, venous diseases, obliterative arterial diseases, and shin splints. Exercise induced compartment syndrome is the least common. A recurrent tightening or tense sensation and aching in anatomically defined compartments is pathognomonic. The symptoms are caused by abnormally high pressure in compartments of the leg during and after exercise. In this report, a case of exercise induced compartment syndrome in a professional footballer is described. PMID:15039267

  6. [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. PMID:26943835

  7. Exercise-induced bronchospasm - pathophysiology and treatment.

    PubMed

    Shephard, R J

    1981-09-01

    The practical importance, prevalence, typical features, physiopathology and therapy of exercise-induced bronchospasm (E.I.B.) are briefly reviewed. The condition is common, especially in children. Prevalence is influenced by the mode, intensity and duration of exercise, the age and possibly the sex of the subjects, the number of test repetitions, and the criterion for presence of spasm. The main site of obstruction is in the large airways. Symptoms appear a few minutes post-effort, peaking 10-15 minutes after exercise. At different times, spasm may arise in the vagal reflex arc, from alterations of sympathetic balance, prostaglandin release, and sensitization of the mast cell. Until recently, the main basis of prophylaxis has been inhalation of sodium cromoglycate (20 mg, 60 minutes prior to competition). Beta agonists have until recently been prohibited in international competitions. However, the use of selective beta agonists such as salbutamol and terbutaline was allowed in the 1978 World Swimming Championship and the 1980 World Cross-Country Championship with a supporting medical letter. The Medical Commission of the International Olympic Committee has also moved recently to sanction the use of salbutamol and terbutaline. Future prophylaxis will thus be based on combinations of selective beta agonists and sodium cromoglycate. PMID:6794921

  8. Telocytes in exercise-induced cardiac growth.

    PubMed

    Xiao, Junjie; Chen, Ping; Qu, Yi; Yu, Pujiao; Yao, Jianhua; Wang, Hongbao; Fu, Siyi; Bei, Yihua; Chen, Yan; Che, Lin; Xu, Jiahong

    2016-05-01

    Exercise can induce physiological cardiac growth, which is featured by enlarged cardiomyocyte cell size and formation of new cardiomyocytes. Telocytes (TCs) are a recently identified distinct interstitial cell type, existing in many tissues and organs including heart. TCs have been shown to form a tandem with cardiac stem/progenitor cells in cardiac stem cell niches, participating in cardiac regeneration and repair. Although exercise-induced cardiac growth has been confirmed as an important way to promote cardiac regeneration and repair, the response of cardiac TCs to exercise is still unclear. In this study, 4 weeks of swimming training was used to induce robust healthy cardiac growth. Exercise can induce an increase in cardiomyocyte cell size and formation of new cardiomyocytes as determined by Wheat Germ Lectin and EdU staining respectively. TCs were identified by three immunofluorescence stainings including double labelling for CD34/vimentin, CD34/platelet-derived growth factor (PDGF) receptor-α and CD34/PDGF receptor-β. We found that cardiac TCs were significantly increased in exercised heart, suggesting that TCs might help control the activity of cardiac stem/progenitor cells, cardiomyocytes or endothelial cells. Adding cardiac TCs might help promote cardiac regeneration and renewal. PMID:26987685

  9. Wheat-dependent exercise-induced anaphylaxis.

    PubMed

    Scherf, K A; Brockow, K; Biedermann, T; Koehler, P; Wieser, H

    2016-01-01

    Wheat-dependent exercise-induced anaphylaxis (WDEIA) is a rare, but potentially severe food allergy exclusively occurring when wheat ingestion is accompanied by augmenting cofactors. It is clinically characterized by anaphylactic reactions ranging from urticaria and angioedema to dyspnoea, hypotension, collapse, and shock. WDEIA usually develops after ingestion of wheat products followed by physical exercise. Other cofactors are acetylsalicylic acid and other non-steroidal anti-inflammatory drugs, alcohol, and infections. The precise mechanisms of WDEIA remain unclear; exercise and other cofactors might increase gastrointestinal allergen permeability and osmolality, redistribute blood flow, or lower the threshold for IgE-mediated mast cell degranulation. Among wheat proteins, ω5-gliadin and high-molecular-weight glutenin subunits have been reported to be the major allergens. In some patients, WDEIA has been discussed to be caused by epicutaneous sensitization with hydrolysed wheat gluten included in cosmetics. Diagnosis is made based on the patient's history in combination with allergy skin testing, determination of wheat-specific IgE serum antibodies, basophil activation test, histamine release test, and/or exercise challenge test. Acute treatment includes application of adrenaline or antihistamines. The most reliable prophylaxis of WDEIA is a gluten-free diet. In less severe cases, a strict limitation of wheat ingestion before exercise and avoidance of other cofactors may be sufficient. PMID:26381478

  10. 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

  11. Exercise-induced cardioprotection: endogenous mechanisms.

    PubMed

    Starnes, Joseph W; Taylor, Ryan P

    2007-09-01

    It is now well established that exercise can result in cardioprotection against ischemia-reperfusion (I-R) injury; however, the adaptations within the heart that provide the protection are still in doubt. The cytoprotective proteins receiving the most attention to date are antioxidant enzymes and heat shock proteins. The extent of I-R injury is dependent on the interactions of several events, including energy depletion, metabolite accumulation, oxidant stress, and calcium overload. Adaptations that directly influence any of these could affect I-R outcome. Thus, the exercise-induced cardioprotective phenotype is likely to include additional cytoprotective proteins beyond antioxidant enzymes or heat shock proteins. In this review, we will consider evidence for some of these in the cytosol, mitochondria, and sarcolemma of the cardiomyocyte. We will not consider potentially important adaptations within vascular tissue or the autonomic nervous system. Results of recent studies support the hypothesis that exercise leads to cardioprotective adaptations that are unique from other forms of preconditioning against I-R injury. PMID:17805086

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

    PubMed

    Joseph, A-M; Nguyen, L M-D; Welter, A E; Dominguez, J M; Behnke, B J; Adhihetty, P J

    2014-01-01

    Mitochondrial dysfunction in various tissues has been associated with numerous 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 was not reduced with age and this was consistent with the lack of change in the mitochondrial biogenesis regulator protein, peroxisome proliferator-activated receptor gamma coactivator 1-alpha and its downstream targets nuclear respiratory factor-1 and mitochondrial transcription factor A. No effect was observed in the pro- or anti-apoptotic proteins, Bax and Bcl-2, respectively, but age increased apoptosis inducing factor levels. Endurance training induced beneficial mitochondrial adaptations that were more prominent in old animals including greater increases in relative mtDNA content, biogenesis/remodeling (mitofusin 2), antioxidant capacity (mitochondrial superoxide dismutase) and lower levels of phosphorylated histone H2AX, an early marker of DNA damage (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

  13. Exercise- and training-induced upregulation of skeletal muscle fatty acid oxidation are not solely dependent on mitochondrial machinery and biogenesis

    PubMed Central

    Yoshida, Yuko; Jain, Swati S; McFarlan, Jay T; Snook, Laelie A; Chabowski, Adrian; Bonen, Arend

    2013-01-01

    Regulation of skeletal muscle fatty acid oxidation (FAO) and adaptation to exercise training have long been thought to depend on delivery of fatty acids (FAs) to muscle, their diffusion into muscle, and muscle mitochondrial content and biochemical machinery. However, FA entry into muscle occurs via a regulatable, protein-mediated mechanism, involving several transport proteins. Among these CD36 is key. Muscle contraction and pharmacological agents induce CD36 to translocate to the cell surface, a response that regulates FA transport, and hence FAO. In exercising CD36 KO mice, exercise duration (?44%), and FA transport (?41%) and oxidation (?37%) are comparably impaired, while carbohydrate metabolism is augmented. In trained CD36 KO mice, training-induced upregulation of FAO is not observed, despite normal training-induced increases in mitochondrial density and enzymes. Transfecting CD36 into sedentary WT muscle (+41%), comparable to training-induced CD36 increases (+44%) in WT muscle, markedly upregulates FAO to rates observed in trained WT mice, but without any changes in mitochondrial density and enzymes. Evidently, in vivo CD36-mediated FA transport is key for muscle fuel selection and training-induced FAO upregulation, independent of mitochondrial adaptations. This CD36 molecular mechanism challenges the view that skeletal muscle FAO is solely regulated by muscle mitochondrial content and machinery. PMID:22890711

  14. Human mitochondrial ferritin improves respiratory function in yeast mutants deficient in iron–sulfur cluster biogenesis, but is not a functional homologue of yeast frataxin

    PubMed Central

    Sutak, Robert; Seguin, Alexandra; Garcia-Serres, Ricardo; Oddou, Jean-Louis; Dancis, Andrew; Tachezy, Jan; Latour, Jean-Marc; Camadro, Jean-Michel; Lesuisse, Emmanuel

    2012-01-01

    We overexpressed human mitochondrial ferritin in frataxin-deficient yeast cells (Δyfh1), but also in another mutant affected in [Fe-S] assembly (Δggc1). Ferritin was correctly processed and expressed in the mitochondria of these cells, but the fraction of total mitochondrial iron bound to ferritin was very low, and most of the iron remained in the form of insoluble particles of ferric phosphate in these mitochondria, as evidenced by gel filtration analysis of the mitochondrial matrix (fast protein liquid chromatography [FPLC]) and by Mössbauer spectroscopy. Mutant cells in which ferritin was overexpressed still accumulated iron in the mitochondria and remained deficient in [Fe-S] assembly, suggesting that human mitochondrial ferritin is not a functional homologue of yeast frataxin. However, the respiratory function was improved in these mutants, which correlates with an improvement of cytochrome and heme synthesis. Overexpression of mitochondrial ferritin in [Fe-S] mutants resulted in the appearance of a small pool of high-spin ferrous iron in the mitochondria, which was probably responsible for the improvement of heme synthesis and of the respiratory function in these mutants. PMID:22950017

  15. Exhaustive exercise-induced cardiac conduction system injury and changes of cTnT and Cx43.

    PubMed

    Chang, Y; Yu, T; Yang, H; Peng, Z

    2015-01-01

    Up to now, studies of exercise-induced cardiac arrhythmia have focused primarily on the working myocardium, with few studies examining to the cardiac conduction system where the rhythmic and synchronized contraction of the heart is initiated. To explore whether the cardiac conduction system is involved in the exercise-induced cardiac injury, we performed histological analysis of sinoatrial node, atrioventricular node and Purkinje fibers and tested the level of structural protein cardiac troponin T and Connexin 43 in Sprague Dawley rats following repeated exhaustive exercise. We found increased collagen deposition, hyperplasia interstitialis, and enhanced activity of lactate dehydrongenase and acid phosphatase in the cardiac conduction system following repeated exhaustive exercise. Mitochondrial alterations, enlarged area of intercalated disc and disappearance of gap junctions were additionally observed through electron transmission microscopy. In addition, significant decreases in cardiac troponin T and Connexin 43 were present in the cardiac conduction system in response to repeated exhaustive exercise. All of these findings demonstrate that repeated exhaustive exercise induces ischemic alterations, damage to cytoskeleton and gap junctions, and tissue fibrosis in the cardiac conduction system in rats. These data may shed a new light on the mechanism of exercised-induced cardiac injury and arrhythmia. PMID:25254896

  16. Asthma Bronchiale and Exercise-Induced Bronchoconstriction.

    PubMed

    Jayasinghe, Harshani; Kopsaftis, Zoe; Carson, Kristin

    2015-01-01

    Exercising regularly has a wide range of beneficial health effects; in particular, it has been well documented to help in the management of chronic illnesses including asthma. However, in some individuals, exertion can also trigger an exacerbation of asthmatic episodes and subsequent acute attacks of breathlessness, coughing, tightness of the chest and wheezing. This physiological process is called exercise-induced bronchoconstriction (EIB) whereby post-exercise forced expiratory volume in 1 s is reduced by 10-15% from baseline. While EIB is highly prevalent in asthmatics and presents with similar respiratory symptoms, asthma and EIB are not mutually exclusive. The aim of this review is to present a broad overview of both conditions in order to enhance the understanding of the similarities and differences distinguishing them as two separate entities. The pathophysiology and mechanisms underlying asthma are well described with research now focussing on defining phenotypes for targeted management strategies. Conversely, the mechanistic understanding of EIB remains largely under-described. Diagnostic pathways for both are established and similar, as are pharmacologic and non-pharmacologic treatments and management approaches, which have enhanced success with early detection. Given the potential for exacerbation of asthma, exercise avoidance is common but counterproductive as current evidence indicates that it is well tolerated and improves quality of life. Literature supporting the benefit of exercise for EIB sufferers is at present favourable, yet extremely limited; therefore, future research should be directed in this area as well as towards further developing the understanding of the pathophysiology and mechanisms underpinning both EIB and asthma. PMID:26068579

  17. 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

  18. Management of Exercise-Induced Bronchospasm in Children

    PubMed Central

    Hendeles, Leslie; Asmus, Michael J.; Chesrown, Sarah

    2003-01-01

    Bronchospasm precipitated by exercise is often indistinguishable from bronchospasm produced by other stimuli. Symptoms result from airflow limitation and include wheezing, cough, chest tightness, dyspnea and sometimes hypoxemia. The prevalence of exercise-induced bronchospasm varies from 30%-90%, but virtually all patients with current asthma will experience a decrease in lung function if the exercise is sufficiently vigorous, especially in cold, dry environmental conditions. Exercise-induced bronchospasm is more prevalent in children than in adults, probably because children are physically more active. It is also more prevalent among elite winter sports athletes. The pathogenesis of exercise-induced bronchospasm involves a defect in respiratory heat exchange that probably triggers mast cell and eosinophil release of bronchoconstricting mediators. The goal of therapy is prevention of symptoms. This may be accomplished by pre-treating patients with isolated exercise-induced bronchospasm using an inhaled rapid-onset ?2-adrenergic agonist before a scheduled activity or by treating the underlying inflammation when exercise-induced bronchospasm is part of the clinical syndrome of persistent asthma. In the later instance, either an inhaled corticosteroid, an oral leukotriene modifier, or a combination of both, depending on severity, may be required to prevent exercise-induced bronchospasm associated with activities of daily living. In addition, some of these patients may still require pre-treatment with a short-acting inhaled ?2-agonist before a scheduled vigorous activity, especially in very cold ambient temperatures. Because the duration of bronchoprotection decreases with daily use (tachyphylaxis), long acting ?2-adrenergic agonists (e.g., formoterol, salmeterol) have a limited role in treating exercise-induced bronchospasm. PMID:23300391

  19. Exercise-induced bronchoconstriction in Tunisian elite athletes is underdiagnosed

    PubMed Central

    Sallaoui, Ridha; Zendah², Ines; Ghedira², Habib; Belhaouz³, Mohcine; Ghrairi³, Mourad; Amri³, Mohamed

    2011-01-01

    Many studies have shown an increased risk of developing exercise-induced bronchoconstriction among the athletic population, particularly at the elite level. Subjective methods for assessing exercise-induced bronchoconstriction such as surveys and questionnaires have been used but have resulted in an underestimation of the prevalence of airway dysfunction when compared with objective measurements. The aim of the present study was to compare the prevalence of exercise-induced bronchoconstriction among Tunisian elite athletes obtained using an objective method with that using a subjective method, and to discuss the possible causes and implications of the observed discrepancy. As the objective method we used spirometry before and after exercise and for the subjective approach we used a medical history questionnaire. All of the recruited 107 elite athletes responded to the questionnaire about respiratory symptoms and medical history and underwent a resting spirometry testing before and after exercise. Post-exercise spirometry revealed the presence of exercise-induced bronchoconstriction in 14 (13%) of the elite athletes, while only 1.8% reported having previously been diagnosed with asthma. In conclusion, our findings indicate that medical history-based diagnoses of exercise-induced bronchoconstriction lead to underestimations of true sufferers. PMID:24198569

  20. Exercise-induced bronchoconstriction in Tunisian elite athletes is underdiagnosed.

    PubMed

    Sallaoui, Ridha; Zendah, Ines; Ghedira, Habib; Belhaouz, Mohcine; Ghrairi, Mourad; Amri, Mohamed

    2011-01-01

    Many studies have shown an increased risk of developing exercise-induced bronchoconstriction among the athletic population, particularly at the elite level. Subjective methods for assessing exercise-induced bronchoconstriction such as surveys and questionnaires have been used but have resulted in an underestimation of the prevalence of airway dysfunction when compared with objective measurements. The aim of the present study was to compare the prevalence of exercise-induced bronchoconstriction among Tunisian elite athletes obtained using an objective method with that using a subjective method, and to discuss the possible causes and implications of the observed discrepancy. As the objective method we used spirometry before and after exercise and for the subjective approach we used a medical history questionnaire. All of the recruited 107 elite athletes responded to the questionnaire about respiratory symptoms and medical history and underwent a resting spirometry testing before and after exercise. Post-exercise spirometry revealed the presence of exercise-induced bronchoconstriction in 14 (13%) of the elite athletes, while only 1.8% reported having previously been diagnosed with asthma. In conclusion, our findings indicate that medical history-based diagnoses of exercise-induced bronchoconstriction lead to underestimations of true sufferers. PMID:24198569

  1. Exercise-Induced Asthma in Asthmatic Children of Southern Iran

    PubMed Central

    Fayezi, Abbas; Amin, Reza; Kashef, Sara; Yasin, Soheila Al; Bahadoram, Mohammad

    2015-01-01

    Background: Asthma is a common illness, especially among children. Exercise-induced asthma is an important consideration, both as a factor, limiting physical activity of patients, and also as an indicator of poor long term control. We investigated pre-Valence of exercise-induced asthma in a group of asthmatic children living in southern Iran. Methods: We conducted treadmill exercise challenge test in 40 young asthmatic patients aged 6 to 18. After 8 minutes exercise to achieve 80% of maximum heart rate predicted for age, patients were examined and spirometry values recorded at frequent intervals. We defined exercise-induced asthma as 10% or more decline in Forced Expiratory Volume in one second (FEV1) within 30 minutes after exercise challenge. Results: Of 40 patients evaluated, 22 patients (55% of total) met our criteria for exercise-induced asthma. Most positive responses (7 of 22, 31.8%) occurred at about 10 minutes after exercise. Cough was the most consistent sign (18 of 22 patients, 81%). In 2 patients (9%), FEV 1 decline did not accompany any symptom or sign. Conclusion: We concluded that Exercise- induced asthma occurs in a relatively smaller subset of southern Iranian asthmatic children. Also treadmill exercise challenge performed by a trained staff, following standard protocol and using enough monitoring and precautions is safe and diagnostic in children and adolescents. PMID:25716378

  2. Resveratrol Attenuates Exercise-Induced Adaptive Responses in Rats Selectively Bred for Low Running Performance

    PubMed Central

    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. PMID:24659933

  3. Dietary supplementation with the microalga Galdieria sulphuraria (Rhodophyta) reduces prolonged exercise-induced oxidative stress in rat tissues.

    PubMed

    Carfagna, Simona; Napolitano, Gaetana; Barone, Daniela; Pinto, Gabriele; Pollio, Antonino; 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

  4. 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

  5. Role of Twin Cys-Xaa9-Cys Motif Cysteines in Mitochondrial Import of the Cytochrome c Oxidase Biogenesis Factor Cmc1*

    PubMed Central

    Bourens, Myriam; Dabir, Deepa V.; Tienson, Heather L.; Sorokina, Irina; Koehler, Carla M.; Barrientos, Antoni

    2012-01-01

    The Mia40 import pathway facilitates the import and oxidative folding of cysteine-rich protein substrates into the mitochondrial intermembrane space. Here we describe the in vitro and in organello oxidative folding of Cmc1, a twin CX9C-containing substrate, which contains an unpaired cysteine. In vitro, Cmc1 can be oxidized by the import receptor Mia40 alone when in excess or at a lower rate by only the sulfhydryl oxidase Erv1. However, physiological and efficient Cmc1 oxidation requires Erv1 and Mia40. Cmc1 forms a stable intermediate with Mia40 and is released from this interaction in the presence of Erv1. The three proteins are shown to form a ternary complex in mitochondria. Our results suggest that this mechanism facilitates efficient formation of multiple disulfides and prevents the formation of non-native disulfide bonds. PMID:22767599

  6. Exercise-induced bronchoconstriction and asthma.

    PubMed Central

    Dryden, Donna M; Spooner, Carol H; Stickland, Michael K; Vandermeer, Ben; Tjosvold, Lisa; Bialy, Liza; Wong, Kai; Rowe, Brian H

    2010-01-01

    OBJECTIVES The objectives are: (1) To assess diagnostic test characteristics of six alternative index tests compared with the selected reference standard-a standardized exercise challenge test (ECT) in patients with suspected exercise-induced bronchoconstriction or asthma (EIB/EIA); (2) to determine the efficacy of a single prophylactic dose of four pharmacologic and one nonpharmacologic interventions vs. placebo to attenuate EIB/EIA in patients with diagnosed EIB/EIA; and (3) to determine if regular daily treatment with short-acting or long-acting beta-agonists (SABA or LABA) causes patients with EIA to develop tachyphylaxis when additional prophylactic doses are used pre-exercise. DATA SOURCES A systematic and comprehensive literature search was conducted in 14 electronic databases (Diagnosis) and the Cochrane Airways Register (Therapy). REVIEW METHODS Study selection, quality assessment, and data extraction were conducted independently by two reviewers. The primary outcome was the maximum percent fall in the post-exercise forced expiratory volume in 1 second (percent fall FEV1). The diagnostic threshold for a positive ECT was a percent fall FEV1 of 10% or more. Sensitivity (SN) and specificity (SP) were calculated. For therapy, mean differences (MD) in the percent fall FEV1 and 95% confidence intervals (CI) (random effects model) were calculated. A positive MD indicates the intervention works better than the control. RESULTS For the diagnostic reviews, 5,318 citations yielded 28 relevant studies; for the therapy reviews, 1,634 citations yielded 109 relevant RCTs. Diagnostic test results versus ECT: self-reported history (2 studies) SN=36-8 percent; SP=85-86 percent; sport specific challenges (5 studies) SN=0-100 percent, SP=0-100 percent; eucapnic voluntary hyperpnea (7 studies) SN=25-90 percent, SP=0-71 percent; free running asthma screening test (3 studies) SN=60-67 percent, SP=47-67 percent; mannitol (3 studies) SN=58-96 percent, SP=65-78 percent. All SN and SP calculations indicated substantial heterogeneity that could not be explained by sensitivity or subgroup analyses. Therapy results: SABA offered greater protection than mast cell stabilizers (MCS) (12 studies); MD=6.8 (95 percent CI: 4.5, 9.2) but combining them offered no additional benefit; SABA versus MCS plus SABA (5 studies) MD=1.3 (95 percent CI: -6.3, 8.9). Leukotriene receptor antagonists (LTRA), MCS, ipratropium bromide, and interval warmup routines provided statistically significant attenuation of EIA when compared with placebo; inhaled corticosteroids (ICS) and other warmup routines did not. Single-dose intervention versus placebo results are: LTRA (9 studies) MD=8.9 (95 percent CI: 6.9, 11.0); MCS (nedocromil sodium) (17 studies) MD=15.6 (95 percent CI: 13.2, 18.2); interval warmup versus no warmup (4 studies) MD=10.6 (95 percent CI: 6.5, 14.7); ICS (4 studies) MD=5.0 (95 percent CI: 0.0, 9.9); continuous low intensity warmup versus no warmup (3 studies) MD=12.6 (95 percent CI: -1.5, 26.7); continuous high intensity warmup versus no warmup (2 studies) MD=9.8 (95 percent CI: -6.4, 26.0). After daily LABA (salmeterol) use for 3 to 4 weeks (4 studies), the percent fall FEV1 following an ECT at 2 and 4 weeks was greater than at day 1 in the LABA arm indicating that tachyphylaxis to prophylactic LABA use occurred. Daily SABA use for 1 week (1 study) also indicated development of tachyphylaxis. However, both LABA and SABA continued to have an attenuating effect on EIA. CONCLUSIONS Given the small number of studies comparing EIB/EIA diagnostic tests, the heterogeneity of the study populations, and the varied study methodologies, there is no clear evidence that any of the index tests are a suitable replacement for a standardized ECT to diagnose EIB/EIA in the general population. All bronchodilator agents and most anti-inflammatory agents when used as pretreatment are somewhat effective in attenuating the percent fall FEV1 associated with EIA. PMID:20726625

  7. 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

  8. Exercise-induced arterial hypoxemia: consequences for locomotor muscle fatigue.

    PubMed

    Romer, Lee M; Dempsey, Jerome A; Lovering, Andrew; Eldridge, Marlowe

    2006-01-01

    Reductions in arterial O2 saturation (-5 to -10% SaO2 < rest) occur over time during sustained heavy intensity exercise in a normoxic environment, due primarily to the effects of acid pH and increased temperature on the position of the HbO2 dissociation curve. We prevented the desaturation via increased F1O2 (.23 to .29) and showed that exercise time to exhaustion was increased. We used supramaximal magnetic stimulation (1 - 100 Hz) of the femoral nerve to test for quadriceps fatigue. We used mildly hyperoxic inspirates (F1O2 .23 to .29) to prevent O2 desaturation. We then compared the amount of quadriceps fatigue incurred following cycling exercise at SaO2 98% vs. 91% with each trial carried out at equal exercise intensities (90% Max) and for equal durations. Preventing the normal exercise-induced O2 desaturation prevented about one-half the amount of exercise-induced quadriceps fatigue; plasma lactate and effort perception were also reduced. We conclude that the normal exercise-induced O2 desaturation during heavy intensity endurance exercise contributes significantly to exercise performance limitation in part because of its effect on locomotor muscle fatigue. These effects of EIAH were confirmed in mild environmental hypoxia (FIO2 .17, SaO2 88%) which significantly augmented the magnitude of exercise-induced quadriceps fatigue observed in normoxia. PMID:17089878

  9. 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

  10. Diagnosis and Management of Exercise-Induced Asthma.

    ERIC Educational Resources Information Center

    Rupp, Ned T.

    1996-01-01

    Exercise-induced asthma (EIA) affects 12-15% of the population. This comprehensive guide suggests that nearly all individuals with EIA can be active, highlighting both pharmacologic and nonpharmacologic management of asthma and stressing the importance of rigorous patient education in controlling underlying asthma and EIA. (SM)

  11. 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...

  12. 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

  13. 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

  14. Exercise-induced rhabdomyolysis from stationary biking: a case report

    PubMed Central

    Inklebarger, J; Galanis, N; Kirkos, J; Kapetanos, G

    2010-01-01

    There are several reports concerning exercise and rabdomyolysis. There has been no report in the English literature of exercise induced rabdomyolisis from a stationary bike. A 63-year-old female recreational athlete presented to our hospital seeking treatment for lower back, leg pain and stiffness after exercising on a stationary bicycle one day prior. Blood work showed a raised CK of 38,120 U/L, a myoglobin of 5330 and an AST 495 U/L with normal urea and electrolytes. Urinalysis remained negative. She was admitted for oral and intravenous hydration and fluid balance monitoring This is a very rare case of rhabdomyolysis due to exercise. This study highlights the difficulties faced by accident and emergency teams in distinguishing delayed onset muscle soreness (DOMS) from exercise-induced rhabdomyolysis, and reinforces the concept that rhabdomyolysis can occur at any level of exercise intensity. PMID:21311638

  15. 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.

  16. Electron paramagnetic spectroscopic evidence of exercise-induced free radical accumulation in human skeletal muscle.

    PubMed

    Bailey, Damian M; Lawrenson, Leslie; McEneny, Jane; Young, Ian S; James, Philip E; Jackson, Simon K; Henry, Robert R; Mathieu-Costello, Odile; McCord, Joe M; Richardson, Russell S

    2007-02-01

    The present study determined if acute exercise increased free radical formation in human skeletal muscle. Vastus lateralis biopsies were obtained in a randomized balanced order from six males at rest and following single-leg knee extensor exercise performed for 2 min at 50% of maximal work rate (WR(MAX)) and 3 min at 100% WR(MAX). EPR spectroscopy revealed an exercise-induced increase in mitochondrial ubisemiquinone (UQ*-) [0.167 +/- 0.055 vs. rest: 0.106 +/- 0.047 arbitrary units (AU)/g total protein (TP), P < 0.05] and alpha-phenyl-tert-butylnitrone-adducts (112 +/- 41 vs. rest: 29 +/- 9 AU/mg tissue mass, P < 0.05). Intramuscular lipid hydroperoxides also increased (0.320 +/- 0.263 vs. rest: 0.148 +/- 0.071 nmol/mg TP, P < 0.05) despite an uptake of alpha-tocopherol, alpha-carotene and beta-carotene. There were no relationships between mitochondrial volume density and any biomarkers of oxidative stress. These findings provide the first direct evidence for intramuscular free radical accumulation and lipid peroxidation following acute exercise in humans. PMID:17364944

  17. NAMPT regulates mitochondria biogenesis via NAD metabolism and calcium binding proteins during skeletal muscle contraction

    PubMed Central

    Kim, Jeong Seok; Yoon, Chung-Su; Park, Dae Ryoung

    2014-01-01

    [Purpose] The purpose of this study was to investigate the effect that muscle contraction induced NAD metabolism via NAMPT has on mitochondrial biogenesis. [Methods] Primary skeletal muscle cells were isolated from the gastrocnemius in C57BL/6 mice. The muscle cells were stimulated by electrical current at 1Hz for 3 minutes in conditions of normal or NAD metabolism related inhibitor treatment. NAD/NADH level, Sirt1 and mitochondria biogenesis related signal factor’s changes were examined in normal or NAD metabolism related inhibitor treated cells. [Results] Electrical stimulation (ES) induced muscle contractions significantly increased NAD/NADH levels, NAMPT inhibitor FK-866 inhibited ES-induced NAD formation, which caused SIRT1 expression and PGC-1α deacetylation to decrease. Moreover, NAMPT inhibition decreased mitochondrial biogenesis related mRNA, COX-1 and Tfam levels. Along with AMPK inhibitor, compound C decreases SIRT1 expression, PGC-1α deacetylation and muscle contraction induced mitochondrial biogenesis related mRNA increment. These results indicated that the AMPK-NAMPT signal is a key player for muscle contraction induced SIRT1 expression and PGC-1α deacetylation, which influences mitochondrial biogenesis. Inhibition of the AMPK upregulator, Camkkβ, STO-609 decreased AMPK phosphorylation and SIRT1 expression but did not decrease PGC-1α deacetylation. However, CAMKII inhibition via AIP decreased PGC-1α deacetylation. [Conclusion] In conclusion, the results indicate that NAMPT plays an important role in NAD metabolism and mitochondrial biogenesis. However, mitochondrial biogenesis is also controlled by different calcium binding protein signals including Camkkβ and CAMKII. [Keyword] Muscle contraction, NAD metabolism, SIRT1, PGC-1 α, mitochondria biogenesis. PMID:25566462

  18. Exercise-induced pulmonary hemorrhage after running a marathon.

    PubMed

    Ghio, Andrew J; Ghio, Christine; Bassett, Maryann

    2006-01-01

    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 evident on gross inspection of bronchoalveolar lavage fluid, examination of the cytospin, and measurement of hemoglobin, iron, and ferritin concentrations. EIPH in humans may occur without any evidence on clinical presentation; its incidence may be far greater than currently suspected. PMID:17086462

  19. The Curious Question of Exercise-Induced Pulmonary Edema

    PubMed Central

    Bates, Melissa L.; Farrell, Emily T.; Eldridge, Marlowe W.

    2011-01-01

    The question of whether pulmonary edema develops during exercise on land is controversial. Yet, the development of pulmonary edema during swimming and diving is well established. This paper addresses the current controversies that exist in the field of exercise-induced pulmonary edema on land and with water immersion. It also discusses the mechanisms by which pulmonary edema can develop during land exercise, swimming, and diving and the current gaps in knowledge that exist. Finally, this paper discusses how these fields can continue to advance and the areas where clinical knowledge is lacking. PMID:21660232

  20. Mitochondrial Turnover in the Heart

    PubMed Central

    Gustafsson, Åsa B.

    2010-01-01

    Mitochondrial quality control is increasingly recognized as an essential element in maintaining optimally functioning tissues. Mitochondrial quality control depends upon a balance between biogenesis and autophagic destruction. Mitochondrial dynamics (fusion and fission) allows for the redistribution of mitochondrial components. We speculate that this permits sorting of highly functional components into one end of a mitochondrion, while damaged components are segregated at the other end, to be jettisoned by asymmetric fission followed by selective mitophagy. Ischemic preconditioning requires autophagy/mitophagy, resulting in selective elimination of damaged mitochondria, leaving behind a population of robust mitochondria with a higher threshold for opening of the mitochondrial permeability transition pore. In this review we will consider the factors that regulate mitochondrial biogenesis and destruction, the machinery involved in both processes, and the biomedical consequences associated with altered mitochondrial turnover. PMID:21147177

  1. Mitochondrial remodeling in hepatic differentiation and dedifferentiation.

    PubMed

    Wanet, Anaïs; Remacle, Noémie; Najar, Mehdi; Sokal, Etienne; Arnould, Thierry; Najimi, Mustapha; Renard, Patricia

    2014-09-01

    Mitochondrial biogenesis and metabolism have recently emerged as important actors of stemness and differentiation. On the one hand, the differentiation of stem cells is associated with an induction of mitochondrial biogenesis and a shift from glycolysis toward oxidative phosphorylations (OXPHOS). In addition, interfering with mitochondrial biogenesis or function impacts stem cell differentiation. On the other hand, some inverse changes in mitochondrial abundance and function are observed during the reprogramming of somatic cells into induced pluripotent stem cells (iPSCs). Yet although great promises in cell therapy might generate better knowledge of the mechanisms regulating the stemness and differentiation of somatic stem cells (SSCs)-which are preferred over embryonic stem cells (ESCs) and iPSCs because of ethical and safety considerations-little interest was given to the study of their mitochondria. This study provides a detailed characterization of the mitochondrial biogenesis occurring during the hepatogenic differentiation of bone marrow-mesenchymal stem cells (BM-MSCs). During the hepatogenic differentiation of BM-MSCs, an increased abundance of mitochondrial DNA (mtDNA) is observed, as well as an increased expression of several mitochondrial proteins and biogenesis regulators, concomitant with increased OXPHOS activity, capacity, and efficiency. In addition, opposite changes in mitochondrial morphology and in the abundance of several OXPHOS subunits were found during the spontaneous dedifferentiation of primary hepatocytes. These data support reverse mitochondrial changes in a different context from genetically-engineered reprogramming. They argue in favor of a mitochondrial involvement in hepatic differentiation and dedifferentiation. PMID:25084555

  2. Sedentary aging increases resting and exercise-induced intramuscular free radical formation.

    PubMed

    Bailey, Damian M; McEneny, Jane; Mathieu-Costello, Odile; Henry, Robert R; James, Philip E; McCord, Joe M; Pietri, Sylvia; Young, Ian S; Richardson, Russell S

    2010-08-01

    Mitochondrial free radical formation has been implicated as a potential mechanism underlying degenerative senescence, although human data are lacking. Therefore, the present study was designed to examine if resting and exercise-induced intramuscular free radical-mediated lipid peroxidation is indeed increased across the spectrum of sedentary aging. Biopsies were obtained from the vastus lateralis in six young (26 + or - 6 yr) and six aged (71 + or - 6 yr) sedentary males at rest and after maximal knee extensor exercise. Aged tissue exhibited greater (P < 0.05 vs. the young group) electron paramagnetic resonance signal intensity of the mitochondrial ubisemiquinone radical both at rest (+138 + or - 62%) and during exercise (+143 + or - 40%), and this was further complemented by a greater increase in alpha-phenyl-tert-butylnitrone adducts identified as a combination of lipid-derived alkoxyl-alkyl radicals (+295 + or - 96% and +298 + or - 120%). Lipid hydroperoxides were also elevated at rest (0.190 + or - 0.169 vs. 0.148 + or - 0.071 nmol/mg total protein) and during exercise (0.567 + or - 0.259 vs. 0.320 + or - 0.263 nmol/mg total protein) despite a more marked depletion of ascorbate and uptake of alpha/beta-carotene, retinol, and lycopene (P < 0.05 vs. the young group). The impact of senescence was especially apparent when oxidative stress biomarkers were expressed relative to the age-related decline in mitochondrial volume density and absolute power output at maximal exercise. In conclusion, these findings confirm that intramuscular free radical-mediated lipid peroxidation is elevated at rest and during acute exercise in aged humans. PMID:20507973

  3. 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…

  4. 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

  5. Exercise-Induced Anaphylaxis: An Update on Diagnosis and Treatment

    PubMed Central

    Barg, Wojciech; Medrala, Wojciech

    2010-01-01

    Exercise-induced anaphylaxis (EIA) and food-dependent, exercise-induced anaphylaxis (FDEIA) are rare but potentially life-threatening clinical syndromes in which association with exercise is crucial. The range of triggering physical activities is broad, including as mild an effort as a stroll. EIA is not fully repeatable (ie, the same exercise may not always result in anaphylaxis in a given patient). In FDEIA, the combined ingestion of sensitizing food and exercise is necessary to precipitate symptoms. Clinical features and management do not differ significantly from other types of anaphylaxis. The pathophysiology of EIA and FDEIA is not fully understood. Different hypotheses concerning the possible influence of exercise on the development of anaphylactic symptoms are taken into consideration. These include increased gastrointestinal permeability, blood flow redistribution, and most likely increased osmolality. This article also describes current diagnostic and therapeutic possibilities, including changes in lifestyle and preventive properties of antiallergic drugs as well as acute treatment of these dangerous syndromes. PMID:20922508

  6. 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. PMID:22494399

  7. Exercise-induced arterial hypoxaemia in active young women.

    PubMed

    Guenette, Jordan A; Sheel, A William

    2007-12-01

    Studies examining pulmonary gas exchange during exercise have primarily focused on young healthy men, whereas the female response to exercise has received limited attention. Evidence is accumulating that the response of the lungs, airways, and (or) respiratory muscles to exercise is less than ideal and this may significantly compromise oxygen transport in certain groups of otherwise healthy, fit, active, male subjects. Women may be even more susceptible to exercise-induced pulmonary limitations than height-matched men, by virtue of their smaller lung volumes, lower maximal expiratory flow rates, and smaller diffusion surface areas. We have recently shown that exercise-induced arterial hypoxaemia (EIAH) is more prevalent and occurs at relatively lower fitness levels in females than in males. Despite this finding, few physiologically based mechanisms have been identified to explain why women may be more susceptible to EIAH than men. Potential mechanisms of EIAH include relative alveolar hypoventilation, ventilation-perfusion inequality, and diffusion limitation. Whether these mechanisms are different between sexes remains controversial. The primary purpose of this review is to summarize the available data on EIAH in women and to discuss potential sex-based mechanisms for gas exchange impairment. Furthermore, we discuss unresolved questions dealing with pulmonary system limitations during exercise in women. PMID:18059604

  8. Inhaled and oral bronchodilator therapy in exercise induced asthma.

    PubMed

    Anderson, S D; Rozea, P J; Dolton, R; Lindsay, D A

    1975-12-01

    Measurements of peak expiratory flow rate during serial exercise tests were used to assess the efficacy of the beta adrenergic stimulants oral terbutaline (5 mg) and fenoterol aerosol (400 micrograms), in preventing post-exercise bronchoconstriction in 18 asthmatic subjects. While both compounds significantly elevated resting levels of peak expiratory flow rate for at least four hours, there were qualitative and quantitative differences in the effects of the two drugs on exercise induced bronchoconstriction. Oral terbulation did not significantly alter the pattern of response to exercise. However, the peak expiratory flow rates before during and after exercise were significantly higher compared with placebo at two, four and six hours after the drug. The importance of examination of actual values for peak expiratory flow rates as well as percentage changes when testing oral bronchodilators is emphasised. Aerosol fenoterol completely blocked post-exercise bronchoconstriction immediately after inhalation and for up to four hours in most subjects. Bronchodilatation occurred in all subjects during exercise in the presence of both the active and placebo drugs. It is postulated that the superiority of the aerosol in blocking exercise induced bronchoconstriction may be function of its activity at the surface of the bronchial mucosa. PMID:779751

  9. 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.

  10. 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

  11. Serotonin is required for exercise-induced adult hippocampal neurogenesis.

    PubMed

    Klempin, Friederike; Beis, Daniel; Mosienko, Valentina; Kempermann, Gerd; Bader, Michael; Alenina, Natalia

    2013-05-01

    Voluntary wheel running has long been known to induce precursor cell proliferation in adult hippocampal neurogenesis in rodents. However, mechanisms that couple activity with the promitotic effect are not yet fully understood. Using tryptophan hydroxylase (TPH) 2 deficient (Tph2-deficient) mice that lack brain serotonin, we explored the relationship between serotonin signaling and exercise-induced neurogenesis. Surprisingly, Tph2-deficient mice exhibit normal baseline hippocampal neurogenesis but impaired activity-induced proliferation. Our data demonstrate that the proproliferative effect of running requires the release of central serotonin in young-adult and aged mice. Lack of brain serotonin further results in alterations at the stage of Sox2-positive precursor cells, suggesting physiological adaptations to changes in serotonin supply to maintain homeostasis in the neurogenic niche. We conclude that serotonin plays a direct and acute regulatory role in activity-dependent hippocampal neurogenesis. The understanding of exercise-induced neurogenesis might offer preventive but also therapeutic opportunities in depression and age-related cognitive decline. PMID:23658167

  12. Acute versus chronic exercise-induced left-ventricular remodeling.

    PubMed

    Weiner, Rory B; Baggish, Aaron L

    2014-11-01

    Exercise-induced cardiac remodeling (EICR) is the process by which the heart adapts to the physiologic stress of exercise. Non-invasive cardiovascular imaging has led to advances in the understanding of EICR, with sport-specific changes in left-ventricular (LV) structure and function being described; however, the majority of data stem from cross-sectional and short-duration longitudinal studies. Due to the paucity of long-term longitudinal EICR studies, the time course of this process and any distinct differentiation between acute and chronic adaptations remain largely unexplored. In order to clarify the natural history of EICR, longer duration longitudinal study is required. Such work will determine whether exercise-induced changes in myocardial structure and function occur in discrete stages. Examination of prolonged exposures to exercise training will also be necessary to determine normative values across the age and training spectrums of athletic patients. This information will help to distinguish the boundary between physiology and pathology in athletic patients. PMID:25300444

  13. Exercise-Induced Oxidative Stress and Dietary Antioxidants

    PubMed Central

    Yavari, Abbas; Javadi, Maryam; Mirmiran, Parvin; Bahadoran, Zahra

    2015-01-01

    Context: Overproduction of reactive oxygen and nitrogen species during physical exercise, exercise induced oxidative stress and antioxidant supplementation is interesting and controversial concepts that have been considered during the past decades. Evidence Acquisition: In this review, we aimed to summarize current evidence in relation to antioxidant supplementation outcomes during exercise and physical activity. For this aim, we obtained relevant articles through searches of the Medline and PubMed databases between 1980 to 2013. Although major studies have indicated that antioxidants could attenuate biomarkers of exercise-induced oxidative stress and the use of antioxidant supplement is a common phenomenon among athletes and physically active people, there are some doubts regarding the benefits of these. Results: It seems that the best recommendations regarding antioxidants and exercise are having a balanced diet rich in natural antioxidants and phytochemicals. Conclusions: Regular consumption of various fresh fruits and vegetables, whole grains, legumes and beans, sprouts and seeds is an effective and safe way to meet all antioxidant requirements in physically active persons and athletes. PMID:25883776

  14. Exercise-Induced Syncope in a Sedentary Woman

    PubMed Central

    Rickard, John W.; Zakaria, Sammy

    2014-01-01

    Vasovagal (neurocardiogenic) syncope, a subtype of reflex syncope, has many well-known triggers. However, we found no previous report of vasovagal exercise-induced syncope in a sedentary person. We present the case of a 35-year-old sedentary woman who experienced vasovagal syncope as she underwent an exercise stress test. Results of evaluations, including resting and stress electrocardiography and echocardiography, were normal. Her presentation is highly unusual: syncope has typically not been associated with exercise except in young athletes, people with structural heart abnormalities, or people with a prolonged QT syndrome. To our knowledge, this is the first report of vasovagal syncope associated with exercise in a sedentary patient who had normal cardiac and electrophysiologic function. We suggest possible physiologic mechanisms and diagnostic strategies. PMID:25593529

  15. Exercise-induced arterial hypoxaemia in athletes: a review.

    PubMed

    Prefaut, C; Durand, F; Mucci, P; Caillaud, C

    2000-07-01

    During exercise, healthy individuals are able to maintain arterial oxygenation, whereas highly-trained endurance athletes may exhibit an exercise-induced arterial hypoxaemia (EIAH) that seems to reflect a gas exchange abnormality. The effects of EIAH are currently debated, and different hypotheses have been proposed to explain its pathophysiology. For moderate exercise, it appears that a relative hypoventilation induced by endurance training is involved. For high-intensity exercise, ventilation/perfusion (V(A)/Q) mismatching and/or diffusion limitation are thought to occur. The causes of this diffusion limitation are still under debate, with hypotheses being capillary blood volume changes and interstitial pulmonary oedema. Moreover, histamine is released during exercise in individuals exhibiting EIAH, and questions persist as to its relationship with EIAH and its contribution to interstitial pulmonary oedema. Further investigations are needed to better understand the mechanisms involved and to determine the long term consequences of repetitive hypoxaemia in highly trained endurance athletes. PMID:10907757

  16. 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…

  17. 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

  18. 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…

  19. 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

  20. Surgical treatment of exercise-induced laryngeal dysfunction.

    PubMed

    Maat, Robert C; Roksund, Ola D; Olofsson, Jan; Halvorsen, Thomas; Skadberg, Britt T; Heimdal, John-Helge

    2007-04-01

    A method for combined ergo-spirometry and continuous laryngeal inspection during exercise, entitled continuous laryngoscopy exercise test (CLE-test) has been developed in order to study airway obstruction at the laryngeal level during exercise. The aim of the study was to apply the CLE-test on patients experiencing respiratory distress during exercise in order to reveal the usefulness of the CLE-test both as a diagnostic tool in the selection of patients for surgery and in evaluation of treatment effects postoperatively. Until now, 81 patients with a history of exercise-induced stridor have undergone the CLE-test. Ten of these patients were selected for surgical treatment based on the severity of symptoms and their motivation for treatment. All ten patients underwent endoscopic supraglottoplasty (ES), with laser incision in both aryepiglottic folds anterior to the cuneiform cartilages and removal of the mucosa around the top of the tubercles. Each patient was examined by the CLE-test before and 3 months after surgery. Eight patients felt subjectively that their breathing capacity during exercise was improved. When pre- and postoperative ergo-spirometry evaluations were compared, increased peak oxygen consumption was observed in four out of ten patients and better maximal minute ventilation in seven out of ten. Postoperative evaluation of the laryngeal images showed less prominent aryepiglottic folds. The typical adduction of the supraglottic structures concomitant with inspiratory stridor found preoperatively was not present in any of the patients during exercise postoperatively. The ES procedure is an efficient surgical treatment for exercise-induced laryngeal supraglottic obstruction and the CLE-test eases the selection of patients for surgery and facilitates the evaluation of treatment effects. PMID:17203312

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

    PubMed Central

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

    2014-01-01

    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. PMID:24674856

  2. Impact of age on exercise-induced ATP supply during supramaximal plantar flexion in humans.

    PubMed

    Layec, Gwenael; Trinity, Joel D; Hart, Corey R; Kim, Seong-Eun; Groot, H Jonathan; Le Fur, Yann; Sorensen, Jacob R; Jeong, Eun-Kee; Richardson, Russell S

    2015-08-15

    Currently, the physiological factors responsible for exercise intolerance and bioenergetic alterations with age are poorly understood due, at least in art, to the confounding effect of reduced physical activity in the elderly. Thus, in 40 healthy young (22 ± 2 yr) and old (74 ± 8 yr) activity-matched subjects, we assessed the impact of age on: 1) the relative contribution of the three major pathways of ATP synthesis (oxidative ATP synthesis, glycolysis, and the creatine kinase reaction) and 2) the ATP cost of contraction during high-intensity exercise. Specifically, during supramaximal plantar flexion (120% of maximal aerobic power), to stress the functional limits of the skeletal muscle energy systems, we used (31)P-labeled magnetic resonance spectroscopy to assess metabolism. Although glycolytic activation was delayed in the old, ATP synthesis from the main energy pathways was not significantly different between groups. Similarly, the inferred peak rate of mitochondrial ATP synthesis was not significantly different between the young (25 ± 8 mM/min) and old (24 ± 6 mM/min). In contrast, the ATP cost of contraction was significantly elevated in the old compared with the young (5.1 ± 2.0 and 3.7 ± 1.7 mM·min(-1)·W(-1), respectively; P < 0.05). Overall, these findings suggest that, when young and old subjects are activity matched, there is no evidence of age-related mitochondrial and glycolytic dysfunction. However, this study does confirm an abnormal elevation in exercise-induced skeletal muscle metabolic demand in the old that may contribute to the decline in exercise capacity with advancing age. PMID:26041112

  3. 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. PMID:25728299

  4. Poxvirus Membrane Biogenesis

    PubMed Central

    2015-01-01

    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. PMID:25728299

  5. Exercise-induced effects on a gym atmosphere.

    PubMed

    Žitnik, M; Bučar, K; Hiti, B; Barba, Ž; Rupnik, Z; Založnik, A; Žitnik, E; Rodrìguez, L; Mihevc, I; Žibert, J

    2016-06-01

    We report results of analysis of a month-long measurement of indoor air and environment quality parameters in one gym during sporting activities such as football, basketball, volleyball, badminton, boxing, and fitness. We have determined an average single person's contribution to the increase of temperature, humidity, and dust concentration in the gym air volume of 12500 m(3) : during 90-min exercise performed at an average heart rate of 143 ± 10 bpm, a single person evaporated 0.94 kg of water into the air by sweating, contributed 0.03 K to the air temperature rise and added 1.5 μg/m(3) and 5 ng/m(3) to the indoor concentration of inhalable particles (PM10 ) and Ca concentration, respectively. As the breathing at the observed exercise intensity was about three times faster with respect to the resting condition and as the exercise-induced PM10 concentration was about two times larger than outdoors, a sportsman in the gym would receive about a sixfold higher dose of PM10 inside than he/she would have received at rest outside. PMID:26095910

  6. Diaphragmatic breathing reduces exercise-induced oxidative stress.

    PubMed

    Martarelli, Daniele; Cocchioni, Mario; Scuri, Stefania; Pompei, Pierluigi

    2011-01-01

    Diaphragmatic breathing is relaxing and therapeutic, reduces stress, and is a fundamental procedure of Pranayama Yoga, Zen, transcendental meditation and other meditation practices. Analysis of oxidative stress levels in people who meditate indicated that meditation correlates with lower oxidative stress levels, lower cortisol levels and higher melatonin levels. It is known that cortisol inhibits enzymes responsible for the antioxidant activity of cells and that melatonin is a strong antioxidant; therefore, in this study, we investigated the effects of diaphragmatic breathing on exercise-induced oxidative stress and the putative role of cortisol and melatonin hormones in this stress pathway. We monitored 16 athletes during an exhaustive training session. After the exercise, athletes were divided in two equivalent groups of eight subjects. Subjects of the studied group spent 1 h relaxing performing diaphragmatic breathing and concentrating on their breath in a quiet place. The other eight subjects, representing the control group, spent the same time sitting in an equivalent quite place. Results demonstrate that relaxation induced by diaphragmatic breathing increases the antioxidant defense status in athletes after exhaustive exercise. These effects correlate with the concomitant decrease in cortisol and the increase in melatonin. The consequence is a lower level of oxidative stress, which suggests that an appropriate diaphragmatic breathing could protect athletes from long-term adverse effects of free radicals. PMID:19875429

  7. Exercise-Induced Pulmonary Edema in a Triathlon.

    PubMed

    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

  8. Exercise-Induced Systemic Venous Hypertension in the Fontan Circulation.

    PubMed

    Navaratnam, Devaraj; Fitzsimmons, Samantha; Grocott, Michael; Rossiter, Harry B; Emmanuel, Yaso; Diller, Gerard-Paul; Gordon-Walker, Timothy; Jack, Sandy; Sheron, Nick; Pappachan, John; Pratap, Jayant Nick; Vettukattil, Joseph J; Veldtman, Gruschen

    2016-05-15

    Increasingly end-organ injury is being demonstrated late after institution of the Fontan circulation, particularly liver fibrosis and cirrhosis. The exact mechanisms for these late phenomena remain largely elusive. Hypothesizing that exercise induces precipitous systemic venous hypertension and insufficient cardiac output for the exercise demand, that is, a possible mechanism for end-organ injury, we sought to demonstrate the dynamic exercise responses in systemic venous perfusion (SVP) and concurrent end-organ perfusion. Ten stable Fontan patients and 9 control subjects underwent incremental cycle ergometry-based cardiopulmonary exercise testing. SVP was monitored in the right upper limb, and regional tissue oxygen saturation was monitored in the brain and kidney using near-infrared spectroscopy. SVP rose profoundly in concert with workload in the Fontan group, described by the regression equation 15.97 + 0.073 watts per mm Hg. In contrast, SVP did not change in healthy controls. Regional renal (p <0.01) and cerebral tissue saturations (p <0.001) were significantly lower and decrease more rapidly in Fontan patients. We conclude that in a stable group of adult patients with Fontan circulation, high-intensity exercise was associated with systemic venous hypertension and reduced systemic oxygen delivery. This physiological substrate has the potential to contribute to end-organ injury. PMID:27032711

  9. Incidence of exercise-induced arterial hypoxemia in prepubescent females.

    PubMed

    Laursen, Paul B; Tsang, Garry C K; Smith, Gareth J; van Velzen, Min V; Ignatova, B B; Sprules, Erica B; Chu, Kelly S; Coutts, Kenneth D; McKenzie, Donald C

    2002-07-01

    Due to the recent discovery of exercise-induced arterial hypoxemia (EIAH) in healthy active women with normal levels of peak oxygen uptake (V'(O(2)peak), this study examined the incidence of EIAH in prepubescent females. Nineteen healthy, active, prepubescent females (X +/- SD: age = 11.1 +/- 1.6 years; height = 145.8 +/- 9.1 cm; weight = 35.6 +/- 7.0 kg) performed a progressive maximal exercise test on an electronically braked cycle ergometer starting at 0 W and increasing power by 15 W. min(-1). During this test, expired gases, heart rate (HR), and percent arterial oxyhemoglobin saturation (%SaO(2)) were measured. Results for physiological variables at maximal exercise were as follows: V'(O(2)peak) = 43.7 +/- 7.0 ml x kg(-1) x min(-1); HR(max) = 199 +/- 5 beats x min(-1); %SaO(2) = 96.6 +/- 1.2%. For nearly all subjects, the %SaO(2) at maximal exercise was above levels that would reduce V'(O(2)peak). Therefore, in comparison to previous reports of EIAH in adult women with similar V'(O(2)peak), EIAH does not appear to occur in the prepubescent female population. PMID:12112795

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

    PubMed Central

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

    2013-01-01

    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 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 sub-population 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, i.e. 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 impact. PMID:23470300

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

    PubMed Central

    Assumpo, Cludio de Oliveira; Lima, Leonardo Coelho Rabello; Oliveira, Felipe Bruno Dias; Greco, Camila Coelho; Denadai, Benedito Srgio

    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 (~1530 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

  12. Exercise-induced muscle damage and running economy in humans.

    PubMed

    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

  13. Unraveling the complexities of SIRT1-mediated mitochondrial regulation in skeletal muscle.

    PubMed

    Philp, Andrew; Schenk, Simon

    2013-07-01

    Sirtuin 1 (SIRT1) is a purported central regulator of skeletal muscle mitochondrial biogenesis. Herein, we discuss our recent work using conditional mouse models, which highlight the complexities of SIRT1 biology in vivo, and question the role of SIRT1 in regulating mitochondrial function and mitochondrial adaptations to endurance exercise. Furthermore, we discuss the possible contribution of proposed SIRT1 substrates to muscle mitochondrial biogenesis. PMID:23792490

  14. [Advances of studies on acupuncture and moxibustion for exercise-induced fatigue].

    PubMed

    Zhang, Yan-hong; Liu, Jun; Li, Xiao-feng; Jia, Chun-sheng

    2010-03-01

    This paper introduces recent advances in research and clinical trials on treating exercise-induced fatigue with acupuncture, focusing on the areas of oxygen free radical scavenging and anti-lipid peroxidation activity, the regulation of immune function, prevention of dysfunction exercise induced hypothalamus-pituitary-gonadal axis, improvement of energy metabolism, the ability to maintain internal environment, the ability to alleviate delayed-on set muscle soreness (DOMS), and anti-central nervous system fatigue. This paper is intended to explain that because of its safety, effectiveness, less adverse reactions, and not involving stimulants, acupuncture has great potential to protect against exercise-induced fatigue. However, there are problems of acupoints selection, manipulation and indicators. Therefore, it needs further investigations to explore the advantages of acupuncture treatment for the exercise-induced fatigue. PMID:20496745

  15. The role of antioxidant vitamins and enzymes in the prevention of exercise-induced muscle damage.

    PubMed

    Dekkers, J C; van Doornen, L J; Kemper, H C

    1996-03-01

    A growing amount of evidence indicates that free radicals play an important role as mediators of skeletal muscle damage and inflammation after strenuous exercise. It has been postulated that the generation of oxygen free radicals is increased during exercise as a result of increases in mitochondrial oxygen consumption and electron transport flux, inducing lipid peroxidation. The literature suggests that dietary antioxidants are able to detoxify the peroxides produced during exercise, which could otherwise result in lipid peroxidation, and that they are capable of scavenging peroxyl radicals and therefore may prevent muscle damage. Endogenous antioxidant enzymes also play a protective role in the process of lipid peroxidation. The studies reviewed (rodent and human) show significant increases of malondialdehyde (a product of lipid peroxidation) after exercise to exhaustion, and also favourable changes in plasma antioxidant levels and in antioxidant enzyme activity. In trained individuals and trained rats, the antioxidant enzyme activity increases markedly. In this way, the increased oxidative stress induced by exercise is compromised by increased antioxidant activity, preventing lipid peroxidation. Human studies have shown that dietary supplementation with antioxidant vitamins has favourable effects on lipid peroxidation after exercise. Although several points of discussion still exist, the question whether antioxidant vitamins and antioxidant enzymes play a protective role in exercise-induced muscle damage can be answered affirmatively. The human studies reviewed indicate that antioxidant vitamin supplementation can be recommended to individuals performing regular heavy exercise. Moreover, trained individuals have an advantage compared with untrained individuals, as training results in increased activity of several major antioxidant enzymes and overall antioxidant status. However, future studies are needed in order to be able to give more specific information and recommendations on this topic. PMID:8776010

  16. Mitochondrial Therapeutics for Cardioprotection

    PubMed Central

    Carreira, Raquel S.; Lee, Pamela; Gottlieb, Roberta A.

    2013-01-01

    Mitochondria represent approximately one-third of the mass of the heart and play a critical role in maintaining cellular function—however, they are also a potent source of free radicals and pro-apoptotic factors. As such, maintaining mitochondrial homeostasis is essential to cell survival. As the dominant source of ATP, continuous quality control is mandatory to ensure their ongoing optimal function. Mitochondrial quality control is accomplished by the dynamic interplay of fusion, fission, autophagy, and mitochondrial biogenesis. This review examines these processes in the heart and considers their role in the context of ischemia-reperfusion injury. Interventions that modulate mitochondrial turnover, including pharmacologic agents, exercise, and caloric restriction are discussed as a means to improve mitochondrial quality control, ameliorate cardiovascular dysfunction, and enhance longevity. PMID:21718247

  17. Effects of polyphenolic antioxidants on exercise-induced oxidative stress.

    PubMed

    Morillas-Ruiz, J M; Villegas García, J A; López, F J; Vidal-Guevara, M L; Zafrilla, P

    2006-06-01

    Polyphenols are of increasing interest to consumers and food manufacturers for several reasons. Commonly referred to as antioxidants (they are the most abundant antioxidants in our diets), they may prevent various oxidative stress-related diseases, such as cancer, cardiovascular disease, inflammation and others. Physical activity is known to induce oxidative stress in individuals after intensive exercise. In this study, the effect of the flavonoid contents (which are the most abundant polyphenols) was investigated, as the only antioxidant in a replacement drink designed for sportsmen on various oxidative stress biomarkers after two identical trials of sub-maximal aerobic exercise, in a group of 30 sportsmen. In one of the trials, the cyclists consumed the antioxidant supplement (with 2.3g polyphenols/trial), and in another they consumed a placebo. Blood samples were collected both at rest and after exercise immediately and 45 minutes (min) later, for measurements of plasmatic indices of oxidative stress: lipid oxidation (TBARS), total antioxidant status (TAS); protein oxidation (carbonyl groups, CO) and the lactate dehydrogenase (LDH) and creatine kinase (CK) enzymes for each trial. All values were adjusted for changes in plasma volume. No changes were detected in plasma TAS and LDH after exercise or after the polyphenolic supplement. CK and TBARS increased after exercise in both tests. However, in response to strenuous exercise, the polyphenol-supplemented test showed a smaller increase in plasma TBARS and CK than the placebo test. CO increased by 12% in response to the placebo test, whereas it decreased by 23% in the polyphenol-supplement test. This may indicate that the antioxidant supplement offered protection against exercise-induced oxidative stress. PMID:16426710

  18. Air quality and temperature effects on exercise-induced bronchoconstriction.

    PubMed

    Rundell, Kenneth W; Anderson, Sandra D; Sue-Chu, Malcolm; Bougault, Valerie; Boulet, Louis-Philippe

    2015-04-01

    Exercise-induced bronchoconstriction (EIB) is exaggerated constriction of the airways usually soon after cessation of exercise. This is most often a response to airway dehydration in the presence of airway inflammation in a person with a responsive bronchial smooth muscle. Severity is related to water content of inspired air and level of ventilation achieved and sustained. Repetitive hyperpnea of dry air during training is associated with airway inflammatory changes and remodeling. A response during exercise that is related to pollution or allergen is considered EIB. Ozone and particulate matter are the most widespread pollutants of concern for the exercising population; chronic exposure can lead to new-onset asthma and EIB. Freshly generated emissions particulate matter less than 100 nm is most harmful. Evidence for acute and long-term effects from exercise while inhaling high levels of ozone and/or particulate matter exists. Much evidence supports a relationship between development of airway disorders and exercise in the chlorinated pool. Swimmers typically do not respond in the pool; however, a large percentage responds to a dry air exercise challenge. Studies support oxidative stress mediated pathology for pollutants and a more severe acute response occurs in the asthmatic. Winter sport athletes and swimmers have a higher prevalence of EIB, asthma and airway remodeling than other athletes and the general population. Because of fossil fuel powered ice resurfacers in ice rinks, ice rink athletes have shown high rates of EIB and asthma. For the athlete training in the urban environment, training during low traffic hours and in low traffic areas is suggested. PMID:25880506

  19. 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. PMID:25977451

  20. Quantification of exercise-induced pulmonary haemorrhage with bronchoalveolar lavage.

    PubMed

    Meyer, T S; Fedde, M R; Gaughan, E M; Langsetmo, I; Erickson, H H

    1998-07-01

    Exercise-induced pulmonary haemorrhage (EIPH) causes serious economic losses in the horse racing industry. Endoscopic examination indicates that 40-90% of horses exhibit EIPH following sprint exercise, but the limitations of the endoscope prevent diagnosis in many horses. Bronchoalveolar lavage (BAL) was utilised to detect red blood cells (RBCs) in the terminal airways in 6 horses. Two lavages were performed at weekly intervals prior to exercise, one within 90 min after exercise, and 5 at weekly intervals after exercise. The horses were exercised strenuously at 12.5-14.6 m/s on a treadmill (3 degree incline). Heart rates ranged from 192-207 beats/min, and mean pulmonary arterial pressures (mPAP) ranged from 80-102 mmHg. Neither epistaxis nor endoscopic evidence of EIPH was seen in any of the 6 horses following exercise. However, the number of RBCs in the lavage fluid increased significantly over control values immediately after exercise in all horses but returned to control values by one week after exercise. Haemosiderophages in the BAL fluid did not increase until one week after exercise and remained elevated for 3 weeks after exercise. Twenty per cent of the total population of alveolar macrophages contained haemosiderin. A positive relationship occurred between the number of RBCs in the lavage fluid and mPAP; the amount of haemorrhage increased as the mPAP exceeded 80 to 90 mmHg. The results with BAL used as the diagnostic tool, suggest that all strenuously exercised horses may exhibit EIPH; the amount of haemorrhage appears to be associated with the magnitude of the high pulmonary arterial pressure. PMID:9705109

  1. Inhaled hyaluronic acid against exercise-induced bronchoconstriction in asthma.

    PubMed

    Kunz, L I Z; van Rensen, E L J; Sterk, P J

    2006-01-01

    Hyaluronic acid (HA) is a polysaccharide that is present in human tissues and body fluids. HA has various functions, including a barrier effect, water homeostasis, stabilizing the extracellular matrix, increased mucociliary clearance and elastin injury prevention. It may therefore exert prophylactic activity in the treatment of asthma. We tested the hypothesis that HA inhalation will prevent exercise-induced bronchoconstriction (EIB) in a randomised double-blinded placebo-controlled crossover study. Sixteen asthmatic patients with EIB were included in the study (mean (SD)) (age 24.5 (7.3) yr, FEV1 88.6 (11.3) %predicted, PC20 methacholine (g-mean (SD in DD)) 0.4 (1.5) mg/ml). On two separate visits an exercise challenge was performed 15 min post-inhalation of either HA (3 ml 0.1% in PBS) or placebo (3 ml PBS). The maximum fall in FEV1 and the AUC 30 min post-exercise were used as outcomes. After inhalation of both HA and placebo, baseline FEV1 decreased significantly (HA 4.1 (3.1)%, placebo 2.9 (4.1)%, P<0.017). The maximum fall in FEV1 following exercise challenge was not significantly different between HA versus placebo (median HA 22.50%, placebo 27.20%, P=0.379), as was the AUC (median HA 379.3 min*%fall, placebo 498.9 min*%fall, P=0.501). We conclude that at the current dose, inhaled HA does not significantly protect against EIB. This suggests that HA is not effective as a prophylaxis for EIB in patients with asthma. PMID:16140028

  2. Alveolar epithelial integrity in athletes with exercise-induced hypoxemia.

    PubMed

    Edwards, M R; Hunte, G S; Belzberg, A S; Sheel, A W; Worsley, D F; McKenzie, D C

    2000-10-01

    The effect of incremental exercise to exhaustion on the change in pulmonary clearance rate (k) of aerosolized (99m)Tc-labeled diethylenetriaminepentaacetic acid ((99m)Tc-DTPA) and the relationship between k and arterial PO(2) (Pa(O(2))) during heavy work were investigated. Ten male cyclists (age = 25 +/- 2 yr, height = 180.9 +/- 4.0 cm, mass = 80.1 +/- 9.5 kg, maximal O(2) uptake = 5. 25 +/- 0.35 l/min, mean +/- SD) completed a pulmonary clearance test shortly (39 +/- 8 min) after a maximal O(2) uptake test. Resting pulmonary clearance was completed >/=24 h before or after the exercise test. Arterial blood was sampled at rest and at 1-min intervals during exercise. Minimum Pa(O(2)) values and maximum alveolar-arterial PO(2) difference ranged from 73 to 92 Torr and from 30 to 55 Torr, respectively. No significant difference between resting k and postexercise k for the total lung (0.55 +/- 0.20 vs. 0. 57 +/- 0.17 %/min, P > 0.05) was observed. Pearson product-moment correlation indicated no significant linear relationship between change in k for the total lung and minimum Pa(O(2)) (r = -0.26, P > 0.05). These results indicate that, averaged over subjects, pulmonary clearance of (99m)Tc-DTPA after incremental maximal exercise to exhaustion in highly trained male cyclists is unchanged, although the sampling time may have eliminated a transient effect. Lack of a linear relationship between k and minimum Pa(O(2)) during exercise suggests that exercise-induced hypoxemia occurs despite maintenance of alveolar epithelial integrity. PMID:11007593

  3. Undiagnosed exercise-induced bronchoconstriction in ski-mountaineers.

    PubMed

    Durand, F; Kippelen, P; Ceugniet, F; Gomez, V R; Desnot, P; Poulain, M; Préfaut, C

    2005-04-01

    Because the practise conditions put the ski-mountaineering athletes potentially at risk for exercise-induced bronchoconstriction (EIB), this study was conducted to estimate the prevalence of EIB in this population. Thirty-one highly-trained ski-mountaineers with racing experience participating in the race were evaluated. EIB was determined after a European race at high altitude and frigid conditions. Pre-race investigations included pulmonary function measurements and a questionnaire enquiring about i) training habits, ii) respiratory history during training and/or competition. Pulmonary function was also tested after the race. None of the athletes reported a basal airway obstruction. Two groups were determined after post-race airway response: i) EIB (+) group exhibiting a fall in FEV (1) > or = 10 % (n = 15) and ii) EIB (-) without fall in FEV (1) or fall < 10 % (n = 16). Neither training habits nor baseline lung function were associated with the post-race airway response. Six of the 31 ski-mountaineers had a previous physician-made diagnosis of asthma and/or EIB, nevertheless 23 of our athletes complained about at least one characteristic symptom of asthma during practise. Four of our 15 EIB (+) had a previous physician-made diagnosis of asthma/EIB indicating that 73 % of EIB (+) athletes were undiagnosed for EIB. The proportion of allergic athletes was not significantly different between EIB (+) and EIB (-). This study showed that approximatively half of highly-trained ski-mountaineers with racing experience can develop EIB after a race and that 73 % of them are unaware of the problem. PMID:15776341

  4. Noninvasive profiling of exercise-induced hypoxemia in competitive cyclists.

    PubMed

    Siegler, Jason C; Robergs, Robert A; Faria, Eric W; Wyatt, Frank B; McCarthy, Jason

    2007-01-01

    The purpose of this case study was to profile maximal exercise and the incidence of exercise-induced arterial hypoxemia (EIAH) at three different altitudes within a group of competitive cyclists residing and training at 1,500 m. Ten male cyclists (category I or II professional road cyclists: ages, 27.7 +/- 6.1; weight, 69.9 +/- 6.9 kg) participated in three randomly assigned VO2max tests at sea level (SL), 1,500 m and 3000 m. Arterial saturation (pulse oximetry), ventilation, and power output (PO) were recorded continuously throughout the test. The SaO2 percentages at VO2max were significantly higher at SL when compared with 1500 m (p < 0.001); however, no difference was observed between VO2max values at either altitude (SL: 72.3 +/- 2.5 mL.kg-1.min-1, 1,500 m: 70.6 +/- 2.3 mL.kg-1.min-1), only when compared with 3,000 m: 63.9 +/- 2.1 mL.kg-1.min-1, p < 0.021. Percent SaO2 did correspond with maximal PO, and there was an overall main effect observed between POs as they continually declined from SL to 3,000 m (SL: 403.3 +/- 10.6 W; 1,500 m: 376.1 +/- 9.8 W; 3,000 m: 353.9 +/- 7.8 W; p < 0.0001). The results of this case study revealed that training and residing at 1,500 m did not reduce the incidence of EIAH during maximal exercise at 1,500 m for this selected group of cyclists. PMID:17365952

  5. Supraglottoplasty as treatment of exercise induced laryngeal obstruction (EILO).

    PubMed

    Mehlum, Camilla Slot; Walsted, Emil Schwarz; Godballe, Christian; Backer, Vibeke

    2016-04-01

    Breathing difficulties during exertion may be caused by exercise-induced laryngeal obstruction (EILO). The diagnosis depends on visualization of the larynx during exercise, i.e. by continuous laryngoscopic exercise (CLE) test. In case of severe supraglottic collapse and pronounced symptoms during strenuous exertion, surgical treatment (supraglottoplasty) has been suggested. The aims of this study were to evaluate outcome and patient satisfaction after supraglottoplasty for EILO and to compare our results with previously reported data. During the period December 2010 to October 2013, 17 patients diagnosed with moderate to severe supraglottic EILO were treated by supraglottoplasty with microlaryngoscopic laser technique at our institutions. The severity of patients symptoms (VAS score) and CLE scores was evaluated pre- and postoperatively. We found a decrease in patients symptoms from median 80 points VAS score preoperatively to 20 points postoperatively (p < 0.001) and a decrease in CLE sum score from median 4.0 points to 2.5 points (p < 0.05). Several previous studies have recommended surgery for selected patients with supraglottic involvement, but these have mainly been based on case reports or on very few patients. This study is the second larger-scale study that documents the positive effect of supraglottoplasty as treatment of EILO in terms of reduced respiratory symptoms and decreased laryngeal obstruction assessed by post-operative CLE test. We suggest that surgery is a well-tolerated and effective treatment option for selected EILO patients with moderate to severe supraglottic obstruction during exercise and a high level of physical activity. PMID:26541712

  6. Importing Mitochondrial Proteins: Machineries and Mechanisms

    PubMed Central

    Chacinska, Agnieszka; Koehler, Carla M.; Milenkovic, Dusanka; Lithgow, Trevor; Pfanner, Nikolaus

    2014-01-01

    Most mitochondrial proteins are synthesized on cytosolic ribosomes and must be imported across one or both mitochondrial membranes. There is an amazingly versatile set of machineries and mechanisms, and at least four different pathways, for the importing and sorting of mitochondrial precursor proteins. The translocases that catalyze these processes are highly dynamic machines driven by the membrane potential, ATP, or redox reactions, and they cooperate with molecular chaperones and assembly complexes to direct mitochondrial proteins to their correct destinations. Here, we discuss recent insights into the importing and sorting of mitochondrial proteins and their contributions to mitochondrial biogenesis. PMID:19703392

  7. MicroRNA-27b Regulates Mitochondria Biogenesis in Myocytes

    PubMed Central

    Zhang, Shunhua; Du, Jingjing; Bai, Lin; Zhang, Yi; Jiang, Yanzhi; Li, Xuewei; Wang, Jinyong; Zhu, Li

    2016-01-01

    MicroRNAs (miRNAs) are small, non-coding RNAs that affect the post-transcriptional regulation of various biological pathways. To date, it is not fully understood how miRNAs regulate mitochondrial biogenesis. This study aimed at the identification of the role of miRNA-27b in mitochondria biogenesis. The mitochondria content in C2C12 cells was significantly increased during myogenic differentiation and accompanied by a marked decrease of miRNA-27b expression. Furthermore, the expression of the predicted target gene of miRNA-27b, forkhead box j3 (Foxj3), was also increased during myogenic differentiation. Luciferase activity assays confirmed that miRNA-27b directly targets the 3’-untranslated region (3’-UTR) of Foxj3. Overexpression of miRNA-27b provoked a decrease of mitochondria content and diminished expression of related mitochondrial genes and Foxj3 both at mRNA and protein levels. The expression levels of downstream genes of Foxj3, such as Mef2c, PGC1α, NRF1 and mtTFA, were also decreased in C2C12 cells upon overexpression of miRNA-27b. These results suggested that miRNA-27b may affect mitochondria biogenesis by down-regulation of Foxj3 during myocyte differentiation. PMID:26849429

  8. 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. PMID:26186742

  9. Deciphering protein-protein interactions during the biogenesis of cytochrome c oxidase from Paracoccus denitrificans.

    PubMed

    Gurumoorthy, Priya; Ludwig, Bernd

    2015-02-01

    Biogenesis of the mitochondrial cytochrome c oxidase (COX) is a complex process due to its numerous subunits encoded by two genomes, as well as the localization of redox centers deep within the membrane. Here, we have assessed the biogenesis of the homologous aa₃-type oxidase of the soil bacterium Paracoccus denitrificans. First, protein partners were analyzed using various membrane solubilization strategies to show interactions between COX and CtaG, a chaperone implicated in CuB site metallation. Using an unbiased MS approach after immunological pull-down from untreated or cross-linked membranes, we then extend our view towards a hypothetical 'biogenesis complex' by identifying two further metal-inserting chaperones, Surf1c and Sco, together with enzymes catalyzing heme a synthesis. Our study also tentatively supports previous speculation regarding the existence of a predominantly co-translational mechanism for cofactor insertion during COX biogenesis. PMID:25420759

  10. Role of Surf1 in heme recruitment for bacterial COX biogenesis.

    PubMed

    Hannappel, Achim; Bundschuh, Freya A; Ludwig, Bernd

    2012-06-01

    Biogenesis of the mitochondrial cytochrome c oxidase (COX) is a highly complex process involving subunits encoded both in the nuclear and the organellar genome; in addition, a large number of assembly factors participate in this process. The soil bacterium Paracoccus denitrificans is an interesting alternative model for the study of COX biogenesis events because the number of chaperones involved is restricted to an essential set acting in the metal centre formation of oxidase, and the high degree of sequence homology suggests the same basic mechanisms during early COX assembly. Over the last years, studies on the P. denitrificans Surf1 protein shed some light on this important assembly factor as a heme a binding protein associated with Leigh syndrome in humans. Here, we summarise our current knowledge about Surf1 and its role in heme a incorporation events during bacterial COX biogenesis. This article is part of a Special Issue entitled: Biogenesis/Assembly of Respiratory Enzyme Complexes. PMID:21945856

  11. Oxidants, antioxidants, and the beneficial roles of exercise-induced production of reactive species.

    PubMed

    Gomes, Elisa Couto; Silva, Albená Nunes; de Oliveira, Marta Rubino

    2012-01-01

    This review offers an overview of the influence of reactive species produced during exercise and their effect on exercise adaptation. Reactive species and free radicals are unstable molecules that oxidize other molecules in order to become stable. Although they play important roles in our body, they can also lead to oxidative stress impairing diverse cellular functions. During exercise, reactive species can be produced mainly, but not exclusively, by the following mechanisms: electron leak at the mitochondrial electron transport chain, ischemia/reperfusion and activation of endothelial xanthine oxidase, inflammatory response, and autooxidation of catecholamines. Chronic exercise also leads to the upregulation of the body's antioxidant defence mechanism, which helps minimize the oxidative stress that may occur after an acute bout of exercise. Recent studies show a beneficial role of the reactive species, produced during a bout of exercise, that lead to important training adaptations: angiogenesis, mitochondria biogenesis, and muscle hypertrophy. The adaptations occur depending on the mechanic, and consequently biochemical, stimulus within the muscle. This is a new area of study that promises important findings in the sphere of molecular and cellular mechanisms involved in the relationship between oxidative stress and exercise. PMID:22701757

  12. Mitochondrial Signaling: Forwards, Backwards, and In Between

    PubMed Central

    Whelan, Sean P.; Zuckerbraun, Brian S.

    2013-01-01

    Mitochondria are semiautonomous organelles that are a defining characteristic of almost all eukaryotic cells. They are vital for energy production, but increasing evidence shows that they play important roles in a wide range of cellular signaling and homeostasis. Our understanding of nuclear control of mitochondrial function has expanded over the past half century with the discovery of multiple transcription factors and cofactors governing mitochondrial biogenesis. More recently, nuclear changes in response to mitochondrial messaging have led to characterization of retrograde mitochondrial signaling, in which mitochondria have the ability to alter nuclear gene expression. Mitochondria are also integral to other components of stress response or quality control including ROS signaling, unfolded protein response, mitochondrial autophagy, and biogenesis. These avenues of mitochondrial signaling are discussed in this review. PMID:23819011

  13. Exercise-induced arterial hypoxaemia in healthy young women

    PubMed Central

    Harms, Craig A; McClaran, Steven R; Nickele, Glenn A; Pegelow, David F; Nelson, William B; Dempsey, Jerome A

    1998-01-01

    We questioned whether exercise-induced arterial hypoxaemia (EIAH) occurs in healthy active women, who have smaller lungs, reduced lung diffusion, and lower maximal O2 consumption rate () than age- and height-matched men.Twenty-nine healthy young women with widely varying fitness levels ( 57 ± 6 ml kg−1 min−1; range, 35–70 ml kg−1 min−1; or 148 ± 5 %; range, 93–188 % predicted) and normal resting lung function underwent an incremental treadmill test to during the follicular phase of their menstrual cycle. Arterial blood samples were taken at rest and near the end of each workload.Arterial PO2 (Pa,O2) decreased > 10 mmHg below rest in twenty-two of twenty-nine subjects at (Pa,O2, 77.5 ± 0.9 mmHg; range, 67–88 mmHg; arterial O2 saturation (Sa,O2), 92.3 ± 0.2 %; range, 87–94 %). The remaining seven subjects maintained Pa,O2 within 10 mmHg of rest. Pa,O2 at was inversely related to the alveolar to arterial O2 difference (A-aDO2) (r = -0.93; 35–52 mmHg) and to arterial PCO2 (Pa,CO2) (r = -0.62; 26–39 mmHg).EIAH was inversely related to (r = -0.49); however, there were many exceptions. Almost half of the women with significant EIAH had within 15 % of predicted normal values ( 40–55 ml kg−1 min−1); among subjects with very high (55–70 ml kg−1 min−1), the degree of excessive A-aDO2 and EIAH varied markedly (e.g. A-aDO2, 30–50 mmHg; Pa,O2, 68–91 mmHg).In the women with EIAH at many began to experience an excessive widening of their A-aDO2 during moderate intensity exercise, which when combined with a weak ventilatory response, led to a progressive hypoxaemia. Inactive, less fit subjects had no EIAH and narrower A-aDO2 when compared with active, fitter subjects at the same (40–50 ml kg−1 min−1).These data demonstrate that many active healthy young women experience significant EIAH, and at a that is substantially less than those in their active male contemporaries. The onset of EIAH during submaximal exercise, and/or its occurrence at a relatively low implies that lung structure/function subserving alveolar to arterial O2 transport is abnormally compromised in many of these habitually active subjects. PMID:9518719

  14. Exercise-induced arterial hypoxaemia in healthy young women.

    PubMed

    Harms, C A; McClaran, S R; Nickele, G A; Pegelow, D F; Nelson, W B; Dempsey, J A

    1998-03-01

    1. We questioned whether exercise-induced arterial hypoxaemia (EIAH) occurs in healthy active women, who have smaller lungs, reduced lung diffusion, and lower maximal O2 consumption rate (VO2,max) than age- and height-matched men. 2. Twenty-nine healthy young women with widely varying fitness levels (VO2,max, 57 +/- 6 ml kg-1 min-1; range, 35-70 ml kg-1 min-1; or 148 +/- 5%; range, 93-188% predicted) and normal resting lung function underwent an incremental treadmill test to VO2,max during the follicular phase of their menstrual cycle. Arterial blood samples were taken at rest and near the end of each workload. 3. Arterial PO2 (Pa,O2) decreased > 10 mmHg below rest in twenty-two of twenty-nine subjects at VO2,max (Pa,O2, 77.5 +/- 0.9 mmHg; range, 67-88 mmHg; arterial O2 saturation (Sa,O2), 92.3 +/- 0.2%; range, 87-94%). The remaining seven subjects maintained Pa,O2 within 10 mmHg of rest. Pa,O2 at VO2,max was inversely related to the alveolar to arterial O2 difference (A-aDO2) (r = -0.93; 35-52 mmHg) and to arterial PCO2 (Pa,CO2) (r = -0.62; 26-39 mmHg). 4. EIAH was inversely related to VO2,max (r = -0.49); however, there were many exceptions. Almost half of the women with significant EIAH had VO2,max within 15% of predicted normal values (VO2,max, 40-55 ml kg-1 min-1); among subjects with very high VO2,max (55-70 ml kg-1 min-1), the degree of excessive A-aDO2 and EIAH varied markedly (e.g. A-aDO2, 30-50 mmHg; Pa,O2, 68-91 mmHg). 5. In the women with EIAH at VO2,max, many began to experience an excessive widening of their A-aDO2 during moderate intensity exercise, which when combined with a weak ventilatory response, led to a progressive hypoxaemia. Inactive, less fit subjects had no EIAH and narrower A-aDO2 when compared with active, fitter subjects at the same VO2 (40-50 ml kg-1 min-1). 6. These data demonstrate that many active healthy young women experience significant EIAH, and at a VO2,max that is substantially less than those in their active male contemporaries. The onset of EIAH during submaximal exercise, and/or its occurrence at a relatively low VO2,max, implies that lung structure/function subserving alveolar to arterial O2 transport is abnormally compromised in many of these habitually active subjects. PMID:9518719

  15. 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.

  16. 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. PMID:27032551

  17. Rescue of Heart Failure by Mitochondrial Recovery

    PubMed Central

    2016-01-01

    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. PMID:27032551

  18. The effect of treadmill training and N-acetyl-l-cysteine intervention on biogenesis of cytochrome c oxidase (COX).

    PubMed

    Sun, Y; Qi, Z; He, Q; Cui, D; Qian, S; Ji, L; Ding, S

    2015-10-01

    Mitochondrial biogenesis refers to increased content of mitochondria, which has been shown to be promoted by aerobic exercise. During this process, oxidative stress is considered the essential initiator. Even though some studies have addressed the issue as to whether antioxidants would hamper the effects of exercise on mitochondrial biogenesis, no consensus has been achieved. Therefore, the purpose of the present study was to investigate the effects of exercise and antioxidant intervention on mitochondrial biogenesis, as well as COX biogenesis. Thirty-two clean-grade male ICR mice were randomly assigned to a control group (Con), exercise group (Ex), N-acetyl-l-cysteine group (NAC), or NAC plus exercise group (NEx). The NAC and NEx groups were injected with NAC (0.1 mg/g/2 days) intraperitoneally for 3 weeks, whereas the Con and Ex groups were administered saline for the same period of time. Mice assigned to Ex and NEx groups started exercise training 1 week before drug intervention was initiated. After 1 week of acclimatization, the mice were allowed to run at a speed of 28 m/min for 60 min, 6 days a week. The results showed that exercise training caused an increase in mRNA and protein levels of COXIV, whereas NAC intervention lowered the two so significantly that even exercise training could not reverse the effect of NAC intervention. Our data suggest that even though antioxidant intervention could alleviate oxidative damage caused by exercise, it was not necessarily beneficial for mitochondrial biogenesis. PMID:26159509

  19. Exercise-Induced Intrapulmonary Arteriovenous Shunt in a Patient Complaining of Dyspnea during Strenuous Exercise

    PubMed Central

    Kim, Tae-Jun; Hong, Seong-Eun; Jung, Dong-Min; Choi, Nan-Young; Kim, Yong-Kyun; Park, Seung-Ah; Kim, Soon-Young; Park, Woo-Jung

    2014-01-01

    A 51-year-old highly fit man presented for dyspnea with strenuous aerobic exercise. The patient was asymptomatic and all tests were normal at rest. With increasing exercise intensity, he suddenly complained of dyspnea and showed a severe exercise-induced hypoxemia with an excessive alveolar-arterial oxygen tension difference. In agitated saline contrast echocardiography at peak exercise, a large amount of left to right shunt was identified after > 5 cardiac cycles, which suggests the presence of exercise-induced intrapulmonary arteriovenous shunt in this patient. PMID:25031800

  20. Organelle biogenesis and interorganellar connections

    PubMed Central

    Daniele, Tiziana; Schiaffino, Maria Vittoria

    2014-01-01

    Membrane contact sites (MCSs) allow the exchange of molecules and information between organelles, even when their membranes cannot fuse directly. In recent years, a number of functions have been attributed to these contacts, highlighting their critical role in cell homeostasis. Although inter-organellar connections typically involve the endoplasmic reticulum (ER), we recently reported the presence of a novel MCSs between melanosomes and mitochondria. Melanosome-mitochondrion contacts appear mediated by fibrillar bridges resembling the protein tethers linking mitochondria and the ER, both for their ultrastructural features and the involvement of Mitofusin 2. The frequency of these connections correlates spatially and timely with melanosome biogenesis, suggesting a functional link between the 2 processes and in general that organelle biogenesis in the secretory pathway requires interorganellar crosstalks at multiple steps. Here, we summarize the different functions attributed to MCSs, and discuss their possible relevance for the newly identified melanosome-mitochondrion liaison. PMID:25346798

  1. Mitochondrial dysfunction in heart failure

    PubMed Central

    Rosca, Mariana G.; Hoppel, Charles L.

    2013-01-01

    Heart failure (HF) is a complex chronic clinical syndrome. Energy deficit is considered to be a key contributor to the development of both cardiac and skeletal myopathy. In HF several components of cardiac and skeletal muscle bioenergetics are altered, such as oxygen availability, substrate oxidation, mitochondrial ATP production, and ATP transfer to the contractile apparatus via the creatine kinase shuttle. This review focuses on alterations in mitochondrial biogenesis and respirasome organization, substrate oxidation coupled with ATP synthesis in the context of their contribution to the chronic energy deficit, and mechanical dysfunction of the cardiac and skeletal muscle in HF. We conclude that HF is associated with decreased mitochondrial biogenesis and function in both heart and skeletal muscle, supporting the concept of a systemic mitochondrial cytopathy. The sites of mitochondrial defects are located within the electron transport and phosphorylation apparatus, and differ with the etiology and progression of HF in the two mitochondrial populations (subsarcolemmal and interfibrillar) of cardiac and skeletal muscle. The roles of adrenergic stimulation, the renin-angiotensin system, and cytokines are evaluated as factors responsible for the systemic energy deficit. We propose a cylic AMP-mediated mechanism by which increased adrenergic stimulation contributes to the mitochondrial dysfunction. PMID:22948484

  2. 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...

  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. PMID:22645172

  4. 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.…

  5. Increased Protein Maintains Nitrogen Balance during Exercise-Induced Energy Deficit

    Technology Transfer Automated Retrieval System (TEKTRAN)

    PURPOSE: This study examined how a high-protein diet affected nitrogen balance and protein turnover during an exercise-induced energy deficit. METHODS: Twenty-two men completed a 4-d (D1-4) baseline period (BL) of an energy balance diet while maintaining usual physical activity level, followed by 7 ...

  6. High protein diet maintains glucose production during exercise-induced energy deficit: a controlled trial

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Inadequate energy intake induces changes in endogenous glucose production (GP) to preserve muscle mass. Whether addition provision of dietary protein modulates GP response to energy deficit is unclear. The objective was to determine whether exercise-induced energy deficit effects on glucose metaboli...

  7. 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…

  8. Pharmacological approaches to restore mitochondrial function

    PubMed Central

    Andreux, Pénélope A.; Houtkooper, Riekelt H.; Auwerx, Johan

    2014-01-01

    Mitochondrial dysfunction is not only a hallmark of rare inherited mitochondrial disorders, but is also implicated in age-related diseases, including those that affect the metabolic and nervous system, such as type 2 diabetes and Parkinson’s disease. Numerous pathways maintain and/or restore proper mitochondrial function, including mitochondrial biogenesis, mitochondrial dynamics, mitophagy, and the mitochondrial unfolded protein response. New and powerful phenotypic assays in cell-based models, as well as multicellular organisms, have been developed to explore these different aspects of mitochondrial function. Modulating mitochondrial function has therefore emerged as an attractive therapeutic strategy for a range of diseases, which has spurred active drug discovery efforts in this area. PMID:23666487

  9. Regulators of mitochondrial dynamics in cancer.

    PubMed

    Senft, Daniela; Ronai, Ze'ev A

    2016-04-01

    Mitochondrial dynamics encompasses processes associated with mitochondrial fission and fusion, affecting their number, degree of biogenesis, and the induction of mitophagy. These activities determine the balance between mitochondrial energy production and cell death programs. Processes governing mitochondrial dynamics are tightly controlled in physiological conditions and are often deregulated in cancer. Mitochondrial protein homeostasis, transcriptional regulation, and post-translational modification are among processes that govern the control of mitochondrial dynamics. Cancer cells alter mitochondrial dynamics to resist apoptosis and adjust their bioenergetic and biosynthetic needs to support tumor initiating and transformation properties including proliferation, migration, and therapeutic resistance. This review focuses on key regulators of mitochondrial dynamics and their role in cancer. PMID:26896558

  10. Mitochondrial quality control systems sustain brain mitochondrial bioenergetics in early stages of type 2 diabetes.

    PubMed

    Santos, R X; Correia, S C; Alves, M G; Oliveira, P F; Cardoso, S; Carvalho, C; Seiça, R; Santos, M S; Moreira, P I

    2014-09-01

    Mitochondria have a crucial role in the supply of energy to the brain. Mitochondrial alterations can lead to detrimental consequences on the function of brain cells and are thought to have a pivotal role in the pathogenesis of several neurologic disorders. This study was aimed to evaluate mitochondrial function, fusion-fission and biogenesis and autophagy in brain cortex of 6-month-old Goto-Kakizaki (GK) rats, an animal model of nonobese type 2 diabetes (T2D). No statistically significant alterations were observed in mitochondrial respiratory chain and oxidative phosphorylation system. A significant decrease in the protein levels of OPA1, a protein that facilitates mitochondrial fusion, was observed in brain cortex of GK rats. Furthermore, a significant decrease in the protein levels of LC3-II and a significant increase in protein levels of mTOR phosphorylated at serine residue 2448 were observed in GK rats suggesting a suppression of autophagy in diabetic brain cortex. No significant alterations were observed in the parameters related to mitochondrial biogenesis. Altogether, these results demonstrate that during the early stages of T2D, brain mitochondrial function is maintained in part due to a delicate balance between mitochondrial fusion-fission and biogenesis and autophagy. However, future studies are warranted to evaluate the role of mitochondrial quality control pathways in late stages of T2D. PMID:24833464

  11. Pathophysiological mechanisms of exercise-induced anaphylaxis: an EAACI position statement.

    PubMed

    Ansley, L; Bonini, M; Delgado, L; Del Giacco, S; Du Toit, G; Khaitov, M; Kurowski, M; Hull, J H; Moreira, A; Robson-Ansley, P J

    2015-10-01

    This document is the result of a consensus on the mechanisms of exercise-induced anaphylaxis (EIAn), an unpredictable and potentially fatal syndrome. A multidisciplinary panel of experts including exercise physiologists, allergists, lung physicians, paediatricians and a biostatistician reached the given consensus. Exercise-induced anaphylaxis (EIAn) describes a rare and potentially fatal syndrome in which anaphylaxis occurs in conjunction with exercise. The pathophysiological mechanisms underlying EIAn have not yet been elucidated although a number of hypotheses have been proposed. This review evaluates the validity of each of the popular theories in relation to exercise physiology and immunology. On the basis of this evidence, it is concluded that proposed mechanisms lack validity, and it is recommended that a global research network is developed with a common approach to the diagnosis and treatment of EIAn in order to gain sufficient power for scientific evaluation. PMID:26100553

  12. Exercise and other indirect challenges to demonstrate asthma or exercise-induced bronchoconstriction in athletes.

    PubMed

    Rundell, Kenneth W; Slee, Joshua B

    2008-08-01

    The prevalence of exercise-induced bronchoconstriction is reported to be high among recreational and elite athletes, yet diagnosis is often symptom-based. Indirect challenges such as the laboratory exercise challenge provide objective criteria for proper diagnosis and treatment. However, a standardized protocol using appropriate exercise intensity, duration, and dry air inhalation is often not implemented, and thus a false-negative test may result. This article reviews and describes the symptom-based diagnosis, the exercise challenge, and other indirect challenges such as eucapnic voluntary hyperpnea, hypertonic saline inhalation, and inhaled powdered mannitol as methods to diagnose and evaluate exercise-induced bronchoconstriction. Advantages and disadvantages of each diagnostic procedure are presented. PMID:18678339

  13. 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...

  14. 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. PMID:25724495

  15. 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.

  16. 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. PMID:12683615

  17. 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).

  18. Impact of Metformin on Exercise-Induced Metabolic Adaptations to Lower Type 2 Diabetes Risk.

    PubMed

    Malin, Steven K; Braun, Barry

    2016-01-01

    Combining metformin with exercise has been proposed to improve glucose homeostasis. However, we primarily discuss evidence suggesting that metformin and other pharmacological agents/dietary supplements (e.g., statins, resveratol, or antioxidants) may in fact oppose exercise-induced benefits on insulin sensitivity and cardiometabolic health. We explore the novel hypothesis that attenuation of oxidative stress from exercise by these exogenous compounds blunts metabolic adaptation. PMID:26583801

  19. 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. PMID:25438993

  20. 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.

  1. Hemodynamic effects of high intensity interval training in COPD patients exhibiting exercise-induced dynamic hyperinflation.

    PubMed

    Nasis, I; Kortianou, E; Vasilopoulou, ?; Spetsioti, S; Louvaris, Z; Kaltsakas, G; Davos, C H; Zakynthinos, S; Koulouris, N G; Vogiatzis, I

    2015-10-01

    Dynamic hyperinflation (DH) has a significant adverse effect on cardiovascular function during exercise in COPD patients. COPD patients with (n = 25) and without (n = 11) exercise-induced DH undertook an incremental (IET) and a constant-load exercise test (CLET) sustained at 75% peak work (WRpeak) prior to and following an interval cycling exercise training regime (set at 100% WRpeak with 30-s work/30-s rest intervals) lasting for 12 weeks. Cardiac output (Q) was assessed by cardio-bio-impedance (PhysioFlow, enduro, PF-O7) to determine Q mean response time (QMRT) at onset (QMRT(ON)) and offset (QMRT(OFF)) of CLET. Post-rehabilitation only those patients exhibiting exercise-induced DH demonstrated significant reductions in QMRT(ON) (from 82.2 4.3 to 61.7 4.2 s) and QMRT(OFF) (from 80.5 3.8 to 57.2 4.9 s ). These post-rehabilitation adaptations were associated with improvements in inspiratory capacity, thereby suggesting that mitigation of the degree of exercise-induced DH improves central hemodynamic responses in COPD patients. PMID:26112284

  2. Mitochondrial Plasticity in Obesity and Diabetes Mellitus

    PubMed Central

    Jelenik, Tomas

    2013-01-01

    Abstract Significance: Insulin resistance and its related diseases, obesity and type 2 diabetes mellitus (T2DM), have been linked to changes in aerobic metabolism, pointing to a possible role of mitochondria in the development of insulin resistance. Recent Advances: Refined methodology of ex vivo high-resolution respirometry and in vivo magnetic resonance spectroscopy now allows describing several features of mitochondria in humans. In addition to measuring mitochondrial function at baseline and after exercise-induced submaximal energy depletion, the response of mitochondria to endocrine and metabolic challenges, termed mitochondrial plasticity, can be assessed using hyperinsulinemic clamp tests. While insulin resistant states do not uniformly relate to baseline and post-exercise mitochondrial function, mitochondrial plasticity is typically impaired in insulin resistant relatives of T2DM, in overt T2DM and even in type 1 diabetes mellitus (T1DM). Critical Issues: The variability of baseline mitochondrial function in the main target tissue of insulin action, skeletal muscle and liver, may be attributed to inherited and acquired changes in either mitochondrial quantity or quality. In addition to certain gene polymorphisms and aging, circulating glucose and lipid concentrations correlate with both mitochondrial function and plasticity. Future Directions: Despite the associations between features of mitochondrial function and insulin sensitivity, the question of a causal relationship between compromised mitochondrial plasticity and insulin resistance in the development of obesity and T2DM remains to be resolved. Antioxid. Redox Signal. 19, 258268. PMID:22938510

  3. 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

    2014-06-01

    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. PMID:24814483

  4. Biogenesis of light harvesting proteins.

    PubMed

    Dall'Osto, Luca; Bressan, Mauro; Bassi, Roberto

    2015-09-01

    The LHC family includes nuclear-encoded, integral thylakoid membrane proteins, most of which coordinate chlorophyll and xanthophyll chromophores. By assembling with the core complexes of both photosystems, LHCs form a flexible peripheral moiety for enhancing light-harvesting cross-section, regulating its efficiency and providing protection against photo-oxidative stress. Upon its first appearance, LHC proteins underwent evolutionary diversification into a large protein family with a complex genetic redundancy. Such differentiation appears as a crucial event in the adaptation of photosynthetic organisms to changing environmental conditions and land colonization. The structure of photosystems, including nuclear- and chloroplast-encoded subunits, presented the cell with a number of challenges for the control of the light harvesting function. Indeed, LHC-encoding messages are translated in the cytosol, and pre-proteins imported into the chloroplast, processed to their mature size and targeted to the thylakoids where are assembled with chromophores. Thus, a tight coordination between nuclear and plastid gene expression, in response to environmental stimuli, is required to adjust LHC composition during photoacclimation. In recent years, remarkable progress has been achieved in elucidating structure, function and regulatory pathways involving LHCs; however, a number of molecular details still await elucidation. In this review, we will provide an overview on the current knowledge on LHC biogenesis, ranging from organization of pigment-protein complexes to the modulation of gene expression, import and targeting to the photosynthetic membranes, and regulation of LHC assembly and turnover. Genes controlling these events are potential candidate for biotechnological applications aimed at optimizing light use efficiency of photosynthetic organisms. This article is part of a Special Issue entitled: Chloroplast biogenesis. PMID:25687893

  5. Abnormal expression of key genes and proteins in the canonical Wnt/β-catenin pathway of articular cartilage in a rat model of exercise-induced osteoarthritis

    PubMed Central

    LIU, SHEN-SHEN; ZHOU, PU; ZHANG, YANQIU

    2016-01-01

    To investigate the molecular pathogenesis of the canonical Wnt/β-catenin pathway in exercise-induced osteoarthritis (OA), 30 male healthy Sprague Dawley rats were divided into three groups (control, normal exercise-induced OA and injured exercise-induced OA groups) in order to establish the exercise-induced OA rat model. The mRNA and protein expression levels of Runx-2, BMP-2, Ctnnb1, Sox-9, collagen II, Mmp-13, Wnt-3a and β-catenin in chon-drocytes were detected by reverse transcription-quantitative polymerase chain reaction, western blotting and immunohistochemical staining. The mRNA levels of Runx-2, BMP-2 and Ctnnb1 were upregulated in the normal exercise-induced OA and injured exercise-induced OA groups; while Runx-2 and BMP-2 were upregulated in the injured exercise-induced OA group when compared with the normal exercise-induced OA group. The protein levels of Mmp-13, Wnt-3a and β-catenin were increased and collagen II was reduced in the normal exercise-induced OA and injured exercise-induced OA groups. Ctnnb1, Wnt-3a and β-catenin, which are key genes and proteins in the canonical Wnt/β-catenin pathway, were abnormally expressed in chondrocytes of the exercise-induced OA rat model. Ctnnb1, β-catenin and Wnt-3a were suggested to participate in the pathogenesis of exercise-induced OA by abnormally activating the Wnt/β-catenin pathway during physical exercise due to excessive pressure. The results of the present study may provide an improved understanding of the pathogenesis of exercise-induced OA. PMID:26794964

  6. [The role of mitochondrial dynamics in neurodegeneration].

    PubMed

    Li, Wen-Wei; Zhu, Min; Lv, Chuan-Zhen

    2011-10-01

    Mitochondria are highly dynamic organelles, which undergo continuous cycles of fission and fusion. Mitochondrial dynamics (fission and fusion) plays important roles in maintaining neuronal functions, including biogenesis, mitochondrial distribution and cell injury or death. Mfnl/2 and Opal mediate mitochondrial fusion, whereas Drp1 and Fis1 regulate mitochondrial fission. Mutations of Opal cause autosomal dominant optic atrophy, and mutations of Mfn2 lead to Charcot-Marie-Tooth disease type 2A. Moreover, increasing evidences show that abnormal mitochondrial dynamics are involved in pathogenesis of late-onset neurodegenerative disorders, such as Alzheimer's disease, Parkinson's disease and Huntington's disease. This paper reviews the current advances of abnormal mitochondrial dynamics relevant to neuronal loss in neurodegenerative diseases. PMID:22242401

  7. 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. PMID:24866464

  8. Peroxisome assembly: matrix and membrane protein biogenesis.

    PubMed

    Ma, Changle; Agrawal, Gaurav; Subramani, Suresh

    2011-04-01

    The biogenesis of peroxisomal matrix and membrane proteins is substantially different from the biogenesis of proteins of other subcellular compartments, such as mitochondria and chloroplasts, that are of endosymbiotic origin. Proteins are targeted to the peroxisome matrix through interactions between specific targeting sequences and receptor proteins, followed by protein translocation across the peroxisomal membrane. Recent advances have shed light on the nature of the peroxisomal translocon in matrix protein import and the molecular mechanisms of receptor recycling. Furthermore, the endoplasmic reticulum has been shown to play an important role in peroxisomal membrane protein biogenesis. Defining the molecular events in peroxisome assembly may enhance our understanding of the etiology of human peroxisome biogenesis disorders. PMID:21464226

  9. Personality Does not Influence Exercise-Induced Mood Enhancement Among Female Exercisers.

    PubMed

    Lane, Andrew M; Milton, Karen E; Terry, Peter C

    2005-09-01

    The present study investigated the influence of personality on exercise-induced mood changes. It was hypothesised that (a) exercise would be associated with significant mood enhancement across all personality types, (b) extroversion would be associated with positive mood and neuroticism with negative mood both pre- and post-exercise, and (c) personality measures would interact with exercise-induced mood changes. Participants were 90 female exercisers (M = 25.8 yr, SD = 9.0 yr) who completed the Eysenck Personality Inventory (EPI) once and the Brunel Mood Scale (BRUMS) before and after a 60-minute exercise session. Median splits were used to group participants into four personality types: stable introverts (n = 25), stable extroverts (n = 20), neurotic introverts (n = 26), and neurotic extroverts (n = 19). Repeated measures MANOVA showed significant mood enhancement following exercise across all personality types. Neuroticism was associated with negative mood scores pre- and post-exercise but the effect of extroversion on reported mood was relatively weak. There was no significant interaction effect between exercise-induced mood enhancement and personality. In conclusion, findings lend support to the notion that exercise is associated with improved mood. However, findings show that personality did not influence this effect, although neuroticism was associated with negative mood. Key PointsResearch in general psychology has found that stable personality trait are associated changes in mood states. Ninety females exercisers completed a personality test and mood scales before and after exercise. Results indicated mood changes were not associated with personality, although neuroticism was associated with negative mood. PMID:24453525

  10. Mitochondrial Retrograde Signaling: Triggers, Pathways, and Outcomes

    PubMed Central

    da Cunha, Fernanda Marques; Torelli, Nicole Quesada; Kowaltowski, Alicia J.

    2015-01-01

    Mitochondria are essential organelles for eukaryotic homeostasis. Although these organelles possess their own DNA, the vast majority (>99%) of mitochondrial proteins are encoded in the nucleus. This situation makes systems that allow the communication between mitochondria and the nucleus a requirement not only to coordinate mitochondrial protein synthesis during biogenesis but also to communicate eventual mitochondrial malfunctions, triggering compensatory responses in the nucleus. Mitochondria-to-nucleus retrograde signaling has been described in various organisms, albeit with differences in effector pathways, molecules, and outcomes, as discussed in this review. PMID:26583058

  11. Mitochondrial Dynamics: Functional Link with Apoptosis

    PubMed Central

    Otera, Hidenori; Mihara, Katsuyoshi

    2012-01-01

    Mitochondria participate in a variety of physiologic processes, such as ATP production, lipid metabolism, iron-sulfur cluster biogenesis, and calcium buffering. The morphology of mitochondria changes dynamically due to their frequent fusion and division in response to cellular conditions, and these dynamics are an important constituent of apoptosis. The discovery of large GTPase family proteins that regulate mitochondrial dynamics, together with novel insights into the role of mitochondrial fusion and fission in apoptosis, has provided important clues to understanding the molecular mechanisms of cellular apoptosis. In this paper, we briefly summarize current knowledge of the role of mitochondrial dynamics in apoptosis and cell pathophysiology in mammalian cells. PMID:22536251

  12. Exercise-induced acute compartment syndrome in a young man, occurring after a short race

    PubMed Central

    Matar, Mousa; Vaitilingham, Siddharthan; Chalise, Shyam; Irooegbu, Nkem; Bang, Jane

    2016-01-01

    We describe a case of exercise-induced acute compartment syndrome (ACS) in a 23-year-old man who presented to his primary care physician 48 hours after he attempted to run a 5K race. He noticed searing pain in his left leg after the first half mile but had no other symptoms. He was referred to the emergency department and diagnosed with ACS, and a fasciotomy was done. A presentation of limb pain that is out of proportion to a known or suspected injury should prompt consideration of ACS. Early recognition and surgical management are essential to achieving the best possible outcome. PMID:27034546

  13. Exercise-induced pulmonary hemorrhage in horses: the role of pulmonary veins.

    PubMed

    Derksen, Frederik; Williams, Kurt; Stack, Alice

    2011-04-01

    While airway endoscopy and bronchoalveolar lavage are the methodsof choice for diagnosing exercise-induced pulmonary hemorrhage (EIPH), these techniques do not allow accurate evaluation of the severity of bleeding. EIPH pathology is characterized by occlusive remodeling of pulmonary veins. Affected veins have large collagen deposits in their walls, which reduces their lumens. In the caudodorsal regions, pulmonary vein wall remodeling is associated with hemosiderin accumulation, bronchial circulation angiogenesis, and fibrosis of the alveolar interstitium, bronchovascular bundle, septa, and pleura. During exercise, venous occlusion increases regional pulmonary capillary pressure, likely causing capillary rupture and resulting in bleeding. PMID:21870340

  14. Association between circulating angiotensin-converting enzyme and exercise-induced pulmonary haemorrhage in Thoroughbred racehorses.

    PubMed

    Costa, M F M; Ronchi, F A; Ivanow, A; Carmona, A K; Casarini, D; Slocombe, R F

    2012-10-01

    Exercise-induced pulmonary haemorrhage has an impact on racehorse performance. Although endoscopic diagnosis (with or without the aid of bronchoalveolar lavage) is considered to be the standard diagnostic method for this condition, the use of biomarkers that could aid in quantifying risk and severity of the condition would represent an advance in equine sport medicine. This preliminary research investigated the use of angiotensin-converting enzyme (ACE) activity in plasma of racehorses and demonstrated that ACE activity is increased in horses with higher degrees of haemorrhage and is a promising biomarker for EIPH in racehorses. PMID:22196974

  15. Effect of prior high-intensity exercise on exercise-induced arterial hypoxemia in Thoroughbred horses.

    PubMed

    Manohar, M; Goetz, T E; Hassan, A S

    2001-06-01

    Strenuously exercising horses exhibit arterial hypoxemia and exercise-induced pulmonary hemorrhage (EIPH), the latter resulting from stress failure of pulmonary capillaries. The present study was carried out to examine whether the structural changes in the blood-gas barrier caused by a prior bout of high-intensity short-term exercise capable of inducing EIPH would affect the arterial hypoxemia induced during a successive bout of exercise performed at the same workload. Two sets of experiments, double- and single-exercise-bout experiments, were carried out on seven healthy, sound Thoroughbred horses. Experiments were carried out in random order, 7 days apart. In the double-exercise experiments, horses performed two successive bouts (each lasting 120 s) of galloping at 14 m/s on a 3.5% uphill grade, separated by an interval of 6 min. Exertion at this workload induced arterial hypoxemia within 30 s of the onset of galloping as well as desaturation of Hb, a progressive rise in arterial PCO2, and acidosis as exercise duration increased from 30 to 120 s. In the single-exercise-bout experiments, blood-gas/pH data resembled those from the first run of the double-exercise experiments, and all horses experienced EIPH. Thus, in the double-exercise experiments, before the horses performed the second bout of galloping at 14 m/s on a 3.5% uphill grade, stress failure of pulmonary capillaries had occurred. Although arterial hypoxemia developed during the second run, arterial PO2 values were significantly (P < 0.01) higher than in the first run. Thus prior exercise not only failed to accentuate the severity of arterial hypoxemia, it actually diminished the magnitude of exercise-induced arterial hypoxemia. The decreased severity of exercise-induced arterial hypoxemia in the second run was due to an associated increase in alveolar PO2, as arterial PCO2 was significantly lower than in the first run. Thus our data do not support a role for structural changes in the blood-gas barrier related to the stress failure of pulmonary capillaries in causing the exercise-induced arterial hypoxemia in horses. PMID:11356804

  16. Acute Exercise-Induced Compartment Syndrome of the Leg- Don’t Miss It

    PubMed Central

    Khare, Manish Kumar; Mishra, Sumanta; Marhual, Jogesh Chandra

    2016-01-01

    Acute exercise induced compartment syndrome of leg is a very rare and very oftenly missed entity which leads to delay in its management. We are presenting such case in which diagnosis was established two days after the onset of symptoms. Urgent decompressive fasciotomy was done. After 3 months of follow up, patient has got full functional recovery of his affected limb. This case highlights the importance of keeping high index of clinical suspicion to diagnose the problem and manage promptly. We have reviewed the English literature and found only about 40 cases since 1945. PMID:27042521

  17. Role of creatine supplementation in exercise-induced muscle damage: A mini review

    PubMed Central

    Kim, Jooyoung; Lee, Joohyung; Kim, Seungho; Yoon, Daeyoung; Kim, Jieun; Sung, Dong Jun

    2015-01-01

    Muscle damage is induced by both high-intensity resistance and endurance exercise. Creatine is a widely used dietary supplement to improve exercise performance by reducing exercise-induced muscle damage. Many researchers have suggested that taking creatine reduces muscle damage by decreasing the inflammatory response and oxidative stress, regulating calcium homeostasis, and activating satellite cells. However, the underlying mechanisms of creatine and muscle damage have not been clarified. Therefore, this review discusses the regulatory effects of creatine on muscle damage by compiling the information collected from basic science and sports science research. PMID:26535213

  18. 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. PMID:24476485

  19. Exercise-induced acute compartment syndrome in a young man, occurring after a short race.

    PubMed

    Basnet, Bibhusan; Matar, Mousa; Vaitilingham, Siddharthan; Chalise, Shyam; Irooegbu, Nkem; Bang, Jane

    2016-04-01

    We describe a case of exercise-induced acute compartment syndrome (ACS) in a 23-year-old man who presented to his primary care physician 48 hours after he attempted to run a 5K race. He noticed searing pain in his left leg after the first half mile but had no other symptoms. He was referred to the emergency department and diagnosed with ACS, and a fasciotomy was done. A presentation of limb pain that is out of proportion to a known or suspected injury should prompt consideration of ACS. Early recognition and surgical management are essential to achieving the best possible outcome. PMID:27034546

  20. Data on mitochondrial function in skeletal muscle of old mice in response to different exercise intensity.

    PubMed

    Kang, Chounghun; Lim, Wonchung

    2016-06-01

    Endurance exercise is securely linked to muscle metabolic adaptations including enhanced mitochondrial function ("Effects of exercise on mitochondrial oxygen uptake and respiratory enzyme activity in skeletal muscle" [1], "Effects of exercise on mitochondrial content and function in aging human skeletal muscle" [2]). However, the link between exercise intensity and mitochondrial function in aging muscle has not been fully investigated. In order to understand how strenuous exercise affects mitochondrial function in aged mice, male C57BL/6 mice at age 24 months were randomly assigned to 3 groups: non-exercise (NE), low-intensity (LE) and high-intensity treadmill exercise group (HE). Mitochondrial complex activity and respiration were measured to evaluate mitochondrial function in mouse skeletal muscle. The data described here are related to the research article entitled "Strenuous exercise induces mitochondrial damage in skeletal muscle of old mice" [3]. PMID:27222846

  1. Data on mitochondrial function in skeletal muscle of old mice in response to different exercise intensity

    PubMed Central

    Kang, Chounghun; Lim, Wonchung

    2016-01-01

    Endurance exercise is securely linked to muscle metabolic adaptations including enhanced mitochondrial function (“Effects of exercise on mitochondrial oxygen uptake and respiratory enzyme activity in skeletal muscle” [1], “Effects of exercise on mitochondrial content and function in aging human skeletal muscle” [2]). However, the link between exercise intensity and mitochondrial function in aging muscle has not been fully investigated. In order to understand how strenuous exercise affects mitochondrial function in aged mice, male C57BL/6 mice at age 24 months were randomly assigned to 3 groups: non-exercise (NE), low-intensity (LE) and high-intensity treadmill exercise group (HE). Mitochondrial complex activity and respiration were measured to evaluate mitochondrial function in mouse skeletal muscle. The data described here are related to the research article entitled “Strenuous exercise induces mitochondrial damage in skeletal muscle of old mice” [3]. PMID:27222846

  2. Mitochondrial alteration in type 2 diabetes and obesity

    PubMed Central

    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. PMID:24552811

  3. 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 concept that increases in cardiac mitochondrial antioxidant enzymes may contribute to exercise-induced cardioprotection. PMID:20833957

  4. 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. PMID:26233864

  5. Spontaneous Pneumomediastinum in Non-Asthmatic Children with Exercise-Induced Bronchoconstriction

    PubMed Central

    Anantasit, Nattachai; Manuyakorn, Wiparat; Anantasit, Nualnapa; Choong, Karen; Preuthipan, Aroonwan

    2015-01-01

    Case series Patient: Male, 11 • Male, 15 Final Diagnosis: Spontaneous pneumomediastinum Symptoms: — Medication: — Clinical Procedure: None Specialty: Pediatrics and Neonatology Objective: Unusual clinical course Background: Subcutaneous emphysema can result from rupture of the respiratory or gastrointestinal systems, commonly occurring after trauma or surgery, as well as from rupture of alveoli as pneumothorax or pneumomediastinum. Spontaneous pneumomediastinum with subcutaneous emphysema is rare in children without chest or neck trauma. Here, we report 2 cases of spontaneous pneumomediastinum with exercise-induced bronchoconstriction. Case Report: The first case is an 11-year-old boy who presented with neck pain after vigorous exercise. Radiography showed pneumomediastinum. The second case is a 15-year-old boy who presented with pleuritic chest pain and respiratory failure requiring intubation. We extensively investigated the possible causes of pneumomediastinum. Both patients had no history of trauma or asthma, and were diagnosed with exercise-induced bronchoconstriction. They were discharged after conservative treatment, without complication. Conclusions: Early recognition and investigation of serious conditions should be promptly done in spontaneous pneumomediastinum patients. Conservative treatment, extensive investigations of predisposing factors, and treatment are important. PMID:26394070

  6. Exercise-induced cardiac fatigue in low and normal birth weight young black adults.

    PubMed

    Chifamba, Jephat; Mapfumo, Chidochashe; Mawoneke, Dorcas W; Gwaunza, Lenon T; Allen, Larry A; Chinyanga, Herbert M

    2015-03-01

    The objective of the study was to compare the change in diastolic function, E/A ratio, in response to prolonged exercise in low birth weight and normal birth weight individuals. Using a case-control study design, 23 students of the University of Zimbabwe College of Health Sciences who had neonatal clinic cards as proof of birth weight were recruited into the study. Measurements of diastolic function, E/A ratio, were obtained using an echocardiogram before and after 75 minutes of exercise. Among the cohort, seven had low birth weight - <2500 g, three female patients and four male patients - and 16 had normal birth weight - six female patients and 10 male patients). The mean age was 20.7±3.3 years. After prolonged exercise for 75 minutes of running on a treadmill, decreases in diastolic function, E/A ratio, were significantly greater in low birth weight than in normal birth weight individuals (0.48±0.27 versus 0.19±0.18 p<0.05, respectively). There was a significant association between low birth weight and exercise-induced cardiac fatigue (the χ2 test p<0.05, odds ratio 4.64, 95% confidence interval 1.19-18.1). We conclude that low birth weight is associated with exercise-induced diastolic dysfunction in young adults. PMID:24713506

  7. Exercise-induced silent myocardial ischemia: Evaluation by thallium-201 emission computed tomography

    SciTech Connect

    Kurata, C.; Sakata, K.; Taguchi, T.; Kobayashi, A.; Yamazaki, N. )

    1990-03-01

    Factors associated with silent myocardial ischemia (SMI) during exercise testing were studied by means of thallium-201 emission computed tomography (ECT) in 471 patients. Coronary angiography was done in 290, of whom 167 were found to have significant coronary artery disease (CAD). Exercise-induced ischemia and its severity were defined with ECT. During exercise 108 (62%) of 173 patients with ischemia and 57 (50%) of 115 with ischemia and angiographically documented CAD had no chest pain. One third of the patients showed an inconsistency between scintigraphic ischemia and ischemia ST depression. Age, sex, prior myocardial infarction, and diabetes mellitus were not related to SMI. Patients with SMI had less severe ischemia despite a higher peak double product compared to those with painful ischemia. Among 91 with prior myocardial infarction and exercise-induced ischemia, 51 with periinfarction ischemia had a higher frequency of SMI than did 14 with ischemia remote from the prior infarct zone despite similarities in the severity of ischemia. In conclusion, factors localized within ischemic myocardium such as less severe ischemia or adjacency to a prior infarct made SMI more prevalent.

  8. Epistaxis related to exercise-induced pulmonary haemorrhage in south African Thoroughbreds.

    PubMed

    Weideman, H; Schoeman, S J; Jordaan, G F; Kidd, M

    2003-12-01

    This study investigated if environmental factors had an effect on the incidence of epistaxis related to exercise-induced pulmonary haemorrhage (EIPH) among racehorses in southern Africa. Data covering the period 1986-2001 and involving 778 532 race runs were analysed. This included the following information: date of race, age, sex, name of breeder, trainer, distance, jockey, state of going, weight carried, racing centre and altitude. Veterinarians employed by the Jockey Club suspended officially entered horses that presented with epistaxis (frank bleeding from the nostrils) after racing. On-course endoscopy is not performed as a standard practice at any southern African racetrack. Epistaxis was identified in 1287 horses (0.165%). More horses presented with EIPH-related epistaxis (a) at sea level, (b) from May to October, (c) when older (> 3 years), (d) after 1995, (e) on Fridays and Sundays, and (f) more in geldings than in mares or entire males. No association could be established between epistaxis and breeder, trainer, distance run, jockey, state of going and weight carried. It is concluded that the frequency of EIPH-related epistaxis is associated with altitude, winter and spring, sex and age. It is suggested that racing at lower altitudes may increase the probability of exercise-induced pulmonary haemorrhage. PMID:15038426

  9. 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. PMID:24148812

  10. Exercise-induced muscle glucose uptake in mice with graded, muscle-specific GLUT-4 deletion

    PubMed Central

    Howlett, Kirsten F; Andrikopoulos, Sofianos; Proietto, Joseph; Hargreaves, Mark

    2013-01-01

    To investigate the importance of the glucose transporter GLUT-4 for muscle glucose uptake during exercise, transgenic mice with skeletal muscle GLUT-4 expression approximately 30–60% of normal (CON) and approximately 5–10% of normal (KO) were generated using the Cre/Lox system and compared with wild-type (WT) mice during approximately 40 min of treadmill running (KO: 37.7 ± 1.3 min; WT: 40 min; CON: 40 min, P = 0.18). In WT and CON animals, exercise resulted in an overall increase in muscle glucose uptake. More specifically, glucose uptake was increased in red gastrocnemius of WT mice and in the soleus and red gastrocnemius of CON mice. In contrast, the exercise-induced increase in muscle glucose uptake in all muscles was completely abolished in KO mice. Muscle glucose uptake increased during exercise in both red and white quadriceps of WT mice, while the small increases in CON mice were not statistically significant. In KO mice, there was no change at all in quadriceps muscle glucose uptake. No differences in muscle glycogen use during exercise were observed between any of the groups. However, there was a significant increase in plasma glucose levels after exercise in KO mice. The results of this study demonstrated that a reduction in skeletal muscle GLUT-4 expression to approximately 10% of normal levels completely abolished the exercise-induced increase in muscle glucose uptake. PMID:24303141

  11. Skin testing with food, codeine, and histamine in exercise-induced anaphylaxis.

    PubMed

    Lin, R Y; Barnard, M

    1993-06-01

    A 33-year-old Chinese woman with exercise-induced anaphylaxis after ingesting Chinese seafood noodle soup, was studied for skin test reactivity to food, histamine, and codeine. Prick skin tests were negative for shrimp, wheat, and chicken soup base, but were positive at 5 to 6 mm (wheal diameter) to the whole broth after it had been combined with the other ingredients. No significant (> 3 mm) wheals were observed in eight controls who were simultaneously tested with the broth. To assess the role of exercise, three series of skin tests were performed with histamine, codeine, and whole broth before and after aerobic exercise on two occasions. Codeine elicited consistent increases in wheal size after exercise compared with pre-exercise skin tests. Histamine and whole broth wheal sizes did not increase significantly. Three control subjects also had codeine and histamine skin tests before and after exercise, No exercise-associated increases were noted for codeine. Potential insights into mast cell abnormalities in exercise-induced anaphylaxis may be gained by skin testing patterns with codeine and other mast cell degranulating agents. PMID:8507042

  12. Exercise-induced cardioprotection--biochemical, morphological and functional evidence in whole tissue and isolated mitochondria.

    PubMed

    Ascensão, António; Ferreira, Rita; Magalhães, José

    2007-04-12

    Myocardial injury is a major contributor to the morbidity and mortality associated with coronary artery disease. Regular exercise has been confirmed as a pragmatic countermeasure to protect against cardiac injury. Specifically, endurance exercise has been proven to provide cardioprotection against cardiac insults in both young and old animals. Proposed mechanisms to explain the cardioprotective effects of exercise are mediated, at least partially, by redox changes and include the induction of myocardial heat shock proteins, improved cardiac antioxidant capacity, and/or elevation of other cardioprotective molecules. Understanding the molecular basis for exercise-induced cardioprotection is important in developing exercise strategies to protect the heart during and after insults. Data suggest that these positive modulator effects occur at different levels of cellular organization, being mitochondria fundamental organelles that are sensitive to disturbances imposed by exercise on basal homeostasis. At present, which of these protective mechanisms is essential for exercise-induced cardioprotection remains unclear. This review analyzes the biochemical, morphological and functional outcomes of acute and chronic exercise on the overall cardiac muscle tissue and in isolated mitochondria. Some redox-based mechanisms behind the cross-tolerance effects particularly induced by endurance training, against certain stressors responsible for the impairments in cardiac homeostasis caused by aging, diabetes, drug administration or ischemia-reperfusion are also outlined. Further work should be addressed in order to clarify the precise regulatory mechanisms by which physical exercise augments heart tolerance against many cardiotoxic agents. PMID:16860886

  13. Exercise induced release of von Willebrand factor: evidence for hypoxic reperfusion microvascular injury in rheumatoid arthritis.

    PubMed Central

    Farrell, A J; Williams, R B; Stevens, C R; Lawrie, A S; Cox, N L; Blake, D R

    1992-01-01

    Experimental evidence suggests that rheumatoid synovitis may be perpetuated by the generation of reactive oxygen species during hypoxic reperfusion injury. The latter occurs because increased intra-articular pressure during exercise exceeds synovial capillary perfusion pressure, impairing blood flow. The object of this study was to establish a marker for and the mechanism of synovial hypoxic reperfusion injury. Von Willebrand factor (vWF) is only released from endothelial cells and platelets and is an in vivo and in vitro marker of endothelial injury. In vivo exercise induced changes in plasma vWF were therefore investigated in patients with rheumatoid arthritis (RA) compared with controls and in vitro vWF release by human umbilical vein endothelial cells subjected to hypoxia reperfusion. Pre-exercise plasma vWF levels were 1001 and 817 IU/l, increasing after exercise to 1658 and 845 IU/l in patients with RA and controls respectively. Von Willebrand factor release from human umbilical vein endothelial cells followed a biphasic pattern, occurring during both hypoxia and reperfusion. Hypoxia reperfusion induced vWF release by human umbilical vein endothelial cells in vitro suggests that exercise induced vWF release in patients with RA is best explained by synovial hypoxic reperfusion injury. This study supports evidence that generation of reactive oxygen species plays a principal part in synovial hypoxic reperfusion injury and suggests vWF as a useful marker of this phenomenon. Images PMID:1444624

  14. Comparison between two assessment methods for exercise-induced laryngeal obstructions.

    PubMed

    Norlander, Katarina; Christensen, Pernille M; Maat, Robert C; Halvorsen, Thomas; Heimdal, John Helge; Morn, Staffan; Rasmussen, Niels; Nordang, Leif

    2016-02-01

    Exercise-induced laryngeal obstructions (E-ILOs) are important differential diagnoses to exercise-induced asthma and are diagnosed by the continuous laryngoscopy exercise (CLE) test. There are two different methods for evaluating the severity of E-ILOs using recordings from the CLE test; the CLE score and EILOMEA. The aim of this study was to investigate the consistency between these methods. Using their respective method, the developers of each method evaluated 60 laryngoscopic recordings from patients with different subtypes and various levels of severity of E-ILOs. The CLE score evaluates glottic and supraglottic obstructions on a 4-grade scale. EILOMEA uses software to calculate the obstruction severity on continuous scales from a still frame of the larynx during maximal obstruction giving three parameters reflecting glottic and supraglottic obstruction. The means of the EILOMEA measures differed significantly for CLE score 1 vs. 2 and 2 vs. 3, but not for 0 vs. 1 for glottic as well as supraglottic obstructions. The EILOMEA method does not distinguish between CLE score 0 and 1, but otherwise the methods correlate. Since previous studies have suggested that only CLE scores of 2 and 3 reflect a severity of E-ILOs of clinical importance, this lack of the EILOMEA method is not crucial for a correct medical evaluation. PMID:26351037

  15. Unravelling mitochondrial pathways to Parkinson's disease.

    PubMed

    Celardo, I; Martins, L M; Gandhi, S

    2014-04-01

    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. PMID:24117181

  16. Mitochondrial Quality Control as a Therapeutic Target.

    PubMed

    Suliman, Hagir B; Piantadosi, Claude A

    2016-01-01

    In addition to oxidative phosphorylation (OXPHOS), mitochondria perform other functions such as heme biosynthesis and oxygen sensing and mediate calcium homeostasis, cell growth, and cell death. They participate in cell communication and regulation of inflammation and are important considerations in aging, drug toxicity, and pathogenesis. The cell's capacity to maintain its mitochondria involves intramitochondrial processes, such as heme and protein turnover, and those involving entire organelles, such as fusion, fission, selective mitochondrial macroautophagy (mitophagy), and mitochondrial biogenesis. The integration of these processes exemplifies mitochondrial quality control (QC), which is also important in cellular disorders ranging from primary mitochondrial genetic diseases to those that involve mitochondria secondarily, such as neurodegenerative, cardiovascular, inflammatory, and metabolic syndromes. Consequently, mitochondrial biology represents a potentially useful, but relatively unexploited area of therapeutic innovation. In patients with genetic OXPHOS disorders, the largest group of inborn errors of metabolism, effective therapies, apart from symptomatic and nutritional measures, are largely lacking. Moreover, the genetic and biochemical heterogeneity of these states is remarkably similar to those of certain acquired diseases characterized by metabolic and oxidative stress and displaying wide variability. This biologic variability reflects cell-specific and repair processes that complicate rational pharmacological approaches to both primary and secondary mitochondrial disorders. However, emerging concepts of mitochondrial turnover and dynamics along with new mitochondrial disease models are providing opportunities to develop and evaluate mitochondrial QC-based therapies. The goals of such therapies extend beyond amelioration of energy insufficiency and tissue loss and entail cell repair, cell replacement, and the prevention of fibrosis. This review summarizes current concepts of mitochondria as disease elements and outlines novel strategies to address mitochondrial dysfunction through the stimulation of mitochondrial biogenesis and quality control. PMID:26589414

  17. All-Trans-Retinoic Acid Enhances Mitochondrial Function in Models of Human Liver.

    PubMed

    Tripathy, Sasmita; Chapman, John D; Han, Chang Y; Hogarth, Cathryn A; Arnold, Samuel L M; Onken, Jennifer; Kent, Travis; Goodlett, David R; Isoherranen, Nina

    2016-05-01

    All-trans-retinoic acid (atRA) is the active metabolite of vitamin A. The liver is the main storage organ of vitamin A, but activation of the retinoic acid receptors (RARs) in mouse liver and in human liver cell lines has also been shown. AlthoughatRA treatment improves mitochondrial function in skeletal muscle in rodents, its role in modulating mitochondrial function in the liver is controversial, and little data are available regarding the human liver. The aim of this study was to determine whetheratRA regulates hepatic mitochondrial activity.atRA treatment increased the mRNA and protein expression of multiple components of mitochondrialβ-oxidation, tricarboxylic acid (TCA) cycle, and respiratory chain. Additionally,atRA increased mitochondrial biogenesis in human hepatocytes and in HepG2 cells with and without lipid loading based on peroxisome proliferator activated receptor gamma coactivator 1αand 1βand nuclear respiratory factor 1 mRNA and mitochondrial DNA quantification.atRA also increasedβ-oxidation and ATP production in HepG2 cells and in human hepatocytes. Knockdown studies of RARα, RARβ, and PPARδrevealed that the enhancement of mitochondrial biogenesis andβ-oxidation byatRA requires peroxisome proliferator activated receptor delta. In vivo in mice,atRA treatment increased mitochondrial biogenesis markers after an overnight fast. Inhibition ofatRA metabolism by talarozole, a cytochrome P450 (CYP) 26 specific inhibitor, increased the effects ofatRA on mitochondrial biogenesis markers in HepG2 cells and in vivo in mice. These studies show thatatRA regulates mitochondrial function and lipid metabolism and that increasingatRA concentrations in human liver via CYP26 inhibition may increase mitochondrial biogenesis and fatty acidβ-oxidation and provide therapeutic benefit in diseases associated with mitochondrial dysfunction. PMID:26921399

  18. Two dimensional echocardiographic evaluation of exercise-induced left and right ventricular asynergy: correlation with thallium scanning

    SciTech Connect

    Maurer, G.; Nanda, N.C.

    1981-10-01

    Adequate real time two dimensional echocardiograms were prospectively obtained before and immediately after graded treadmill exercise testing in 41 of 48 patients who underwent cardiac catheterization for suspected coronary artery disease. Findings were correlated with thallium perfusion scans performed 5 to 10 minutes and 3 hours after the same exercise test. Exercise-induced wall motion abnormalities were detected in 19 of 23 patients with significant coronary artery disease and no prior myocardial infarction as well as in all 5 patients with known previous infarction. Three patients with coronary artery disease experienced new isolated right ventricular asynergy with exercise that would have been missed if only the left ventricle had been evaluated. Exercise-induced thallium perfusion defects showed good correlation with exercise-induced asynergy as detected with echocardiography. Two dimensional echocardiography performed immediately after treadmill stress testing is a feasible and rewarding technique in the evaluation of patients suspected to have coronary artery disease.

  19. 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

  20. Temperature- and exercise-induced gene expression and metabolic enzyme changes in skeletal muscle of adult zebrafish (Danio rerio)

    PubMed Central

    McClelland, Grant B; Craig, Paul M; Dhekney, Kalindi; Dipardo, Shawn

    2006-01-01

    Both exercise training and cold acclimatization induce muscle remodelling in vertebrates, producing a more aerobic phenotype. In ectothermic species exercise training and cold-acclimatization represent distinct stimuli. It is currently unclear if these stimuli act through a common mechanism or if different mechanisms lead to a common phenotype. The goal of this study was to survey responses that represent potential mechanisms responsible for contraction- and temperature-induced muscle remodelling, using an ectothermic vertebrate. Separate groups of adult zebrafish (Danio rerio) were either swim trained or cold acclimatized for 4 weeks. We found that the mitochondrial marker enzyme citrate synthase (CS) was increased by 1.5× in cold and by 1.3× with exercise (P < 0.05). Cytochrome c oxidase (COx) was increased by 1.2× following exercise training (P < 0.05) and 1.2× (P = 0.07) with cold acclimatization. However, only cold acclimatization increased β-hydroxyacyl-CoA dehydrogenase (HOAD) compared to exercise-trained (by 1.3×) and pyruvate kinase (PK) relative to control zebrafish. We assessed the whole-animal performance outcomes of these treatments. Maximum absolute sustained swimming speed (Ucrit) was increased in the exercise trained group but not in the cold acclimatized group. Real-time PCR analysis indicated that increases in CS are primarily transcriptionally regulated with exercise but not with cold treatments. Both treatments showed increases in nuclear respiratory factor (NRF)-1 mRNA which was increased by 2.3× in cold-acclimatized and 4× in exercise-trained zebrafish above controls. In contrast, peroxisome proliferator-activated receptor (PPAR)-α mRNA levels were decreased in both experimental groups while PPAR-β1 declined in exercise training only. Moreover, PPAR-γ coactivator (PGC)-1α mRNA was not changed by either treatment. In zebrafish, both temperature and exercise produce a more aerobic phenotype, but there are stimulus-dependent responses (i.e. HOAD and PK activities). While similar changes in NRF-1 mRNA suggest that common responses might underlie aerobic muscle remodelling there are distinct changes (i.e. CS and PPAR-β1 mRNA) that contribute to specific temperature- and exercise-induced phenotypes. PMID:16990399

  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. PMID:25667967

  2. Exercise induced hypercoagulability, increased von Willebrand factor and decreased thyroid hormone concentrations in sled dogs

    PubMed Central

    2014-01-01

    Background Sled dogs performing endurance races have been reported to have a high incidence of gastric erosions or ulcerations and an increased risk of gastro intestinal bleeding leading to death in some cases. In addition, these dogs also become hypothyroid during training and exercise. Canine hypothyroidism has been shown to correlate with decreased von Willebrand factor antigen and potentially increased bleeding tendency. Whether increased gastro intestinal bleeding risk is exacerbated due to changes in the hemostatic balance is unknown. The aim of this study was to investigate the hemostatic balance in sled dogs before and after exercise and in addition evaluate any correlation to thyroid status. Twenty sled dogs have been assessed in untrained and trained condition and immediately after exercise. The first sample was collected in the autumn following a resting period, and subsequently the dogs were exposed to increased intensity of training. After four months the peak of physical condition was reached and a 68 km long sled pulling exercise was performed. Samples were collected before and immediately after the exercise. Evaluated parameters were: plasma thromboelastographic (TEG) R, SP, α and MA, activated partial thromboplastin time (aPTT), prothrombin time (PT), fibrinogen, von Willebrand factor (vWf), D-dimer, platelet number, thyroid hormones, hematocrit and C-reactive protein (CRP). Results Exercise induced an overall hypercoagulable state characterized by significant decreases of TEG R and SP and an increase of α, increased concentrations of plasma vWf and decreased aPTT. In addition, a proinflammatory status was seen by a significant increase of serum CRP concentrations. Thyroid status was confirmed to be hypothyroid as training and exercise induced significant decrease of thyroxin (T4), free thyroxin (fT4) and thyroxin stimulating hormone (TSH) concentrations. Fibrinogen decreased significantly and PT increased. The training-induced changes showed correlation between T4, fT4 and aPTT and correlation between TSH and fibrinogen. Exercise-induced changes showed correlation between T4 and PT. Conclusions Exercise was associated with a hypercoagulable state and an increase of vWf concentration in this group of sled dogs. Decreased thyroid hormone concentrations after training and exercise were confirmed, but were associated with increased and not decreased vWf in this group of sled dogs. PMID:24507241

  3. The effect of exercise-induced hypoxemia on blood redox status in well-trained rowers.

    PubMed

    Kyparos, Antonios; Riganas, Christos; Nikolaidis, Michalis G; Sampanis, Michalis; Koskolou, Maria D; Grivas, Gerasimos V; Kouretas, Dimitrios; Vrabas, Ioannis S

    2012-06-01

    Exercise-induced arterial hypoxemia (EIAH), characterized by decline in arterial oxyhemoglobin saturation (SaO(2)), is a common phenomenon in endurance athletes. Acute intensive exercise is associated with the generation of reactive species that may result in redox status disturbances and oxidation of cell macromolecules. The purpose of the present study was to investigate whether EIAH augments oxidative stress as determined in blood plasma and erythrocytes in well-trained male rowers after a 2,000-m rowing ergometer race. Initially, athletes were assigned into either the normoxemic (n = 9, SaO(2) >92%, [Formula: see text]: 62.0 ± 1.9 ml kg(-1) min(-1)) or hypoxemic (n = 12, SaO(2) <92%, [Formula: see text]: 60.5 ± 2.2 ml kg(-1 )min(-1), mean ± SEM) group, following an incremental [Formula: see text] test on a wind resistance braked rowing ergometer. On a separate day the rowers performed a 2,000-m all-out effort on the same rowing ergometer. Following an overnight fast, blood samples were drawn from an antecubital vein before and immediately after the termination of the 2,000-m all-out effort and analyzed for selective oxidative stress markers. In both the normoxemic (SaO(2): 94.1 ± 0.9%) and hypoxemic (SaO(2): 88.6 ± 2.4%) rowers similar and significant exercise increase in serum thiobarbituric acid-reactive substances, protein carbonyls, catalase and total antioxidant capacity concentration were observed post-2,000 m all-out effort. Exercise significantly increased the oxidized glutathione concentration and decreased the ratio of reduced (GSH)-to-oxidized (GSSG) glutathione in the normoxemic group only, whereas the reduced form of glutathione remained unaffected in either groups. The increased oxidation of GSH to GSSG in erythrocytes of normoxemic individuals suggest that erythrocyte redox status may be affected by the oxygen saturation degree of hemoglobin. Our findings indicate that exercise-induced hypoxemia did not further affect the increased blood oxidative damage of lipids and proteins observed after a 2,000-m rowing ergometer race in highly-trained male rowers. The present data do not support any potential link between exercise-induced hypoxemia, oxidative stress increase and exercise performance. PMID:21947454

  4. Mitochondrial protein turnover: methods to measure turnover rates on a large scale

    PubMed Central

    Chan, X’avia CY; Black, Caitlin M; Lin, Amanda J; Ping, Peipei; Lau, Edward

    2016-01-01

    Mitochondrial proteins carry out diverse cellular functions including ATP synthesis, ion homeostasis, cell death signaling, and fatty acid metabolism and biogenesis. Compromised mitochondrial quality control is implicated in various human disorders including cardiac diseases. Recently it has emerged that mitochondrial protein turnover can serve as an informative cellular parameter to characterize mitochondrial quality and uncover disease mechanisms. The turnover rate of a mitochondrial protein reflects its homeostasis and dynamics under the quality control systems acting on mitochondria at a particular cell state. This review article summarizes some recent advances and outstanding challenges for measuring the turnover rates of mitochondrial proteins in health and disease. PMID:25451168

  5. 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...

  6. Molecular Mechanisms for Age-Associated Mitochondrial Deficiency in Skeletal Muscle

    PubMed Central

    Wagatsuma, Akira; Sakuma, Kunihiro

    2012-01-01

    The abundance, morphology, and functional properties of mitochondria decay in skeletal muscle during the process of ageing. Although the precise mechanisms remain to be elucidated, these mechanisms include decreased mitochondrial DNA (mtDNA) repair and mitochondrial biogenesis. Mitochondria possess their own protection system to repair mtDNA damage, which leads to defects of mtDNA-encoded gene expression and respiratory chain complex enzymes. However, mtDNA mutations have shown to be accumulated with age in skeletal muscle. When damaged mitochondria are eliminated by autophagy, mitochondrial biogenesis plays an important role in sustaining energy production and physiological homeostasis. The capacity for mitochondrial biogenesis has shown to decrease with age in skeletal muscle, contributing to progressive mitochondrial deficiency. Understanding how these endogenous systems adapt to altered physiological conditions during the process of ageing will provide a valuable insight into the underlying mechanisms that regulate cellular homeostasis. Here we will summarize the current knowledge about the molecular mechanisms responsible for age-associated mitochondrial deficiency in skeletal muscle. In particular, recent findings on the role of mtDNA repair and mitochondrial biogenesis in maintaining mitochondrial functionality in aged skeletal muscle will be highlighted. PMID:22548174

  7. Role of Magmas in protein transport and human mitochondria biogenesis

    PubMed Central

    Sinha, Devanjan; Joshi, Neha; Chittoor, Balasubramanyam; Samji, Priyanka; D'Silva, Patrick

    2010-01-01

    Magmas, a conserved mammalian protein essential for eukaryotic development, is overexpressed in prostate carcinomas and cells exposed to granulocyte-macrophage colony-stimulating factor (GM-CSF). Reduced Magmas expression resulted in decreased proliferative rates in cultured cells. However, the cellular function of Magmas is still elusive. In this report, we have showed that human Magmas is an ortholog of Saccharomyces cerevisiae Pam16 having similar functions and is critical for protein translocation across mitochondrial inner membrane. Human Magmas shows a complete growth complementation of Δpam16 yeast cells at all temperatures. On the basis of our analysis, we report that Magmas localizes into mitochondria and is peripherally associated with inner mitochondrial membrane in yeast and humans. Magmas forms a stable subcomplex with J-protein Pam18 or DnaJC19 through its C-terminal region and is tethered to TIM23 complex of yeast and humans. Importantly, amino acid alterations in Magmas leads to reduced stability of the subcomplex with Pam18 that results in temperature sensitivity and in vivo protein translocation defects in yeast cells. These observations highlight the central role of Magmas in protein import and mitochondria biogenesis. In humans, absence of a functional DnaJC19 leads to dilated cardiac myophathic syndrome (DCM), a genetic disorder with characteristic features of cardiac myophathy and neurodegeneration. We propose that the mutations resulting in decreased stability of functional Magmas:DnaJC19 subcomplex at human TIM23 channel leads to impaired protein import and cellular respiration in DCM patients. Together, we propose a model showing how Magmas:DnaJC19 subcomplex is associated with TIM23 complex and thus regulates mitochondrial import process. PMID:20053669

  8. Signaling the Mitochondrial Unfolded Protein Response

    PubMed Central

    Pellegrino, Mark W.; Nargund, Amrita M.; Haynes, Cole M.

    2012-01-01

    Mitochondria are compartmentalized organelles essential for numerous cellular functions including ATP generation, iron-sulfur cluster biogenesis, nucleotide and amino acid metabolism as well as apoptosis. To promote biogenesis and proper function, mitochondria have a dedicated repertoire of molecular chaperones to facilitate protein folding and quality control proteases to degrade those proteins that fail to fold correctly. Mitochondrial protein folding is challenged by the complex organelle architecture, the deleterious effects of electron transport chain-generated reactive oxygen species and the mitochondrial genome’s susceptibility to acquiring mutations. In response to the accumulation of unfolded or misfolded proteins beyond the organelle’s chaperone capacity, cells mount a mitochondrial unfolded protein response (UPRmt). The UPRmt is a mitochondria-to-nuclear signal transduction pathway resulting in the induction of mitochondrial protective genes including mitochondrial molecular chaperones and proteases to re-establish protein homeostasis within the mitochondrial protein-folding environment. Here, we review the current understanding of UPRmt signal transduction and the impact of the UPRmt on diseased cells. PMID:22445420

  9. Diagnosis of exercise-induced pain in the anterior aspect of the lower leg.

    PubMed

    Styf, J

    1988-01-01

    Ninety-eight patients with chronic exercise-induced pain in the anterior compartment of the lower leg underwent extensive clinical and laboratory investigations to establish the diagnosis. They all were referred because of a putative chronic compartment syndrome (CCS). Intramuscular pressure was recorded bilaterally during exercise in the anterior tibial muscle in all of them. Conduction-velocity recordings of the deep and superficial peroneal nerves were performed in 29 patients. Other investigations included radiography, plethysmography, and scintigraphy. CCS was diagnosed in 26 of the 98 patients. Other diagnoses included periostitis in 41 patients, compression of the superficial peroneal nerve in 13, and miscellaneous other diagnoses in 18. CCS seems to be an uncommon reason for anterior pain in the lower legs. PMID:3377101

  10. Thromboelastometric Profiles of Horses Affected by Exercise-Induced Pulmonary Hemorrhages

    PubMed Central

    Giordano, Alessia; Meazza, Cecilia; Salvadori, Marco; Paltrinieri, Saverio

    2010-01-01

    Exercise-induced pulmonary hemorrhage (EIPH) commonly occurs in race horses. Thromboelastometry (TEM) investigates the whole hemostatic process by evaluating the viscoelastic properties of the blood clot from its formation to fibrinolysis. The aim of this study was to assess whether horses with EIPH have abnormal thromboelastometric profiles. Intrinsic and extrinsic pathways, fibrinogen activity and fibrinolysis were investigated by TEM before and after the race in negative controls and in horses on which EIPH was confirmed by bronchoscopy. Compared with controls, horses with EIPH had an increased coagulability in both pre- and postrace samplings, especially for the intrinsic pathway and for the fibinrolytic activity. These results suggest that coagulation is preactivated in horses prone to develop EIPH, possibly due to recent or recurrent hemorrhage. PMID:20953331

  11. Thromboelastometric profiles of horses affected by exercise-induced pulmonary hemorrhages.

    PubMed

    Giordano, Alessia; Meazza, Cecilia; Salvadori, Marco; Paltrinieri, Saverio

    2010-01-01

    Exercise-induced pulmonary hemorrhage (EIPH) commonly occurs in race horses. Thromboelastometry (TEM) investigates the whole hemostatic process by evaluating the viscoelastic properties of the blood clot from its formation to fibrinolysis. The aim of this study was to assess whether horses with EIPH have abnormal thromboelastometric profiles. Intrinsic and extrinsic pathways, fibrinogen activity and fibrinolysis were investigated by TEM before and after the race in negative controls and in horses on which EIPH was confirmed by bronchoscopy. Compared with controls, horses with EIPH had an increased coagulability in both pre- and postrace samplings, especially for the intrinsic pathway and for the fibinrolytic activity. These results suggest that coagulation is preactivated in horses prone to develop EIPH, possibly due to recent or recurrent hemorrhage. PMID:20953331

  12. 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 plexus. Growth factors, specifically fibroblast growth factor and IGF-1 receptors and/or their downstream signaling pathways may interact with the Klotho gene which functions as an aging suppressor gene. Neurons may not be the only cells affected by exercise. Glia (astrocytes and microglia), neurovascular units and the Fourth Element may also be affected in a differential fashion by the AD process. Analyses of these factors, as suggested by the multi-dimensional matrix approach, are needed to improve our understanding of this complex multi-factorial process, which is increasingly relevant to conquering the escalating and intersecting world-wide epidemics of dementia, diabetes, and sarcopenia that threaten the global healthcare system. Physical activity and interventions aimed at enhancing and/or mimicking the effects of exercise are likely to play a significant role in mitigating these epidemics, together with the embryonic efforts to develop cognitive rehabilitation for neurodegenerative disorders. PMID:21602910

  13. [A case of apple allergy with initial symptoms like food-dependent exercise-induced anaphylaxis].

    PubMed

    Kaneko, Mari; Yagi, Hisako; Koyama, Harumi; Nakajima, Naoki; Muramatu, Reiko; Takizawa, Takumi; Arakawa, Hirokazu

    2013-06-01

    A 13-year-old boy with two episodes of anaphylaxis after exercise was suspected as food-dependent exercise-induced anaphylaxis (FEIAn). The exercise challenge test after ingestion of an apple was performed, because apple was commonly contained in meals before the both episodes and a prick test for apple was positive. The exercise test was positive accompanied with nasal discharge, sneezing, throat discomfort, swelling of the uvula. The patient was instructed to refrain from exercise for 4 hours after ingestion of apple. In five months, he developed allergic symptoms only by an intake of foods containing heated apple without exercise and showed a slight increase in apple-specific IgE from negative to 0.51 IU/ml. The prognosis of FEIAn has not been well described. Cases with FEIAn to apples like this case require a close follow-up in consideration of development of allergic reactions without exercise. PMID:23969882

  14. Prevention of exercised induced cardiomyopathy following Pip-PMO treatment in dystrophic mdx mice

    PubMed Central

    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.

    2015-01-01

    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. PMID:25758104

  15. Exercise-induced oxidatively damaged DNA in humans: evaluation in plasma or urine?

    PubMed

    Karpouzi, Christina; Nikolaidis, Stefanos; Kabasakalis, Athanasios; Tsalis, George; Mougios, Vassilis

    2016-05-01

    Physical exercise can induce oxidative damage in humans. 8-Hydroxy-2'-deoxyguanosine (8-OHdG) is a widely known biomarker of DNA oxidation, which can be determined in blood and urine. The aim of the present study was to compare these two biological fluids in terms of which is more suitable for the estimation of the oxidative damage of DNA by measuring the concentration of 8-OHdG one hour after maximal exercise by enzyme immunoassay. The concentration of 8-OHdG increased with exercise only in plasma (p < 0.001), and values differed between exercise tests in both plasma and urine (p < 0.05). In conclusion, plasma appears to be more sensitive to exercise-induced 8-OHdG changes than urine and, hence, a more appropriate medium for assessing oxidative damage of DNA, although the poor repeatability of the measurement needs to be addressed in future studies. PMID:26849281

  16. Exercise-induced bronchocontriction, skin sensitivity, and serum IgE in children with eczema.

    PubMed Central

    Price, J F; Cogswell, J J; Joseph, M C; Cochrane, G M

    1976-01-01

    Forty-two children with eczema were studied for exercise-induced astham (EIA), skin sensitivity to prick testing, blood eosinophil count, and immunoglobulins. 29 had a fall in peak expiratory flow rate after exercise greater than 20% and of these, 23 had symptoms of wheezing. 13 of the eczematous children showed a fall of less than 20%. The children with EIA showed greater cutaneous sensitivity (p less than 0.001) and a higher total serum IgE (p less than 0.025). 3 of the group with a fall of less than 20% had allergic rhinitis with skin sensitivity to grass pollen. The remaining 10 had no clinical evidence of allergic disease, other than eczema and skin sensitivity, and total IgE fell within the normal range. It is suggested that in a proportion of chilren with eczema there is little evidence of reaginic allergy. PMID:1015843

  17. 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

  18. 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. PMID:25467962

  19. Mitochondrial Metabolism in Aging Heart.

    PubMed

    Lesnefsky, Edward J; Chen, Qun; Hoppel, Charles L

    2016-05-13

    Altered mitochondrial metabolism is the underlying basis for the increased sensitivity in the aged heart to stress. The aged heart exhibits impaired metabolic flexibility, with a decreased capacity to oxidize fatty acids and enhanced dependence on glucose metabolism. Aging impairs mitochondrial oxidative phosphorylation, with a greater role played by the mitochondria located between the myofibrils, the interfibrillar mitochondria. With aging, there is a decrease in activity of complexes III and IV, which account for the decrease in respiration. Furthermore, aging decreases mitochondrial content among the myofibrils. The end result is that in the interfibrillar area, there is ≈50% decrease in mitochondrial function, affecting all substrates. The defective mitochondria persist in the aged heart, leading to enhanced oxidant production and oxidative injury and the activation of oxidant signaling for cell death. Aging defects in mitochondria represent new therapeutic targets, whether by manipulation of the mitochondrial proteome, modulation of electron transport, activation of biogenesis or mitophagy, or the regulation of mitochondrial fission and fusion. These mechanisms provide new ways to attenuate cardiac disease in elders by preemptive treatment of age-related defects, in contrast to the treatment of disease-induced dysfunction. PMID:27174952

  20. Green tea catechin consumption enhances exercise-induced abdominal fat loss in overweight and obese adults.

    PubMed

    Maki, Kevin C; Reeves, Matthew S; Farmer, Mildred; Yasunaga, Koichi; Matsuo, Noboru; Katsuragi, Yoshihisa; Komikado, Masanori; Tokimitsu, Ichiro; Wilder, Donna; Jones, Franz; Blumberg, Jeffrey B; Cartwright, Yolanda

    2009-02-01

    This study evaluated the influence of a green tea catechin beverage on body composition and fat distribution in overweight and obese adults during exercise-induced weight loss. Participants (n = 132 with 107 completers) were randomly assigned to receive a beverage containing approximately 625 mg of catechins with 39 mg caffeine or a control beverage (39 mg caffeine, no catechins) for 12 wk. Participants were asked to maintain constant energy intake and engage in >or=180 min/wk moderate intensity exercise, including >or=3 supervised sessions per week. Body composition (dual X-ray absorptiometry), abdominal fat areas (computed tomography), and clinical laboratory tests were measured at baseline and wk 12. There was a trend (P = 0.079) toward greater loss of body weight in the catechin group compared with the control group; least squares mean (95% CI) changes, adjusted for baseline value, age, and sex, were -2.2 (-3.1, -1.3) and -1.0 (-1.9, -0.1) kg, respectively. Percentage changes in fat mass did not differ between the catechin [5.2 (-7.0, -3.4)] and control groups [-3.5 (-5.4, 1.6)] (P = 0.208). However, percentage changes in total abdominal fat area [-7.7 (-11.7, -3.8) vs. -0.3 (-4.4, 3.9); P = 0.013], subcutaneous abdominal fat area [-6.2 (-10.2, -2.2) vs. 0.8 (-3.3, 4.9); P = 0.019], and fasting serum triglycerides (TG) [-11.2 (-18.8, -3.6) vs. 1.9 (-5.9, 9.7); P = 0.023] were greater in the catechin group. These findings suggest that green tea catechin consumption enhances exercise-induced changes in abdominal fat and serum TG. PMID:19074207

  1. Influence of prior anterograde shear rate exposure on exercise-induced brachial artery dilation

    PubMed Central

    Ade, Carl J; Brown, Michael G; Ederer, Austin K; Hardy, Rachel N; Reiter, Landon K; Didier, Kaylin D

    2015-01-01

    Shear rate can elicit substantial adaptations to vascular endothelial function. Recent studies indicate that prior exposure to anterograde flow and shear increases endothelium-dependent flow-mediated dilation at rest and that anterograde shear can create an anti-atherosclerotic and provasodilatory state. The primary aim of the present study was therefore to determine the effects of prior exposure to anterograde shear on exercise-induced brachial artery dilation, total forearm blood flow (FBF), and vascular conductance (FVC) during dynamic handgrip exercise. Eight men completed a constant-load exercise test corresponding to 10% maximal voluntary contraction, prior to (baseline) and following a 40 min shear rate intervention (post-SRI) achieved via unilateral forearm heating, which has previously been shown to increase anterograde shear rate in the brachial artery. During the SRI, anterograde shear rate increased 60.9 ± 29.2 sec−1 above baseline (P < 0.05). Post-SRI, the exercise-induced brachial artery vasodilation was significantly increased compared to baseline (4.1 ± 0.7 vs. 4.3 ± 0.6 mm, P < 0.05). Post-SRI FBF mean response time (33.2 ± 16.0 vs. 23.0 ± 11.8 sec, P < 0.05) and FVC mean response time (31.1 ± 12.8 20.2 ± 10.7 sec, P < 0.05) at exercise onset were accelerated compared to baseline. These findings demonstrate that prior exposure to anterograde shear rate increases the vascular responses to exercise and supports the possible beneficial effects of anterograde shear rate in vivo. PMID:26009637

  2. A Semiquantitative Scoring Tool to Evaluate Eccentric Exercise-Induced Muscle Damage in Trained Rats

    PubMed Central

    Rizo-Roca, D.; Ríos-Kristjánsson, J.G.; Núñez-Espinosa, C.; Ascensão, A.A.; Magalhães, J.; Pagès, T.; Viscor, G.

    2015-01-01

    Unaccustomed eccentric exercise is a well-documented cause of exercise-induced muscle damage. However, in trained subjects muscle injury involves only light or moderate tissue damage. Since trained rats are widely used as a model for skeletal muscle injury, here we propose a semiquantitative scoring tool to evaluate muscle damage in trained rats. Twenty male Sprague-Dawley rats were trained for two weeks following a two-week preconditioning period, and randomly divided into two groups: control rats (CTL; n=5) and rats with eccentric exercise-induced muscle damage (INJ; n=15). Injured rats were sacrificed at three time points: 1, 3 and 7 days post injury (n=5 each). Transverse sections from the right soleus were cut (10 µm) and stained with haematoxylin-eosin. Samples were evaluated by two groups of observers (four researchers experienced in skeletal muscle histopathology and four inexperienced) using the proposed tool, which consisted of six items organised in three domains: abnormal fibre morphology, necrotic/(re) degenerating fibres (muscle fibre domain), endomysial and perimysial infiltration (inflammatory state domain) and endomysium and perimysium distension (interstitial compartment domain). We observed the expected time course in the six evaluated items. Furthermore, agreement among observers was evaluated by measuring the Intraclass Correlation Coefficient (ICC). Within the experienced group, items from the muscle fibre and interstitial compartment domains showed good agreement and the two items from the infiltration compartment domain showed excellent agreement. In conclusion, the proposed tool allowed quick and correct evaluation of light to moderate muscle damage in trained rats with good agreement between observers. PMID:26708179

  3. Two male siblings with hereditary renal hypouricemia and exercise-induced ARF.

    PubMed

    Tanaka, Motoko; Itoh, Kazuko; Matsushita, Kazunori; Matsushita, Kazutaka; Wakita, Naoki; Adachi, Masataka; Nonoguchi, Hiroshi; Kitamura, Kenichiro; Hosoyamada, Makoto; Endou, Hitoshi; Tomita, Kimio

    2003-12-01

    Familial renal hypouricemia with exercise-induced acute renal failure (ARF) is rare. A 45-year-old man presented with abdominal pain, vomiting, and oliguria after severe exercise. The diagnosis was ARF based on high serum creatinine (SCr) level (5.1 mg/dL [451 micromol/L]). Renal function recovered completely within 2 weeks of conservative treatment (creatinine clearance [Ccr], 100.4 mL/min [1.67 mL/s]). After remission, laboratory results showed serum urate (SUA) of 0.8 mg/dL (48 micromol/L), and fractional excretion of uric acid (FE(UA)) of 46%. The final diagnosis was ARF associated with idiopathic renal hypouricemia. Other diseases that could increase the excretion of urate were excluded. Because only mild responses were observed both in pyradinamide and benzbromarone loading tests, he was considered to be a presecretory reabsorption disorder type. The younger brother (42 years old) also had episodes of low and middle back pain after severe exercise and experienced similar attacks at least 5 times since the age of 29. SCr level was elevated in every attack. Hypouricemia (SUA, 1.0 mg/dL [59 micromol/L]) and high urinary urate excretion (FE(UA), 65.7%) also were detected. Renal function recovered almost completely without any specific treatment. Radiologic examination of the 2 cases showed bilateral urolithiasis probably caused by the high urinary urate excretion. Sequence analysis of a urate anion exchanger known to regulate blood urate level (URAT1 gene) in both brothers showed homozygous mutation in exon 4 (W258Stop), resulting in a premature truncated URAT1 protein. Both their parents and their children showed heterozygous mutation of the URAT1 gene. This is the first report of the 2 male siblings of familial renal hypouricemia complicated with exercise-induced ARF, with definite demonstration of genetic abnormality in the responsible gene (URAT1). PMID:14655203

  4. Ivabradine reduces myocardial stunning in patients with exercise-inducible ischaemia.

    PubMed

    Maranta, F; Tondi, L; Agricola, E; Margonato, A; Rimoldi, O; Camici, Paolo G

    2015-11-01

    Ivabradine is an effective treatment for angina in patients with stable coronary artery disease (CAD) and for heart failure. Experiments in a canine model have shown that ivabradine reduces both acute left ventricular (LV) dysfunction and post-ischaemic stunning. Aim of this study was to investigate the effect of ivabradine on LV dysfunction and stunning in patients with CAD and exercise-inducible ischaemia. Fifteen patients with ejection fraction >40 % and heart rate >70 bpm were enrolled. After pharmacologic washout, echocardiography was performed at rest, at peak treadmill exercise and during recovery until return to baseline. After 2 weeks of ivabradine (7.5 mg bid) stress echocardiography was repeated at the same workload achieved during washout. Peak global and segmental (ischaemic vs. remote normal segments) LV longitudinal strain (LS) was assessed by 2D speckle tracking analysis. At washout, LS was significantly impaired in ischaemic compared to remote segments at peak stress and for several minutes during recovery. After ivabradine a smaller, albeit still significant, impairment of LS in ischaemic segments was observed at peak whilst no difference with remote segments was present during recovery. Furthermore, the average global LS value improved significantly after treatment. In conclusion, ivabradine reduces both acute LV dysfunction and stunning in patients with CAD and exercise-inducible ischaemia. We hypothesise that this mechanism might contribute to reduce chronic LV dysfunction in patients with CAD. In this setting the drug might limit the development of hibernating myocardium which is believed to result from repeated episodes of ischaemia and stunning. PMID:26419678

  5. Effects of oral glutamine supplementation on exercise-induced gastrointestinal permeability and tight junction protein expression

    PubMed Central

    Lanphere, Kathryn R.; Kravitz, Len; Mermier, Christine M.; Schneider, Suzanne; Dokladny, Karol; Moseley, Pope L.

    2013-01-01

    The objectives of this study are threefold: 1) to assess whether 7 days of oral glutamine (GLN) supplementation reduces exercise-induced intestinal permeability; 2) whether supplementation prevents the proinflammatory response; and 3) whether these changes are associated with upregulation of the heat shock response. On separate occasions, eight human subjects participated in baseline testing and in GLN and placebo (PLA) supplementation trials, followed by a 60-min treadmill run. Intestinal permeability was higher in the PLA trial compared with baseline and GLN trials (0.0604 0.047 vs. 0.0218 0.008 and 0.0272 0.007, respectively; P < 0.05). I?B? expression in peripheral blood mononuclear cells was higher 240 min after exercise in the GLN trial compared with the PLA trial (1.411 0.523 vs. 0.9839 0.343, respectively; P < 0.05). In vitro using the intestinal epithelial cell line Caco-2, we measured effects of GLN supplementation (0, 4, and 6 mM) on heat-induced (37 or 41.8C) heat shock protein 70 (HSP70), heat shock factor-1 (HSF-1), and occludin expression. HSF-1 and HSP70 levels increased in 6 mM supplementation at 41C compared with 0 mM at 41C (1.785 0.495 vs. 0.6681 0.290, and 1.973 0.325 vs. 1.133 0.129, respectively; P < 0.05). Occludin levels increased after 4 mM supplementation at 41C and 6 mM at 41C compared with 0 mM at 41C (1.236 0.219 and 1.849 0.564 vs. 0.7434 0.027, respectively; P < 0.001). GLN supplementation prevented exercise-induced permeability, possibly through HSF-1 activation. PMID:24285149

  6. Effects of prior exercise on exercise-induced arterial hypoxemia in young women.

    PubMed

    St Croix, C M; Harms, C A; McClaran, S R; Nickele, G A; Pegelow, D F; Nelson, W B; Dempsey, J A

    1998-10-01

    Twenty-eight healthy women (ages 27.2 +/- 6.4 yr) with widely varying fitness levels [maximal O2 consumption (VO2 max), 31-70 ml . kg-1 . min-1] first completed a progressive incremental treadmill test to VO2 max (total duration, 13.3 +/- 1.4 min; 97 +/- 37 s at maximal workload), rested for 20 min, and then completed a constant-load treadmill test at maximal workload (total duration, 143 +/- 31 s). At the termination of the progressive test, 6 subjects had maintained arterial PO2 (PaO2) near resting levels, whereas 22 subjects showed a >10 Torr decrease in PaO2 [78.0 +/- 7.2 Torr, arterial O2 saturation (SaO2), 91.6 +/- 2.4%], and alveolar-arterial O2 difference (A-aDO2, 39.2 +/- 7.4 Torr). During the subsequent constant-load test, all subjects, regardless of their degree of exercise-induced arterial hypoxemia (EIAH) during the progressive test, showed a nearly identical effect of a narrowed A-aDO2 (-4.8 +/- 3.8 Torr) and an increase in PaO2 (+5.9 +/- 4.3 Torr) and SaO2 (+1.6 +/- 1.7%) compared with at the end point of the progressive test. Therefore, EIAH during maximal exercise was lessened, not enhanced, by prior exercise, consistent with the hypothesis that EIAH is not caused by a mechanism which persists after the initial exercise period and is aggravated by subsequent exercise, as might be expected of exercise-induced structural alterations at the alveolar-capillary interface. Rather, these findings in habitually active young women point to a functionally based mechanism for EIAH that is present only during the exercise period. PMID:9760353

  7. Hormone therapy attenuates exercise-induced skeletal muscle damage in postmenopausal women

    PubMed Central

    Dieli-Conwright, Christina M.; Spektor, Tanya M.; Rice, Judd C.; Schroeder, E. Todd

    2009-01-01

    Hormone therapy (HT) is a potential treatment to relieve symptoms of menopause and prevent the onset of disease such as osteoporosis in postmenopausal women. We evaluated changes in markers of exercise-induced skeletal muscle damage and inflammation [serum creatine kinase (CK), serum lactate dehydrogenase (LDH), and skeletal muscle mRNA expression of IL-6, IL-8, IL-15, and TNF-α] in postmenopausal women after a high-intensity resistance exercise bout. Fourteen postmenopausal women were divided into two groups: women not using HT (control; n = 6, 59 ± 4 yr, 63 ± 17 kg) and women using traditional HT (HT; n = 8, 59 ± 4 yr, 89 ± 24 kg). Both groups performed 10 sets of 10 maximal eccentric repetitions of single-leg extension on the Cybex dynamometer at 60°/s with 20-s rest periods between sets. Muscle biopsies of the vastus lateralis were obtained from the exercised leg at baseline and 4 h after the exercise bout. Gene expression was determined by RT-PCR for IL-6, IL-8, IL-15, and TNF-α. Blood draws were performed at baseline and 3 days after exercise to measure CK and LDH. Independent t-tests were performed to test group differences (control vs. HT). A probability level of P ≤ 0.05 was used to determine statistical significance. We observed significantly greater changes in mRNA expression of IL-6, IL-8, IL-15, and TNF-α (P ≤ 0.01) in the control group compared with the HT group after the exercise bout. CK and LDH levels were significantly greater after exercise (P ≤ 0.01) in the control group. Postmenopausal women not using HT experienced greater muscle damage after maximal eccentric exercise, indicating a possible protective effect of HT against exercise-induced skeletal muscle damage. PMID:19574506

  8. 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. Al