Control of gene expression and mitochondrial biogenesis in the muscular adaptation to endurance exercise

2006 ◽  
Vol 42 ◽  
pp. 13-29 ◽  
Author(s):  
Anna-Maria Joseph ◽  
Henriette Pilegaard ◽  
Anastassia Litvintsev ◽  
Lotte Leick ◽  
David A. Hood
Keyword(s):  
Gene Expression ◽  
Mitochondrial Biogenesis ◽  
Protein Import ◽  
Metabolic Diseases ◽  
Current Knowledge ◽  
Mitochondrial Fission ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Control Of Gene Expression ◽  
Genes Encoding

Every time a bout of exercise is performed, a change in gene expression occurs within the contracting muscle. Over the course of many repeated bouts of exercise (i.e. training), the cumulative effects of these alterations lead to a change in muscle phenotype. One of the most prominent of these adaptations is an increase in mitochondrial content, which confers a greater resistance to muscle fatigue. This essay reviews current knowledge on the regulation of exercise-induced mitochondrial biogenesis at the molecular level. The major steps involved include, (i) transcriptional regulation of nuclear-encoded genes encoding mitochondrial proteins by the coactivator peroxisome-proliferator-activated receptor g coactivator-1, (ii) control of mitochondrial DNA gene expression by the transcription factor Tfam, (iii) mitochondrial fission and fusion mechanisms, and (iv) import of nuclear-derived gene products into the mitochondrion via the protein import machinery. It is now known that exercise can modify the rates of several of these steps, leading to mitochondrial biogenesis. An understanding of how exercise can produce this effect could help us decide whether exercise is beneficial for patients suffering from mitochondrial disorders, as well as a variety of metabolic diseases.

scholarly journals Electron Transport Disturbances and Neurodegeneration: From Albert Szent-Györgyi’s Concept (Szeged) till Novel Approaches to Boost Mitochondrial Bioenergetics

2015 ◽  
Vol 2015 ◽  
pp. 1-19 ◽  
Author(s):  
Levente Szalárdy ◽  
Dénes Zádori ◽  
Péter Klivényi ◽  
József Toldi ◽  
László Vécsei
Keyword(s):  
Transcriptional Activation ◽  
Current Knowledge ◽  
Genetic Alterations ◽  
Cellular Respiration ◽  
Special Focus ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Disease Modifying Therapy ◽  
Mitochondrial Functions ◽  
Genes Encoding

Impaired function of certain mitochondrial respiratory complexes has long been linked to the pathogenesis of chronic neurodegenerative disorders such as Parkinson’s and Huntington’s diseases. Furthermore, genetic alterations of mitochondrial genome or nuclear genes encoding proteins playing essential roles in maintaining proper mitochondrial function can lead to the development of severe systemic diseases associated with neurodegeneration and vacuolar myelinopathy. At present, all of these diseases lack effective disease modifying therapy. Following a brief commemoration of Professor Albert Szent-Györgyi, a Nobel Prize laureate who pioneered in the field of cellular respiration, antioxidant processes, and the roles of free radicals in health and disease, the present paper overviews the current knowledge on the involvement of mitochondrial dysfunction in central nervous system diseases associated with neurodegeneration including Parkinson’s and Huntington’s disease as well as mitochondrial encephalopathies. The review puts special focus on the involvement and the potential therapeutic relevance of peroxisome proliferator-activated receptor-gamma coactivator 1-alpha (PGC-1α), a nuclear-encoded master regulator of mitochondrial biogenesis and antioxidant responses in these disorders, the transcriptional activation of which may hold novel therapeutic value as a more system-based approach aiming to restore mitochondrial functions in neurodegenerative processes.

scholarly journals Nutritional Regulation of Gene Expression: Carbohydrate-, Fat- and Amino Acid-Dependent Modulation of Transcriptional Activity

2019 ◽  
Vol 20 (6) ◽  
pp. 1386 ◽  
Author(s):  
Diego Haro ◽  
Pedro Marrero ◽  
Joana Relat
Keyword(s):  
Gene Expression ◽  
Amino Acid ◽  
Molecular Mechanisms ◽  
Metabolic Diseases ◽  
Regulation Of Gene Expression ◽  
Peroxisome Proliferator ◽  
Nutritional Regulation ◽  
Control Of Gene Expression ◽  
Nutritional Interventions ◽  
Precise Control

The ability to detect changes in nutrient levels and generate an adequate response to these changes is essential for the proper functioning of living organisms. Adaptation to the high degree of variability in nutrient intake requires precise control of metabolic pathways. Mammals have developed different mechanisms to detect the abundance of nutrients such as sugars, lipids and amino acids and provide an integrated response. These mechanisms include the control of gene expression (from transcription to translation). This review reports the main molecular mechanisms that connect nutrients’ levels, gene expression and metabolism in health. The manuscript is focused on sugars’ signaling through the carbohydrate-responsive element binding protein (ChREBP), the role of peroxisome proliferator-activated receptors (PPARs) in the response to fat and GCN2/activating transcription factor 4 (ATF4) and mTORC1 pathways that sense amino acid concentrations. Frequently, alterations in these pathways underlie the onset of several metabolic pathologies such as obesity, insulin resistance, type 2 diabetes, cardiovascular diseases or cancer. In this context, the complete understanding of these mechanisms may improve our knowledge of metabolic diseases and may offer new therapeutic approaches based on nutritional interventions and individual genetic makeup.

Nuclear receptor-mediated regulation of lipid droplet-associated protein gene expression in adipose tissue

2013 ◽  
Vol 14 (3) ◽  
Author(s):  
Mark Christian
Keyword(s):  
Gene Expression ◽  
Estrogen Receptor Α ◽  
Peroxisome Proliferator ◽  
Adipose Tissues ◽  
Peroxisome Proliferator Activated Receptor ◽  
Genes Encoding ◽  
Associated Proteins ◽  
High Throughput Dna Sequencing ◽  
And Function ◽  
White Fat

AbstractIn adipose tissues, nuclear receptors (NRs) have important metabolic actions on cellular lipid-storing capacity through targeted gene regulation. Lipid droplets (LDs) are the organelles for intracellular triacylglycerol (TAG) storage and are present in all eukaryotic cells. They are small in most cells, but in white adipocytes, they can occupy 90% of the cytoplasm. LDs consist of a TAG core surrounded by a phospholipid monolayer and an array of associated proteins that determine size, stability, inter-droplet interaction, and lipid storage capacity. The genes that encode these proteins are more highly expressed in brown compared with white fat, correlating with the greater LD surface area in multilocular brown adipocytes. Gene expression profiling reveals that most NRs are present in adipose tissues, with some showing greater expression in brown compared with white fat, including peroxisome proliferator-activated receptor (PPAR) α, estrogen-related receptor α, and NURR1. NR signaling is important for the regulated expression of most genes that encode LD-associated proteins. For example, estradiol signals via estrogen receptor α to regulate the levels of PLIN1 and the lipase ATGL controlling LD size and total lipid accumulation. PPARγ is essential for adipocyte differentiation and function, and analysis of data obtained through chromatin immunoprecipitation followed by high-throughput DNA sequencing shows that it binds to the promoters of many genes encoding LD proteins in adipocytes. Of these genes, the greatest PPARγ binding was to regulatory regions for

scholarly journals Ageing in Pgc-1β−/− mice modelling mitochondrial dysfunction induces differential expression of a range of genes regulating ventricular electrophysiology

2019 ◽  
Vol 39 (4) ◽  
Author(s):  
Charlotte E. Edling ◽  
Ibrahim T. Fazmin ◽  
Karan R. Chadda ◽  
Shiraz Ahmad ◽  
Haseeb Valli ◽  
...  
Keyword(s):  
Membrane Potential ◽  
Mitochondrial Dysfunction ◽  
Molecular Mechanisms ◽  
Metabolic Diseases ◽  
Resting Membrane Potential ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Camp Pathway ◽  
Pacemaker Channel ◽  
Genes Encoding

Abstract Mice deficient in mitochondrial promoter peroxisome proliferator activated receptor-γ co-activator-1β (Pgc-1β−/−) is a valuable model for metabolic diseases and has been found to present with several pathologies including ventricular arrhythmia. In the present study, our aim was to shed light on the molecular mechanisms behind the observed arrhythmic substrate by studying how the expression of selected genes critical for cardiac function differs in wild-type (WT) compared with Pgc-1β knockout mice and young compared with aged mice. We found that a clear majority of genes are down-regulated in the Pgc-1β−/− ventricular tissue compared with the WT. Although most individual genes are not significantly differentially expressed, a pattern is apparent when the genes are grouped according to their functional properties. Genes encoding proteins relating to ATPase activity, potassium ion channels relating to repolarisation and resting membrane potential, and genes encoding proteins in the cAMP pathway are found to be significantly down-regulated in the Pgc-1β deficient mice. On the contrary, the pacemaker channel genes Hcn3 and Hcn4 are up-regulated in subsets of the Pgc-1β deficient tissue. Furthermore, we found that with age, especially in the Pgc-1β−/− genotype, most genes are up-regulated including genes relating to the resting membrane potential, calcium homeostasis, the cAMP pathway, and most of the tested adrenoceptors. In conclusion, we here demonstrate how a complex pattern of many modest changes at gene level may explain major functional differences of the action potential related to ageing and mitochondrial dysfunction.

scholarly journals Tributyltin induces a transcriptional response without a brite adipocyte signature in adipocyte models

2018 ◽  
Author(s):  
Stephanie Kim ◽  
Amy Li ◽  
Stefano Monti ◽  
Jennifer J. Schlezinger
Keyword(s):  
Gene Expression ◽  
Mitochondrial Biogenesis ◽  
Adipocyte Differentiation ◽  
Metabolic Effects ◽  
Pathway Enrichment Analysis ◽  
Peroxisome Proliferator ◽  
Multipotent Mesenchymal Stromal Cell ◽  
Data Set ◽  
Peroxisome Proliferator Activated Receptor ◽  
L1 Data

AbstractTributyltin (TBT), a peroxisome proliferator-activated receptor γ (PPARγ)/retinoid X receptor (RXR) ligand and founding member of the environmental obesogen chemical class, induces adipocyte differentiation and suppresses bone formation. A growing number of environmental PPARγ ligands are being identified. However, the potential for environmental PPARγ ligands to induce adverse metabolic effects has been questioned because PPARγ is a therapeutic target in treatment of type II diabetes. We evaluated the molecular consequences of TBT exposure during bone marrow multipotent mesenchymal stromal cell (BM-MSC) differentiation in comparison to rosiglitazone, a therapeutic PPARγ ligand, and LG100268, a synthetic RXR ligand. Mouse primary BM-MSCs (female, C57BL/6J) undergoing bone differentiation were exposed to maximally efficacious and human relevant concentrations of rosiglitazone (100 nM), LG100268 (100 nM) or TBT (80 nM) for 4 days. Gene expression was assessed using microarrays, and in silico functional annotation was performed using pathway enrichment analysis approaches. Pathways related to osteogenesis were downregulated by all three ligands, while pathways related to adipogenesis were upregulated by rosiglitazone and TBT. However, pathways related to mitochondrial biogenesis and brown-in-white (brite) adipocyte differentiation were more significantly upregulated in rosiglitazone-treated than TBT-treated cells. The lack of induction of genes involved in adipocyte energy dissipation by TBT was confirmed by an independent gene expression analysis in BM-MSCs undergoing adipocyte differentiation and by analysis of a publically available 3T3 L1 data set. Furthermore, rosiglitazone, but not TBT, induced mitochondrial biogenesis. This study is the first to show that an environmental PPARγ ligand has a limited capacity to induce health promoting activities of PPARγ.

The emerging role of COX-2, 15-LOX, and PPARγ in metabolic diseases and cancer: An introduction to novel multi-target directed ligands (MTDLs)

2020 ◽  
Vol 27 ◽  
Author(s):  
Rana A. Alaaeddine ◽  
Perihan A. Elzahhar ◽  
Ibrahim AlZaim ◽  
Wassim Abou-Kheir ◽  
Ahmed S.F. Belal ◽  
...  
Keyword(s):  
Metabolic Diseases ◽  
Biological Effects ◽  
Arachidonic Acid Metabolism ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Cellular Targets ◽  
Design And Synthesis ◽  
Early Results ◽  
Cox 2

: Emerging evidence supports an intertwining framework for the involvement of different inflammatory pathways in a common pathological background for a number of disorders. Of importance are pathways involving arachidonic acid metabolism by cyclooxygenase-2 (COX-2) and 15-lipoxygenase (15-LOX). Both enzyme activities and their products are implicated in a range of pathophysiological processes encompassing metabolic impairment leading to adipose inflammation and the subsequent vascular and neurological disorders, in addition to various pro-and anti-tumorigenic effects. A further layer of complexity is encountered by the disparate, and often reciprocal, modulatory effect COX-2 and 15-LOX activities and metabolites exert on each other or on other cellular targets, the most prominent of which is peroxisome proliferator-activated receptor gamma (PPARγ). Thus, effective therapeutic intervention with such multifaceted disorders requires the simultaneous modulation of more than one target. Here, we describe the role of COX-2, 15-LOX, and PPARγ in cancer and complications of metabolic disorders, highlight the value of designing multi-target directed ligands (MTDLs) modifying their activity, and summarize the available literature regarding the rationale and feasibility of design and synthesis of these ligands together with their known biological effects. We speculate on the potential impact of MTDLs in these disorders as well as emphasize the need for structured future effort to translate these early results facilitating the adoption of these, and similar, molecules in clinical research.

scholarly journals PPAR-gamma induced AKT3 expression increases levels of mitochondrial biogenesis driving prostate cancer

Oncogene ◽  
2021 ◽  
Vol 40 (13) ◽  
pp. 2355-2366
Author(s):  
Laura C. A. Galbraith ◽  
Ernest Mui ◽  
Colin Nixon ◽  
Ann Hedley ◽  
David Strachan ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Mitochondrial Biogenesis ◽  
Nuclear Export ◽  
Epithelial To Mesenchymal Transition ◽  
Ppar Gamma ◽  
Peroxisome Proliferator ◽  
Serine Threonine Kinase ◽  
Peroxisome Proliferator Activated Receptor ◽  
Mesenchymal Transition ◽  
And Function

AbstractPeroxisome Proliferator-Activated Receptor Gamma (PPARG) is one of the three members of the PPAR family of transcription factors. Besides its roles in adipocyte differentiation and lipid metabolism, we recently demonstrated an association between PPARG and metastasis in prostate cancer. In this study a functional effect of PPARG on AKT serine/threonine kinase 3 (AKT3), which ultimately results in a more aggressive disease phenotype was identified. AKT3 has previously been shown to regulate PPARG co-activator 1 alpha (PGC1α) localisation and function through its action on chromosome maintenance region 1 (CRM1). AKT3 promotes PGC1α localisation to the nucleus through its inhibitory effects on CRM1, a known nuclear export protein. Collectively our results demonstrate how PPARG over-expression drives an increase in AKT3 levels, which in turn has the downstream effect of increasing PGC1α localisation within the nucleus, driving mitochondrial biogenesis. Furthermore, this increase in mitochondrial mass provides higher energetic output in the form of elevated ATP levels which may fuel the progression of the tumour cell through epithelial to mesenchymal transition (EMT) and ultimately metastasis.

The Protective Mechanism of SIRT1 in the Regulation of Mitochondrial Biogenesis and Mitochondrial Autophagy in Alzheimer’s Disease

2021 ◽  
pp. 1-9
Author(s):  
Fan Ye ◽  
Anshi Wu
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mitochondrial Biogenesis ◽  
Stress Responses ◽  
Histone Deacetylases ◽  
Neuronal Morphology ◽  
Protective Mechanism ◽  
Peroxisome Proliferator ◽  
Class Iii ◽  
Peroxisome Proliferator Activated Receptor

Silent information-regulated transcription factor 1 (SIRT1) is the most prominent and widely studied member of the sirtuins (a family of mammalian class III histone deacetylases). It is a nuclear protein, and the deacetylation of the peroxisome proliferator-activated receptor coactivator-1 has been extensively implicated in metabolic control and mitochondrial biogenesis and is the basis for studies into its involvement in caloric restriction and its effects on lifespan. The present study discusses the potentially protective mechanism of SIRT1 in the regulation of the mitochondrial biogenesis and autophagy involved in the modulation of Alzheimer’s disease, which may be correlated with the role of SIRT1 in affecting neuronal morphology, learning, and memory during development; regulating metabolism; counteracting stress responses; and maintaining genomic stability. Drugs that activate SIRT1 may offer a promising approach to treating Alzheimer’s disease

scholarly journals Cannabis sativa L. as a Natural Drug Meeting the Criteria of a Multitarget Approach to Treatment

2021 ◽  
Vol 22 (2) ◽  
pp. 778
Author(s):  
Anna Stasiłowicz ◽  
Anna Tomala ◽  
Irma Podolak ◽  
Judyta Cielecka-Piontek
Keyword(s):  
Pharmacological Activity ◽  
Transient Receptor Potential ◽  
Cannabis Sativa ◽  
Current Knowledge ◽  
Endocannabinoid System ◽  
Receptor Potential ◽  
Transient Receptor Potential Channels ◽  
Raw Material ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor

Cannabis sativa L. turned out to be a valuable source of chemical compounds of various structures, showing pharmacological activity. The most important groups of compounds include phytocannabinoids and terpenes. The pharmacological activity of Cannabis (in epilepsy, sclerosis multiplex (SM), vomiting and nausea, pain, appetite loss, inflammatory bowel diseases (IBDs), Parkinson’s disease, Tourette’s syndrome, schizophrenia, glaucoma, and coronavirus disease 2019 (COVID-19)), which has been proven so far, results from the affinity of these compounds predominantly for the receptors of the endocannabinoid system (the cannabinoid receptor type 1 (CB1), type two (CB2), and the G protein-coupled receptor 55 (GPR55)) but, also, for peroxisome proliferator-activated receptor (PPAR), glycine receptors, serotonin receptors (5-HT), transient receptor potential channels (TRP), and GPR, opioid receptors. The synergism of action of phytochemicals present in Cannabis sp. raw material is also expressed in their increased bioavailability and penetration through the blood–brain barrier. This review provides an overview of phytochemistry and pharmacology of compounds present in Cannabis extracts in the context of the current knowledge about their synergistic actions and the implications of clinical use in the treatment of selected diseases.

scholarly journals Progressive Reduction in Mitochondrial Mass Is Triggered by Alterations in Mitochondrial Biogenesis and Dynamics in Chronic Kidney Disease Induced by 5/6 Nephrectomy

Biology ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 349
Author(s):  
Rodrigo Prieto-Carrasco ◽  
Fernando E. García-Arroyo ◽  
Omar Emiliano Aparicio-Trejo ◽  
Pedro Rojas-Morales ◽  
Juan Carlos León-Contreras ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Mitochondrial Biogenesis ◽  
Renal Mass ◽  
Renal Damage ◽  
Peroxisome Proliferator ◽  
Progressive Reduction ◽  
Ckd Progression ◽  
Peroxisome Proliferator Activated Receptor ◽  
Mitochondrial Mass ◽  
Mitochondrial Impairment

The five-sixth nephrectomy (5/6Nx) model is widely used to study the mechanisms involved in chronic kidney disease (CKD) progression. Mitochondrial impairment is a critical mechanism that favors CKD progression. However, until now, there are no temporal studies of the change in mitochondrial biogenesis and dynamics that allow determining the role of these processes in mitochondrial impairment and renal damage progression in the 5/6Nx model. In this work, we determined the changes in mitochondrial biogenesis and dynamics markers in remnant renal mass from days 2 to 28 after 5/6Nx. Our results show a progressive reduction in mitochondrial biogenesis triggered by reducing two principal regulators of mitochondrial protein expression, the peroxisome proliferator-activated receptor-gamma coactivator 1-alpha and the peroxisome proliferator-activated receptor alpha. Furthermore, the reduction in mitochondrial biogenesis proteins strongly correlates with the increase in renal damage markers. Additionally, we found a slow and gradual change in mitochondrial dynamics from fusion to fission, favoring mitochondrial fragmentation at later stages after 5/6Nx. Together, our results suggest that 5/6Nx induces the progressive reduction in mitochondrial mass over time via the decrease in mitochondrial biogenesis factors and a slow shift from mitochondrial fission to fusion; both mechanisms favor CKD progression in the remnant renal mass.

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