DOCSLIB.ORG

The Impact of Skeletal Muscle Erα on Mitochondrial Function And

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text

Load more

Copyedited by: oup MINI REVIEW The Impact of Skeletal Muscle ERα on Mitochondrial Function and Metabolic Health Downloaded from https://academic.oup.com/endo/article-abstract/161/2/bqz017/5735479 by University of Southern California user on 19 February 2020 Andrea L. Hevener1,2, Vicent Ribas1, Timothy M. Moore1, and Zhenqi Zhou1 1David Geffen School of Medicine, Department of Medicine, Division of Endocrinology, Diabetes, and Hypertension, University of California, Los Angeles, California 90095; and 2Iris Cantor-UCLA Women’s Health Research Center, University of California, Los Angeles, California 90095 ORCiD numbers: 0000-0003-1508-4377 (A. L. Hevener). The incidence of chronic disease is elevated in women after menopause. Increased expression of ESR1 (the gene that encodes the estrogen receptor alpha, ERα) in muscle is highly associated with metabolic health and insulin sensitivity. Moreover, reduced muscle expression levels of ESR1 are observed in women, men, and animals presenting clinical features of the metabolic syndrome (MetSyn). Considering that metabolic dysfunction elevates chronic disease risk, including type 2 diabetes, heart disease, and certain cancers, treatment strategies to combat metabolic dysfunction and associated pathologies are desperately needed. This review will provide published work supporting a critical and protective role for skeletal muscle ERα in the regulation of mitochondrial function, metabolic homeostasis, and insulin action. We will provide evidence that muscle-selective targeting of ERα may be effective for the preservation of mitochondrial and metabolic health. Collectively published findings support a compelling role for ERα in the control of muscle metabolism via its regulation of mitochondrial function and quality control. Studies identifying ERα-regulated pathways essential for disease prevention will lay the important foundation for the design of novel therapeutics to improve metabolic health of women while limiting secondary complications that have historically plagued traditional hormone replacement interventions. (Endocrinology 161: 1–16, 2020) Key Words: estradiol action, estrogen receptor alpha, mitochondrial function, skeletal muscle metabolism, metabolic health or over 2 decades researchers have shown strong re- lationships between estrogen action and metabolic Abbreviations: AMP 5′, adenosine monophosphate; AMPK, 5′ adenosine F monophosphate-activated protein kinase; AF1, activation function 1; AF2, ac- health in women. Moreover, epidemiological reports in- tivation function 2; AP1, activation protein 1; COX1, mitochondrial cytochrome dicate that chronic disease incidence increases in women C oxidase 1; Cyp19, aromatase cytochrome p450; DBD, DNA binding domain; Drp1, dynamin related protein 1; E2, estradiol; ER, estrogen receptor; ERE, es- following menopause. Considering that menopause trogen response element; ERK, extracellular signal regulated kinase; Esr1, mouse occurs on average at age 51 (www.nia.nih.gov), and gene encoding the estrogen receptor alpha; FABP, fatty acid binding protein; FAT/ CD36, plasma membrane inducible long chain fatty acid translocase shown to that life expectancy has increased for white females to transport fatty acids to the mitochondria; Foxo, subgroup of the forkhead fam- ~81.1 years (National Vital Statistics Reports, 2019) (1), ily of transcription factors with a conserved forkhead box, DNA-binding domain; GPCR, G-protein coupled receptors; GPER, G protein-coupled estrogen receptor; women in the modern era are challenged with height- HRT, hormone replacement therapy; KD, knockdown; KO, knockout; LBD, lig- ened disease risk associated with increasing adiposity and binding domain; mt, mitochondrial; MAPK, mitogen-activated protein kin- ase; MEF2, myocyte enhancer factor 2; MERKO, muscle specific ERα knockout; and metabolic dysfunction for up to 3 decades of life. MetSyn, Metabolic Syndrome; Mfn, Mitochrondrial mitofusin; MNAR, modulator Although many researchers and clinicians have focused of nongenomic estrogen receptors; mt, mitochondrial; OPA1, optic atrophy 1; on the impact of replacement estrogens to ameliorate OVX, ovariectomized; PI3K, phosphoinositide 3-kinase; PKA, protein kinase A; PPAR, peroxisome proliferator activated receptor; PolG, heterodimeric enzyme polymerase gamma that controls mtDNA replication; Polg1, the gene that en- ISSN Online 1945-7170 codes the catalytic subunit of the mtDNA polymerase PolG; Rcan1, regulator of calcineurin 1, a phosphatase that (among many functions) controls Drp1 action Published by Oxford University Press on behalf of the Endocrine Society 2020. and mitochondrial fission; ROS, reactive oxygen species; RR, relative risk; SF1, Received 18 May 2019. Accepted 11 February 2020. steroidogenic factor 1; T2D, type 2 diabetes mellitus; TFAM, mitochondrial tran- First Published Online 13 February 2020. scription factor A; UCP, uncoupling protein Corrected and Typeset 13 February 2020. doi: 10.1210/endocr/bqz017 Endocrinology, February 2020, 161(2):1–16 https://academic.oup.com/endo 1 Copyedited by: oup 2 Hevener et al ERα on Mitochondrial Function and Metabolic Health Endocrinology, February 2020, 161(2):1–16 clinical symptoms and provide protective health benefit, that the ERα form, ERα (encoded by the gene ESR1), is an incomplete understanding of hormone action as an important target to combat metabolic dysfunction by well as estrogen receptor distribution and function has enhancing mitochondrial metabolism. contributed to our continued confusion and failure to advance therapeutic strategies to combat chronic Molecular Mechanisms of Estrogen Downloaded from https://academic.oup.com/endo/article-abstract/161/2/bqz017/5735479 by University of Southern California user on 19 February 2020 disease-associated pathologies for women. Receptor Action Regarding the benefits of exogenous hormone re- placement therapy (HRT) on diabetes risk after meno- Phylogenetic analysis of steroid receptors in basal verte- pause, large randomized clinical trials of postmenopausal brates and reconstruction of the sequences and functional estrogen-based HRT compared with placebo and pro- attributes of ancestral proteins led to the conclusion that spective cohort studies have shown reductions in fasting the primordial steroid receptor was an ER (9). Early glucose, insulin, and incidence of new-onset type 2 dia- studies in reproductive tissues investigating the actions betes (T2D) (2–7). Meta-analyses indicate a 30% lower of estradiol led to the paradigm of classical nuclear ERs relative risk (RR 0.7 [CI, 0.6–0.9]) of new-onset T2D in as ligand-activated transcription factors (10). ERs exist postmenopausal women following HRT compared with in two main forms, α and β, with multiple splice variants placebo (8). The mechanism by which HRT reduces T2D of unknown function. ERs exhibit tissue specificity in incidence in postmenopausal women is not yet known; expression and function, and determination of receptor however, molecular studies in rodents indicate that this specificity is an area of intense investigation (11). The protective effect may be achieved in part as a consequence classical, or genomic mechanism of ER action, describes of estrogen-induced insulin-sensitization. Considering a scenario whereby the ligand-activated ER dissociates that 75% to 85% of insulin-stimulated glucose disposal from its chaperone and binds as a dimer either directly is into skeletal muscle and since skeletal muscle typically to estrogen response elements (EREs) in target genes represents 30% to 40% of total body mass, we have fo- promoters or indirectly to AP-1 or SP-1 response elem- cused our efforts in understanding the effects of estradiol/ ents through protein tethering association with other estrogen receptor (ER) α action in this tissue. transcription factors to DNA (12) (Fig. 1). Overlap in Since insulin resistance and metabolic dysfunction are binding sites for E2-liganded ERα and ERβ is observed identified as major underpinnings in the pathobiology when receptors are expressed individually; however, of chronic diseases that plague our society, in this review when both ERs are present, few sites are shared. Each we will present studies related to the biological actions ER restricts the binding site occupancy of the other, of estradiol and estrogen receptors on mitochondrial with ERα typically dominating (13). Moreover, ligand- function in skeletal muscle, and the impact of these bio- activated ERs promote transcription in a cyclic fashion. logical actions exert on glucose homeostasis and insulin The repeated cycling of the receptor complex on and sensitivity. We will present basic research suggesting off target promoters in the presence of continuous E2 Figure 1. Molecular actions of ERα to activate or repress target genes by classical DNA binding, non-ERE genomic action, or non-genomic actions. ERE, estrogen response element in target gene promoters; P, phosphorylation; TF, transcription factor. Copyedited by: oup doi: 10.1210/endocr/bqz017 https://academic.oup.com/endo 3 stimulation may represent a mechanism of continuous sensing and adaptation to the external hormonal milieu to yield the appropriate transcriptional response (14). In addition to classical signaling, E2-ERα can act within seconds to minutes via extranuclear and Downloaded from https://academic.oup.com/endo/article-abstract/161/2/bqz017/5735479 by University of Southern California user on 19 February 2020 membrane-associated forms of the receptor (15) (Fig. 1). Membrane-associated
Recommended publications
  • Rep 467 Morrish & Sinclair

    Rep 467 Morrish & Sinclair

    Reproduction (2002) 124, 447–457 Review Vertebrate sex determination: many means to an end Bronwyn C. Morrish and Andrew H. Sinclair* Murdoch Children’s Research Institute, Royal Children’s Hospital, Flemington Rd, Melbourne, Victoria 3052, Australia The differentiation of a testis or ovary from a bipotential gonadal primordium is a develop- mental process common to mammals, birds and reptiles. Since the discovery of SRY, the Y-linked testis-determining gene in mammals, extensive efforts have failed to find its orthologue in other vertebrates, indicating evolutionary plasticity in the switch that triggers sex determination. Several other genes are known to be important for sex determination in mammals, such as SOX9, AMH, WT1, SF1, DAX1 and DMRT1. Analyses of these genes in humans with gonadal dysgenesis, mouse models and using in vitro cell culture assays have revealed that sex determination results from a complex interplay between the genes in this network. All of these genes are conserved in other vertebrates, such as chickens and alligators, and show gonad-specific expression in these species during the period of sex determination. Intriguingly, the sequence, sex specificity and timing of expression of some of these genes during sex determination differ among species. This finding indicates that the interplay between genes in the regulatory network leading to gonad development differs between vertebrates. However, despite this, the development of a testis or ovary from a bipotential gonad is remarkably similar across vertebrates. The existence of two sexes is nearly universal in the animal and alligators. Ectopic administration of oestrogen or kingdom and although gonadal morphogenesis is remark- inhibitors of oestrogen synthesis during a critical period of ably similar across vertebrates, the sex-determining mecha- gonadogenesis in chickens and alligators can feminize or nism varies considerably.
  • Mutant P53 Protects Cells from 12-O-Tetradecanoylphorbol-13- Acetate–Induced Death by Attenuatingactivating Transcription Factor 3 Induction

    Mutant P53 Protects Cells from 12-O-Tetradecanoylphorbol-13- Acetate–Induced Death by Attenuatingactivating Transcription Factor 3 Induction

    Research Article Mutant p53 Protects Cells from 12-O-Tetradecanoylphorbol-13- Acetate–Induced Death by AttenuatingActivating Transcription Factor 3 Induction Yosef Buganim,1 Eyal Kalo,1 Ran Brosh,1 Hila Besserglick,1 Ido Nachmany,3 Yoach Rais,2 Perry Stambolsky,1 Xiaohu Tang,1 Michael Milyavsky,1 Igor Shats,1 Marina Kalis,1 Naomi Goldfinger,1 and Varda Rotter1 1Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel; 2Department of Life Science, Bar-Ilan University, Ramat Gan, Israel; and 3Department of General Surgery B, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel Abstract mutated. Notably, the predominant mode of p53 inactivation is by Mutations in p53 are ubiquitous in human tumors. Some p53 point mutation rather than by deletion or truncation. These data mutations not only result in loss of wild-type (WT) activity but coupled with the observation that mutant p53 is generally highly also grant additional functions, termed ‘‘gain of function.’’ overexpressed in tumors have led to the hypothesis that mutant In this study, we explore how the status of p53 affects the p53 possesses gain-of-function activities. This hypothesis is immediate response gene activating transcription factor 3 supported by the results of in vivo and in vitro studies. For (ATF3) in the 12-O-tetradecanoylphorbol-13-acetate (TPA)- example, mice harboring mutant p53 display allele-specific tumor protein kinase C (PKC) pathway. We show that high doses of spectra, higher metastatic frequency, enhanced cell proliferation, TPA induce ATF3 in a WT p53-independent manner correlat- and higher transformation potential compared with their p53-null ingwith PKCs depletion and cell death.
  • Action on Muscle Metabolism and Insulin Sensitivity E Strong Enough for a Man, Made for a Woman

    Action on Muscle Metabolism and Insulin Sensitivity E Strong Enough for a Man, Made for a Woman

    Review The impact of ERa action on muscle metabolism and insulin sensitivity e Strong enough for a man, made for a woman Andrea L. Hevener*, Zhenqi Zhou, Timothy M. Moore, Brian G. Drew, Vicent Ribas ABSTRACT Background: The incidence of chronic disease is elevated in women after menopause. Natural variation in muscle expression of the estrogen receptor (ER)a is inversely associated with plasma insulin and adiposity. Moreover, reduced muscle ERa expression levels are observed in women and animals presenting clinical features of the metabolic syndrome (MetSyn). Considering that metabolic dysfunction impacts nearly a quarter of the U.S. adult population and elevates chronic disease risk including type 2 diabetes, heart disease, and certain cancers, treatment strategies to combat metabolic dysfunction and associated pathologies are desperately needed. Scope of the review: This review will provide evidence supporting a critical and protective role for skeletal muscle ERa in the regulation of metabolic homeostasis and insulin sensitivity, and propose novel ERa targets involved in the maintenance of metabolic health. Major conclusions: Studies identifying ERa-regulated pathways essential for disease prevention will lay the important foundation for the rational design of novel therapeutics to improve the metabolic health of women while limiting secondary complications that have plagued traditional hormone replacement interventions. Ó 2018 Published by Elsevier GmbH. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Keywords Estrogen action; Estrogen receptors; Insulin sensitivity; Metabolic homeostasis 1. INTRODUCTION new-onset T2DM in postmenopausal women following HRT compared with placebo [7]. The mechanism by which HRT reduces T2D incidence For over two decades researchers have shown strong relationships in postmenopausal women is not yet known however molecular between estrogen action and metabolic health in women.
  • An Autoregulatory Loop Controls Peroxisome Proliferator-Activated Receptor Γ Coactivator 1Α Expression in Muscle

    An Autoregulatory Loop Controls Peroxisome Proliferator-Activated Receptor Γ Coactivator 1Α Expression in Muscle

    Institutional Repository of the University of Basel University Library Schoenbeinstrasse 18-20 CH-4056 Basel, Switzerland http://edoc.unibas.ch/ Year: 2003 An autoregulatory loop controls peroxisome proliferator-activated receptor γ coactivator 1α expression in muscle Handschin, C. and Rhee, J. and Lin, J. and Tarr, P. T. and Spiegelman, B. M. Posted at edoc, University of Basel Official URL: http://edoc.unibas.ch/dok/A5258732 Originally published as: Handschin, C. and Rhee, J. and Lin, J. and Tarr, P. T. and Spiegelman, B. M.. (2003) An autoregulatory loop controls peroxisome proliferator-activated receptor γ coactivator 1α expression in muscle. Proceedings of the National Academy of Sciences of the United States of America, Vol. 100, H. 12. S. 7111-7116. An Autoregulatory Loop Controls PGC-1 Expression in Muscle Christoph Handschin, James Rhee, Jiandie Lin, Paul T. Tarr, and Bruce M. Spiegelman* Dana-Farber Cancer Institute and Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115 Published in Proc Natl Acad Sci U S A. 2003 Jun 10;100(12):7111-6. PMID: 12764228. doi: 10.1073/pnas.1232352100 Copyright © National Academy of Sciences; Proceedings of the National Academy of Sciences USA Page 1 of 24 Classification: Biological Sciences, Cell Biology An Autoregulatory Loop Controls PGC-1 Expression in Muscle Christoph Handschin, James Rhee, Jiandie Lin, Paul T. Tarr, and Bruce M. Spiegelman* Dana-Farber Cancer Institute and Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115 * To whom
  • Analysis of the Gene Coding for Steroidogenic Factor 1 (SF1, NR5A1) in a Cohort of 50 Egyptian Patients with 46,XY Disorders of Sex Development

    Analysis of the Gene Coding for Steroidogenic Factor 1 (SF1, NR5A1) in a Cohort of 50 Egyptian Patients with 46,XY Disorders of Sex Development

    S Tantawy and others SF1 in Egyptians with 46,XY DSD 170:5 759–767 Clinical Study Analysis of the gene coding for steroidogenic factor 1 (SF1, NR5A1) in a cohort of 50 Egyptian patients with 46,XY disorders of sex development Sally Tantawy1,2, Inas Mazen2, Hala Soliman3, Ghada Anwar4, Abeer Atef4, Mona El-Gammal2, Ahmed El-Kotoury2, Mona Mekkawy5, Ahmad Torky2, Agnes Rudolf1, Pamela Schrumpf1, Annette Gru¨ ters1, Heiko Krude1, Marie-Charlotte Dumargne6, Rebekka Astudillo1, Anu Bashamboo6, Heike Biebermann1 and Birgit Ko¨ hler1 1Institute of Experimental Paediatric Endocrinology, University Children’s Hospital, Charite´ , Humboldt University, Correspondence Berlin, Germany, 2Department of Clinical Genetics and 3Department of Medical Molecular Genetics, Division of should be addressed Human Genetics and Genome Research, National Research Centre, Cairo, Egypt, 4Department of Paediatrics, to S Tantawy Cairo University, Cairo, Egypt, 5Department of Cytogenetics, Division of Human Genetics and Genome Research, Email National Research Centre, Cairo, Egypt and 6Human Developmental Genetics, Institut Pasteur, Paris, France [email protected] Abstract Objective: Steroidogenic factor 1 (SF1, NR5A1) is a key transcriptional regulator of genes involved in the hypothalamic– pituitary–gonadal axis. Recently, SF1 mutations were found to be a frequent cause of 46,XY disorders of sex development (DSD) in humans. We investigate the frequency of NR5A1 mutations in an Egyptian cohort of XY DSD. Design: Clinical assessment, endocrine evaluation and genetic analysis of 50 Egyptian XY DSD patients (without adrenal insufficiency) with a wide phenotypic spectrum. Methods: Molecular analysis of NR5A1 gene by direct sequencing followed by in vitro functional analysis of the European Journal of Endocrinology two novel missense mutations detected.
  • Global Mef2 Target Gene Analysis in Skeletal and Cardiac Muscle

    Global Mef2 Target Gene Analysis in Skeletal and Cardiac Muscle

    GLOBAL MEF2 TARGET GENE ANALYSIS IN SKELETAL AND CARDIAC MUSCLE STEPHANIE ELIZABETH WALES A DISSERTATION SUBMITTED TO THE FACULTY OF GRADUATE STUDIES IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY GRADUATE PROGRAM IN BIOLOGY YORK UNIVERSITY TORONTO, ONTARIO FEBRUARY 2016 © Stephanie Wales 2016 ABSTRACT A loss of muscle mass or function occurs in many genetic and acquired pathologies such as heart disease, sarcopenia and cachexia which are predominantly found among the rapidly increasing elderly population. Developing effective treatments relies on understanding the genetic networks that control these disease pathways. Transcription factors occupy an essential position as regulators of gene expression. Myocyte enhancer factor 2 (MEF2) is an important transcription factor in striated muscle development in the embryo, skeletal muscle maintenance in the adult and cardiomyocyte survival and hypertrophy in the progression to heart failure. We sought to identify common MEF2 target genes in these two types of striated muscles using chromatin immunoprecipitation and next generation sequencing (ChIP-seq) and transcriptome profiling (RNA-seq). Using a cell culture model of skeletal muscle (C2C12) and primary cardiomyocytes we found 294 common MEF2A binding sites within both cell types. Individually MEF2A was recruited to approximately 2700 and 1600 DNA sequences in skeletal and cardiac muscle, respectively. Two genes were chosen for further study: DUSP6 and Hspb7. DUSP6, an ERK1/2 specific phosphatase, was negatively regulated by MEF2 in a p38MAPK dependent manner in striated muscle. Furthermore siRNA mediated gene silencing showed that MEF2D in particular was responsible for repressing DUSP6 during C2C12 myoblast differentiation. Using a p38 pharmacological inhibitor (SB 203580) we observed that MEF2D must be phosphorylated by p38 to repress DUSP6.
  • The Repression of MEF2 Transcription Factors Exerted by Class Iia Hdacs

    The Repression of MEF2 Transcription Factors Exerted by Class Iia Hdacs

    81,9(56,7<2)8',1( BBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBB 3K'Course in Biomedical Sciences and Biotechnology ;;9,,&<&/( THE REPRESSION OF MEF2 TRANSCRIPTION FACTORS EXERTED BY CLASS IIA HDACS AND THEIR DEGRADATION STIMULATED BY CDK4 DETERMINE THE ACQUISITION OF HALLMARKS OF TRANSFORMATION IN FIBROBLASTS. 3K'6WXGHQW'L*LRUJLR(URV 7XWRUSURI&ODXGLR%UDQFROLQL (URV'L*LRUJLR To my family, Sara and those who believe in the research against cancer ABSTRACT 1 RIASSUNTO 2 INTRODUCTION 3 1. The HDACs world 3 2. Class IIa HDACs: similarities and differences between class IIa and class I HDACs 4 3. Class IIa HDACs: HDACs with orphan substrates or missed during evolution? 7 4. Pathways of regulation 10 a) regulation of class IIa HDACs transcription and modulation of the stability of the messengers (RNAi) 10 b) sub-cellular localization 11 5. Partners and biological functions 20 6. Class IIa HDACs as regulators of proliferation and cancer 28 7. MEF2 family of transcription factors 37 8. On the molecular basis of the MEF2-Class IIa HDACs axis: structure of MEF2/DNA, MEF2/Cabin1/DNA, MEF2/HDAC9/DNA and MEF2/DNA/p300 complexes. 38 9. Pathways of regulation 40 a) binding to repressors and co-activators 41 b) post-translational modifications 42 c) regulation of MEF2s transcription and modulation of the stability of the messengers (RNAi) 49 d) regulation of protein stability 51 10. Main functional roles 53 11. MEF2 as a regulator of differentiation programs 54 12. A lesson from the study of the knock-outs. 56 The role of MEF2s and of the MEF2-class IIa HDACs axis in myogenesis 57 The role of MEF2 TFs in cardiomyogenesis 59 The role of MEF2 TFs and of the MEF2-class IIa HDACs axis in endochondral bone ossification 59 The role of MEF2s and of the MEF2-class IIa HDACs axis in vasculogenesis and differentiation of vascular smooth muscle cells 60 The role of MEF2 TFs in neuronal development 60 The role of MEF2s in hematopoiesis and T cell development 61 The role of MEF2s in melanogenesis 62 The role of MEF2s in neural crest development 62 1.
  • The Function of the MEF2 Family of Transcription Factors in Cardiac Development, Cardiogenomics, and Direct Reprogramming

    The Function of the MEF2 Family of Transcription Factors in Cardiac Development, Cardiogenomics, and Direct Reprogramming

    Journal of Cardiovascular Development and Disease Review The Function of the MEF2 Family of Transcription Factors in Cardiac Development, Cardiogenomics, and Direct Reprogramming Cody A. Desjardins and Francisco J. Naya * Department of Biology, Program in Cell and Molecular Biology, Boston University, 24 Cummington Mall Boston, Boston, MA 02215, USA; [email protected] * Correspondence: [email protected]; Tel.: +1-617-353-2469; Fax: +1-617-353-6340 Academic Editors: Sean M. Wu and Neil C. Chi Received: 5 June 2016; Accepted: 8 August 2016; Published: 11 August 2016 Abstract: Proper formation of the mammalian heart requires precise spatiotemporal transcriptional regulation of gene programs in cardiomyocytes. Sophisticated regulatory networks have evolved to not only integrate the activities of distinct transcription factors to control tissue-specific gene programs but also, in many instances, to incorporate multiple members within these transcription factor families to ensure accuracy and specificity in the system. Unsurprisingly, perturbations in this elaborate transcriptional circuitry can lead to severe cardiac abnormalities. Myocyte enhancer factor–2 (MEF2) transcription factor belongs to the evolutionarily conserved cardiac gene regulatory network. Given its central role in muscle gene regulation and its evolutionary conservation, MEF2 is considered one of only a few core cardiac transcription factors. In addition to its firmly established role as a differentiation factor, MEF2 regulates wide variety of, sometimes antagonistic, cellular processes such as cell survival and death. Vertebrate genomes encode multiple MEF2 family members thereby expanding the transcriptional potential of this core transcription factor in the heart. This review highlights the requirement of the MEF2 family and their orthologs in cardiac development in diverse animal model systems.
  • The Nuclear Receptor Pparb/D Programs Muscle Glucose Metabolism in Cooperation with AMPK and MEF2

    The Nuclear Receptor Pparb/D Programs Muscle Glucose Metabolism in Cooperation with AMPK and MEF2

    Downloaded from genesdev.cshlp.org on September 23, 2021 - Published by Cold Spring Harbor Laboratory Press The nuclear receptor PPARb/d programs muscle glucose metabolism in cooperation with AMPK and MEF2 Zhenji Gan,1,3 Eileen M. Burkart-Hartman,2,3,4 Dong-Ho Han,2 Brian Finck,2 Teresa C. Leone,1,2 Emily Y. Smith,1 Julio E. Ayala,1 John Holloszy,2 and Daniel P. Kelly1,2,5 1Diabetes and Obesity Research Center, Sanford-Burnham Medical Research Institute, Orlando, Florida 32827, USA: 2Department of Medicine, Washington University School of Medicine, St. Louis, Missouri 63110, USA To identify new gene regulatory pathways controlling skeletal muscle energy metabolism, comparative studies were conducted on muscle-specific transgenic mouse lines expressing the nuclear receptors peroxisome proliferator-activated receptor a (PPARa; muscle creatine kinase [MCK]-PPARa)orPPARb/d (MCK-PPARb/d). MCK-PPARb/d mice are known to have enhanced exercise performance, whereas MCK-PPARa mice perform at low levels. Transcriptional profiling revealed that the lactate dehydrogenase b (Ldhb)/Ldha gene expression ratio is increased in MCK-PPARb/d muscle, an isoenzyme shift that diverts pyruvate into the mitochondrion for the final steps of glucose oxidation. PPARb/d gain- and loss-of-function studies in skeletal myotubes demonstrated that PPARb/d, but not PPARa, interacts with the exercise-inducible kinase AMP-activated protein kinase (AMPK) to synergistically activate Ldhb gene transcription by cooperating with myocyte enhancer factor 2A (MEF2A) in aPPARb/d ligand-independent manner. MCK-PPARb/d muscle was shown to have high glycogen stores, increased levels of GLUT4, and augmented capacity for mitochondrial pyruvate oxidation, suggesting a broad reprogram- ming of glucose utilization pathways.
  • A Primer on the Use of Mouse Models for Identifying Direct Sex Chromosome Effects That Cause Sex Differences in Non-Gonadal Tissues Paul S

    A Primer on the Use of Mouse Models for Identifying Direct Sex Chromosome Effects That Cause Sex Differences in Non-Gonadal Tissues Paul S

    Burgoyne and Arnold Biology of Sex Differences (2016) 7:68 DOI 10.1186/s13293-016-0115-5 REVIEW Open Access A primer on the use of mouse models for identifying direct sex chromosome effects that cause sex differences in non-gonadal tissues Paul S. Burgoyne1 and Arthur P. Arnold2* Abstract In animals with heteromorphic sex chromosomes, all sex differences originate from the sex chromosomes, which are the only factors that are consistently different in male and female zygotes. In mammals, the imbalance in Y gene expression, specifically the presence vs. absence of Sry, initiates the differentiation of testes in males, setting up lifelong sex differences in the level of gonadal hormones, which in turn cause many sex differences in the phenotype of non-gonadal tissues. The inherent imbalance in the expression of X and Y genes, or in the epigenetic impact of X and Y chromosomes, also has the potential to contribute directly to the sexual differentiation of non-gonadal cells. Here, we review the research strategies to identify the X and Y genes or chromosomal regions that cause direct, sexually differentiating effects on non-gonadal cells. Some mouse models are useful for separating the effects of sex chromosomes from those of gonadal hormones. Once direct “sex chromosome effects” are detected in these models, further studies are required to narrow down the list of candidate X and/or Y genes and then to identify the sexually differentiating genes themselves. Logical approaches to the search for these genes are reviewed here. Keywords: Sex determination, Sexual differentiation, Sex chromosomes, X chromosome, Y chromosome, Testosterone, Estradiol, Gonadal hormones Background complement, including differences in the parental source In animals with an unmatched (heteromorphic) pair of of the X chromosome.
  • The Role of Gata2 in Hematopoietic and Vascular Development By

    The Role of Gata2 in Hematopoietic and Vascular Development By

    The Role of Gata2 in Hematopoietic and Vascular Development by William D Brandt A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy (Cellular and Molecular Biology) in The University of Michigan 2009 Doctoral Committee: Professor James Douglas Engel, Chair Professor Eric R Fearon Professor Deborah L Gumucio Associate Professor Thomas M Glaser William D Brandt 2009 Dedication To my family, without whom this PhD would never have been possible. ii Acknowledgements The Engel lab and the University of Michigan will always have my deepest gratitude, particularly the lab’s proprietor and my thesis advisor Doug Engel, whose love of science and good nature has always been a source of inspiration. Doug has been instrumental in my growth as a nascent scientist and I will forever be indebted to him. My gratitude also goes to Kim-Chew Lim and Tomo Hosoya, whose wealth of knowledge and support were relied upon regularly. To Deb Gumucio, Tom Glaser, and Eric Fearon, whose advice and support facilitated my maturation from a naïve student to a proficient scientist – thank you. And to Lori Longeway and Kristin Hug, whose capabilities as department representatives I repeatedly put to the test; you came through for me every time. Thank you. Finally, no amount of words can express how truly grateful and indebted I am to my parents and sister – Cary, Kim, and Jenelle. I would not be in this position today without their unerring love and support. iii Table of Contents Dedication ii Acknowledgements iii List of Figures v List of Tables vi Abstract vii Chapter 1.
  • The Spectrum of Phenotypes Associated with Mutations In

    The Spectrum of Phenotypes Associated with Mutations In

    European Journal of Endocrinology (2009) 161 237–242 ISSN 0804-4643 CLINICAL STUDY The spectrum of phenotypes associated with mutations in steroidogenic factor 1 (SF-1, NR5A1, Ad4BP) includes severe penoscrotal hypospadias in 46,XY males without adrenal insufficiency Birgit Ko¨hler, Lin Lin1, Inas Mazen2, Cigdem Cetindag, Heike Biebermann, Ilker Akkurt3, Rainer Rossi4, Olaf Hiort5, Annette Gru¨ters and John C Achermann1 Department of Pediatric Endocrinology, University Children’s Hospital, Charite´, Humboldt University, Augustenburger Platz 1, 13353 Berlin, Germany, 1Developmental Endocrinology Research Group, UCL Institute of Child Health, University College London, London, UK, 2Department of Clinical Genetics, National Research Center, Cairo, Egypt, 3Children’s Hospital Altona, Hamburg, Germany, 4Children’s Hospital Neuko¨lln, Berlin, Germany and 5Division of Pediatric Endocrinology, Department of Pediatrics, University of Lu¨beck, Lu¨beck, Germany (Correspondence should be addressed to B Ko¨hler; Email: [email protected]) Abstract Objective: Hypospadias is a frequent congenital anomaly but in most cases an underlying cause is not found. Steroidogenic factor 1 (SF-1, NR5A1, Ad4BP) is a key regulator of human sex development and an increasing number of SF-1 (NR5A1) mutations are reported in 46,XY disorders of sex development (DSD). We hypothesized that NR5A1 mutations could be identified in boys with hypospadias. Design and methods: Mutational analysis of NR5A1 in 60 individuals with varying degrees of hypospadias from the German DSD network. Results: Heterozygous NR5A1 mutations were found in three out of 60 cases. These three individuals represented the most severe end of the spectrum studied as they presented with penoscrotal hypospadias, variable androgenization of the phallus and undescended testes (three out of 20 cases (15%) with this phenotype).