title: Ndrg2 is a PGC-1α/ERRα target gene that controls protein synthesis and expression of contractile-type genes in C2C12 myotubes.
abstract: The stress-responsive, tumor suppressor N-myc downstream-regulated gene 2 (Ndrg2) is highly expressed in striated muscle. In response to anabolic and catabolic signals, Ndrg2 is suppressed and induced, respectively, in mouse C2C12 myotubes. However, little is known about the mechanisms regulating Ndrg2 expression in muscle, as well as the biological role for Ndrg2 in differentiated myotubes. Here, we show that Ndrg2 is a target of a peroxisome proliferator-activated receptor-gamma coactivator-1α (PGC-1α) and estrogen-related receptor alpha (ERRα) transcriptional program and is induced in response to endurance exercise, a physiological stress known also to increase PGC-1α/ERRα activity. Analyses of global gene and protein expression profiles in C2C12 myotubes with reduced levels of NDRG2, suggest that NDRG2 affects muscle growth, contractile properties, MAPK signaling, ion and vesicle transport and oxidative phosphorylation. Indeed, suppression of NDRG2 in myotubes increased protein synthesis and the expression of fast glycolytic myosin heavy chain isoforms, while reducing the expression of embryonic myosin Myh3, other contractile-associated genes and the MAPK p90 RSK1. Conversely, enhanced expression of NDRG2 reduced protein synthesis, and furthermore, partially blocked the increased protein synthesis rates elicited by a constitutively active form of ERRα. In contrast, suppressing or increasing levels of NDRG2 did not affect mRNA expression of genes involved in mitochondrial biogenesis that are regulated by PGC-1α or ERRα. This study shows that in C2C12 myotubes Ndrg2 is a novel PGC-1α/ERRα transcriptional target, which influences protein turnover and the regulation of genes involved in muscle contraction and function.
authors.affiliation: Centre for Physical Activity and Nutrition Research, School of Exercise and Nutrition Sciences, Deakin University, Burwood 3125, Australia. Electronic address: victoria.foletta@deakin.edu.au.
authors.forename: Victoria C
authors.initials: VC
authors.lastname: Foletta
authors.affiliation: Centre for Physical Activity and Nutrition Research, School of Exercise and Nutrition Sciences, Deakin University, Burwood 3125, Australia.
authors.forename: Erin L
authors.initials: EL
authors.lastname: Brown
authors.affiliation: Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Yoshitake
authors.initials: Y
authors.lastname: Cho
authors.affiliation: Centre for Physical Activity and Nutrition Research, School of Exercise and Nutrition Sciences, Deakin University, Burwood 3125, Australia.
authors.forename: Rod J
authors.initials: RJ
authors.lastname: Snow
authors.affiliation: Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Anastasia
authors.initials: A
authors.lastname: Kralli
authors.affiliation: Centre for Physical Activity and Nutrition Research, School of Exercise and Nutrition Sciences, Deakin University, Burwood 3125, Australia.
authors.forename: Aaron P
authors.initials: AP
authors.lastname: Russell
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002460:Cell Line; D015444:Exercise; D005786:Gene Expression Regulation; D063990:Gene Ontology; D023281:Genomics; D006801:Humans; D020935:MAP Kinase Signaling System / Q000235:genetics; D051379:Mice; D063269:Mitochondrial Turnover / Q000235:genetics; D008954:Models, Biological; D009119:Muscle Contraction / Q000235:genetics*; D018485:Muscle Fibers, Skeletal / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D010807:Physical Endurance; D014176:Protein Biosynthesis / Q000235:genetics*; D011506:Proteins / Q000235:genetics* / Q000378:metabolism; D040901:Proteomics; D011960:Receptors, Estrogen / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D000097983:ERRalpha Estrogen-Related Receptor
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D011506:Proteins; D011960:Receptors, Estrogen; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D000097983:ERRalpha Estrogen-Related Receptor; C466228:NDRG2 protein, human; C485172:Ndr2 protein, mouse; C485290:Ppargc1a protein, mouse
keywords: Bioinformatics; C2C12 myotube; Estrogen-related receptor alpha (ERRα); N-myc downstream-regulated gene 2 (Ndrg2); Peroxisome proliferator-activated receptor-gamma coactivator-1α (PGC-1α); Protein synthesis