ALS-causing mutations differentially affect PGC-1alpha expression and function in the brain vs. peripheral tissues
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE77919 | GEO | 2016/11/10
SECONDARY ACCESSION(S): PRJNA312104
REPOSITORIES: GEO
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Project description:In the present study we have studied the mechanistic and functional aspects of NCoR1 function in mouse skeletal muscle. NCoR1 muscle-specific knockout mice exhibited an increased oxidative metabolism. Global gene expression analysis revealed a high overlap between the effects of NCoR1 deletion and peroxisome proliferator-activated receptor (PPAR) gamma coactivator 1alpha (PGC-1alpha) overexpression on oxidative metabolism in skeletal muscle. The repressive effect of NCoR1 on oxidative phosphorylation gene expression specifically antagonizes PGC-1alpha-mediated coactivation of ERRalpha. We therefore delineated the molecular mechanism by which a transcriptional network controlled by corepressor and coactivator proteins determines the metabolic properties of skeletal muscle, thus representing a potential therapeutic target for metabolic diseases. Gene expression of a total of 20 gastrocnemius samples from control (CON, n = 5), NCoR1 muscle-specific knockout (NCoR1 MKO, n = 5), wild type (WT, n = 5) and PGC-1alpha muscle-specific transgenic (PGC-1alpha mTg, n = 5) adult male mice was analyzed using GeneChip® Gene 1.0 ST Array System (Affymetrix). NCoR1 MKO and PGC-1alpha mTg samples were compared to CON and WT samples, respectively.
2013-01-08 | E-GEOD-40439 | biostudies-arrayexpress
Project description:We examined global gene expression patterns in response to PGC-1 expression in cells derived from liver or muscle. As our study revealed regulation of HSF1 by PGC-1alpha, in some experiments we knocked-down HSF1 using siRNAs in addition to inducing PGC-1alpha expression. Cells were grown in 24-well plates and adenoviruses encoding either GFP ("Ad-GFP"), PGC-1alpha ("Ad-PGC-1alpha") or PGC-1beta ("Ad-PGC-1beta") were directly added to the culture medium. For experiments involving siRNA transfections, cells were transfected with the indicated siRNAs 48hr prior to infection with adenoviruses encoding either GFP ("Ad-GFP") or PGC-1alpha ("Ad-PGC-1alpha").
2015-09-19 | E-GEOD-51498 | biostudies-arrayexpress
Project description:The present study examines the impact of altering energy provision on mitochondrial biogenesis in muscle cells. C2C12 myoblasts were chronically treated with supraphysiological levels of sodium pyruvate for 72 hr. Treated cells exhibited increased mitochondrial protein expression, basal respiratory rate and maximal oxidative capacity. The increase in mitochondrial biogenesis was independent of increases in PGC-1alpha and PGC-1alpha mRNA expression. To further assess whether PGC-1alpha expression was necessary for pyruvate action, cells were infected with adenovirus containing shRNA for PGC-1alpha prior to treatment with pyruvate. Despite a 70% reduction in PGC-1alpha mRNA the effect of pyruvate was preserved. Furthermore, pyruvate induced mitochondrial biogenesis in primary myoblasts from PGC-1alpha null mice. These data suggest that regulation of mitochondrial biogenesis by pyruvate in myoblasts is independent of PGC-1alpha, suggesting the existence of a novel energy-sensing pathway regulating oxidative capacity. Keywords: basal state versus treatment at one time point
2006-08-12 | GSE5497 | GEO
Project description:We examined global gene expression patterns in response to PGC-1 expression in cells derived from liver or muscle. As our study revealed regulation of HSF1 by PGC-1alpha, in some experiments we knocked-down HSF1 using siRNAs in addition to inducing PGC-1alpha expression.
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Project description:In the present study we have studied the mechanistic and functional aspects of NCoR1 function in mouse skeletal muscle. NCoR1 muscle-specific knockout mice exhibited an increased oxidative metabolism. Global gene expression analysis revealed a high overlap between the effects of NCoR1 deletion and peroxisome proliferator-activated receptor (PPAR) gamma coactivator 1alpha (PGC-1alpha) overexpression on oxidative metabolism in skeletal muscle. The repressive effect of NCoR1 on oxidative phosphorylation gene expression specifically antagonizes PGC-1alpha-mediated coactivation of ERRalpha. We therefore delineated the molecular mechanism by which a transcriptional network controlled by corepressor and coactivator proteins determines the metabolic properties of skeletal muscle, thus representing a potential therapeutic target for metabolic diseases.
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Project description:We found that TLS can work as a PGC-1alpha cofactor and this assay was carried out to test the functional dependency of TLS on PGC-1alpha on a whole genome scale Three independently-isolated cultures of primary hepatocytes from PGC-1α+/+ and PGC-1α-/- mice were infected with shTLS or control adenovirus. RNA was extracted by Trizol extraction, re-purified with RNAeasy (Invitrogen), and checked for integrity and quantity with the Agilent Bio-Analyzer QC. RNA was amplified and labeled with the One-Color Microarray-Based Gene Expression Analysis Protocol (Agilent Technologies, Palo Alto, CA, USA). Samples were hybridized to a G4122F 4x44K whole mouse genome microarray (Agilent Technologies). Arrays were scanned at 5 mm resolution with a G2565BA DNA microarray scanner (Agilent Technologies) at the default settings for 4x44k format one-color arrays. Images were analyzed using Feature Extraction software v10.1.1.1 (Agilent Technologies). Raw signals were thresholded to 1 and normalized by quantile (Bolstad et al., 2003) was performed using GeneSpring software. Data were analyzed on the log2 scale. Default flags were considered as absent, except for saturated spots that were flagged as marginal.
2013-07-26 | E-GEOD-23242 | biostudies-arrayexpress
Project description:PGC-1alpha has been proposed to couple gene transcription and RNA processing via SR-rich domains and an RNA recognition motif located at the C-terminal domain (CTD). However, the full extent by which the CTD of PGC-1alpha regulates its function in gene expression and RNA processing remains largely unknown. Here, we used RNA-seq to evaluate the effects of CTD deletion (dCTD) on PGC-1alpha function. We found that deletion of the CTD of PGC-1alpha virtually abolished its effects on transcriptome remodeling and the resulting increase in oxidative capacity in skeletal muscle cells. Moreover, we implemented in vitro affinity purification followed by sequencing (in vitro AP-seq), which revealed more than 700 RNAs bound to the CTD of PGC-1alpha. The majority of these RNAs were transcribed at DNA regulatory elements such as promoters and distal intergenic regions. These results demonstrate that PGC-1alpha function is highly modulated at the CTD via multivalent protein-RNA interactions.
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2006-04-03 | GSE4330 | GEO
Project description:Title: Total Skeletal Muscle PGC-1 Deficiency Uncouples Mitochondrial Derangements from Fiber Type Determination and Insulin Sensitivity Abstract: Evidence is emerging that the PGC-1 coactivators serve a critical role in skeletal muscle metabolism, function, and disease. Mice with total PGC-1 deficiency in skeletal muscle (PGC-1α-/- βf/f/MLC-Cre mice) were generated and characterized. PGC-1α-/-βf/f/MLC-Cre mice exhibit a dramatic reduction in exercise performance compared to single PGC-1α- or PGC-1β-deficient mice and wild-type controls. The exercise phenotype of the PGC-1α-/-βf/f/MLC-Cre mice was associated with a marked diminution in muscle oxidative capacity and mitochondrial structural derangements consistent with fusion/fission and biogenic defects together with rapid depletion of muscle glycogen stores during exercise. Surprisingly, the skeletal muscle fiber type profile of the PGC-1α-/-βf/f/MLCCre mice was not significantly different than the wild-type mice. Moreover, insulin sensitivity and glucose tolerance were also not altered in the PGC-1α-/-βf/f/MLC-Cre mice. Taken together, we conclude that PGC-1 coactivators are necessary for the oxidative and mitochondrial programs of skeletal muscle but are dispensable for fundamental fiber type determination and insulin sensitivity. RNA from PGC-1alpha-/- beta f/f/Mlc1fcre was obtained and gene expression pattern compared with PGC-1alpha -/-, PGC-1beta f/f, and PGC-1beta f/f/Mlc1fCre controls. Results file descriptions: 1. GSE23365_skfloxAKO_PPexcl_genesup_GEO-8-16-2010: This table contains genes that were upregulated ≥2.0 fold in gastrocnemius muscle from PGC-1alpha-/- - mice, PGC-1beta f/f/Mlc1fCre mice and PGC-1alpha-/- - beta f/f/Mlc1fCre mice. All groups are normalized to PGC-1beta f/f mice and values are expressed as mean±SEM. The column “description’ contains the gene name, and the column “ID” contains Agilent probe names. 2. GSE23365_skfloxAKO_PPexcl_genesdown_GEO-8-16-2010 This table contains genes that were downregulated ≤0.7 fold in gastrocnemius muscle from PGC-1alpha-/- - mice, PGC-1beta f/f/Mlc1fCre mice and PGC-1alpha-/- - beta f/f/Mlc1fCre mice. All groups are normalized to PGC-1beta f/f mice and values are expressed as mean±SEM. The column “description’ contains the gene name, and the column “ID” contains Agilent probe names.
2010-12-01 | E-GEOD-23365 | biostudies-arrayexpress