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Microarray analysis of skeletal muscle in PGC1α transgenic mice

ABSTRACT: Peroxisome proliferator-activated receptor (PPAR) γ coactivator 1α (PGC1α) is a coactivator of various nuclear receptors and other transcription factors that shows increased expression in skeletal muscle during exercise. In skeletal muscle, PGC1α is considered to be involved in contractile protein function, mitochondrial function, metabolic regulation, intracellular signaling, and transcriptional responses. Several isoforms of PGC1α mRNA have recently been identified. PGC1α-a is a full-length isoform of PGC1α that was the first to be isolated. PGC1α-b is another isoform of PGC1α, which is considered to be similar in function to PGC1α-a, differing by only 16 amino acids at the amino terminus. We have previously generated independent lines of transgenic mice that overexpress PGC1α-a or PGC1α-b in skeletal muscle. The microarray data shows that energy metabolism-related pathways such as the TCA cycle, branched-chain amino acid metabolism, purine nucleotide pathway, and malate–aspartate shuttle are activated in PGC1α transgenic mice compared with wild-type mice.

ORGANISM(S): Mus musculus

PROVIDER: GSE67049 | GEO | 2015/09/18

SECONDARY ACCESSION(S): PRJNA278804

REPOSITORIES: GEO

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Microarray analysis of skeletal muscle in PGC1α transgenic mice

Project description:Peroxisome proliferator-activated receptor (PPAR) γ coactivator 1α (PGC1α) is a coactivator of various nuclear receptors and other transcription factors that shows increased expression in skeletal muscle during exercise. In skeletal muscle, PGC1α is considered to be involved in contractile protein function, mitochondrial function, metabolic regulation, intracellular signaling, and transcriptional responses. Several isoforms of PGC1α mRNA have recently been identified. PGC1α-a is a full-length isoform of PGC1α that was the first to be isolated. PGC1α-b is another isoform of PGC1α, which is considered to be similar in function to PGC1α-a, differing by only 16 amino acids at the amino terminus. We have previously generated independent lines of transgenic mice that overexpress PGC1α-a or PGC1α-b in skeletal muscle. The microarray data shows that energy metabolism-related pathways such as the TCA cycle, branched-chain amino acid metabolism, purine nucleotide pathway, and malate–aspartate shuttle are activated in PGC1α transgenic mice compared with wild-type mice. For microarray analysis, RNA was isolated from the gastrocnemius skeletal muscle of wild-type control mice (12 weeks of age) as well as transgenic mice [PGC1α-a (E) (Miura et al., J. Biol. Chem. 278:31385-90, 2003), 12 weeks of age; PGC1α-b (02-1) (Miura et al., Endocrinology 149:4527-33, 2008), 14 weeks of age; and PGC1α-b (03-2) (Miura et al., Endocrinology 2008), 14 weeks of age]. Samples from wild-type and transgenic mice (N = 5 for each group) were pooled before use.

2015-09-18 | E-GEOD-67049 | biostudies-arrayexpress

Tissue- and Pathway-Specific Metabolomic Profiles of the Steroid Receptor Coactivator (SRC) family

Project description:The rapidly growing family of coregulators of nuclear receptors includes coactivators that promote transcription and corepressors that harbor the opposing function. In recent years, coregulators have begun to emerge as important regulators of metabolic homeostasis, including the p160 Steroid Receptor Coactivator (SRC) family. Members of the SRC family have been ascribed important roles in control of gluconeogenesis in liver and fatty acid oxidation in skeletal muscle. To provide a deeper and more granular understanding of the metabolic impact of SRC family members, we have performed targeted metabolomics analysis of key metabolic byproducts of glucose, fatty acid, and amino acid metabolism in mice with global knockout of SRC-1, SRC-2, or SRC-3. We measured amino acids, acyl carnitines, and organic acids in five tissues with key metabolic functions (liver, heart, skeletal muscle, brain, plasma) isolated from SRC-1, -2, or -3 knockout mice and their wild-type littermates in the fed and fasted conditions, thereby unveiling unique metabolic functions of each SRC coactivator. Overall, we observed entire groups or subgroups of metabolites belonging to discrete metabolic pathways that were influenced in different tissues and/or feeding states due to ablation of individual SRC isoforms. Surprisingly, we identified very few metabolites that changed universally across the three SRC knockout models. These findings demonstrate that coactivator function has very limited redundancy even within the homologous SRC coactivator family. Furthermore, this work also demonstrates the use of metabolomics as a means for identifying novel metabolic regulatory functions of transcriptional coregulators.

2013-04-10 | MTBLS30 | MetaboLights

Role of p110a subunit of PI3-kinase in skeletal muscle mitochondria

Project description:Skeletal muscle insulin resistance, decreased phosphatidylinositol 3-kinase (PI3K) activation and altered mitochondrial function are hallmarks of type 2 diabetes. We created mice with a muscle-specific knockout of p110α or p110β, the two major catalytic subunits of PI3K. We find that mice with muscle-specific knockout of p110α, but not p110β, display impaired muscle insulin signaling and reduced muscle size due to enhanced proteasomal and autophagic activity. Despite insulin resistance and muscle atrophy, M-p110αKO mice show decreased serum myostatin, increased mitochondrial mass, increased mitochondrial fusion visualized by intravital microscopy, and increased PGC1α expression, especially PCG1α2 and PCG1α3. This leads to enhanced mitochondrial oxidative capacity, striking increases in muscle NADH content, and higher muscle free radical release measured in vivo using pMitoTimer reporter. Thus, p110α is the dominant catalytic isoform of PI3K in muscle in control of insulin sensitivity and muscle mass, and has a unique role in mitochondrial homeostasis in skeletal muscle.

2019-03-12 | GSE124394 | GEO

Intervention study of ß-hydroxy-ß-methyl butyric acid on sarcopenia in patients with colorectal cancer

Project description:Interventions: Experimental group:ß- hydroxy- ß- methyl butyrate;Control Group:No Primary outcome(s): skeletal muscle index;tumor necrosis factor-like weak apoptosis-inducing factor;peroxisome proliferator-activated receptor coactivator 1-a;growth differentiation factor 15;grip strength;pace;leg circumference Study Design: Parallel

| 2716507 | ecrin-mdr-crc

A metabolic co-regulator bioinformatics screen reveals that PGC1α suppresses prostate cancer metastasis

Project description:The current view of cellular transformation and cancer progression supports the notion that cancer cells must reprogram their metabolism in order to survive and progress in different microenvironments. Master co-regulators of metabolism orchestrate the modulation of multiple metabolic pathways through transcriptional programs, and hence constitute a probabilistically parsimonious mechanism for general metabolic rewiring. Here we show that the transcriptional co-activator PGC1α suppresses prostate cancer progression and metastasis. A metabolic co-regulator data mining analysis unveiled that PGC1α is consistently down-regulated in multiple prostate cancer patient datasets and its alteration is associated with reduced disease-free survival and metastasis. Genetically engineered mouse model studies revealed that compound prostate epithelium-specific deletion of Pgc1a and Pten promotes prostate cancer progression and metastasis, whereas, conversely, PGC1α expression in cell lines inhibits the pre-existing metastatic capacity. Through the application of integrative metabolomics and transcriptomics we demonstrate that PGC1α expression in prostate cancer is sufficient to elicit a global metabolic rewiring that opposes cell growth, consisting of sustained oxidative metabolism at the expense of anabolism. This metabolic program is regulated downstream the Oestrogen-related receptor alpha (ERRα), and PGC1α mutants lacking ERRα activation capacity lack metabolic rewiring capacity and metastasissuppressive function. Importantly, an ERRα signature in prostate cancer recapitulates the prognostic features of PGC1A. Our findings uncover an unprecedented causal contribution of PGC1α to the metabolic switch in prostate cancer and to the suppression of metastatic dissemination.

2016-03-16 | GSE75193 | GEO

The Skeletal Muscle Molecular Clock Regulates Sarcomere Length Through Titin Splicing [2]

Project description:Circadian rhythms have been implicated in regulating skeletal muscle structure and function, but no mechanisms have connected the molecular clock to sarcomeric proteins. We identified an isoform shift in the sarcomeric ruler, titin, and showed that the skeletal muscle molecular clock regulates titin isoform and subsequently sarcomere length through RBM20, an RNA binding protein that controls titin splicing. Restoring RBM20 expression in iMSBmal1-/- TA muscle partially restored titin isoform.

2022-09-07 | GSE189863 | GEO

The Skeletal Muscle Molecular Clock Regulates Sarcomere Length Through Titin Splicing [1]

2022-09-07 | GSE172067 | GEO

Gene expression analysis of Ncor1 muscle-specific knockout and PGC-1alpha muscle-specific transgenic skeletal muscle

2013-01-08 | GSE40439 | GEO

Gene expression analysis of Ncor1 muscle-specific knockout and PGC-1alpha muscle-specific transgenic skeletal muscle

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 GeneChipÂ® 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

PGC-1α isoform heterodimerization restricts transcription factor docking and limits metabolic adaptations in skeletal muscle

Project description:The PGC-1a gene is expressed as several transcriptional coactivator variants that regulate numerous adaptive processes. These include thermogenesis, hepatic metabolism, neuroprotection, and skeletal muscle adaptation to exercise training. To support such diverse functions, PGC-1 isoform expression and activation are under tight tissue- and context-specific control. Notably, PGC-1 isoforms generated by alternative gene promoter usage, and splicing are highly induced in skeletal muscle upon exercise. Here we show that PGC-12 and 3 are PGC-11 dimerization partners that limit its activity. Skeletal muscle PGC-12 and PGC-13 transgenics have reduced exercise performance and strength, which partially overlaps with PGC-1 loss-of-function. Mechanistically, PGC-11/3 dimerization precludes ERR recruitment and coactivation, so their co-expression in skeletal muscle impairs the innate bioenergetic adaptations characteristic of PGC-11 transgenics and reduces oxidative metabolism gene expression and exercise capacity. Removing this break to PGC-1a1 activity may have therapeutic applications in metabolic diseases and increase responsiveness to training.

2022-05-21 | GSE203299 | GEO

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