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Analysis of PGC-1alpha overexpression effects on the whole transcriptome in cultured skeletal muscle cells

ABSTRACT: The transcriptional coactivator peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1α) is a chief activator of the mitochondrial and metatolic program in skeletal muscle (skm) and prevents atrophy. Here we tested whether PGC-1α overexpression could restructure the transcriptome and metabolism of cultured human skeletal myotubes, which display an athropic phenotype. An oligonucleotide microarray analysis was used to reveal PGC-1α effects on the whole transcriptome, and the possible impact on fuel metabolism reprogramming was examined. Fifty-three different genes displayed changed expression levels in response to PGC-1α: 42 upregulated and 11 downregulated. Main associations of gene ontologies (GO) for the upregulated genes were mitochondrial components and processes and this correlated with an increase in COX activity, an indicator of mitochondrial content. Palmitate and lactate oxidation to CO2 was enhanced, but not glucose oxidation. The other most significant GO associations of upregulated genes were chemotaxis and cytokine activity, and accordingly, several cytokines, including IL8, CXCL6, CCL5 and CCL8, were within top induced genes. Among the most regulated genes were also potential metabolic regulators of fatty acid and glucose storage. FITM1/FIT1 induction was associated with an increased number of lipid droplets with smaller area, while triglyceride levels were modestly increased in oleate-incubated cells. Downregulation of CALM1, the calcium-modulated δ subunit of phosphorylase kinase, was linked to inactivation of glycogen phosphorylase and greater accumulation of glycogen. The most upregulated gene was PVALB, which is also related to calcium signaling. In conclusion, only the deficient mitochondrial transcriptional program of cultured myotubes is rescued by PGC-1α. New PGC-1α gene targets and pathways arise, some of which may mediate its activating effects in processes such as lipid and carbohydrate storage and angiogenesis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE28206 | GEO | 2012/03/15

SECONDARY ACCESSION(S): PRJNA139647

REPOSITORIES: GEO

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Project description:The transcriptional coactivator peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1Î±) is a chief activator of the mitochondrial and metatolic program in skeletal muscle (skm) and prevents atrophy. Here we tested whether PGC-1Î± overexpression could restructure the transcriptome and metabolism of cultured human skeletal myotubes, which display an athropic phenotype. An oligonucleotide microarray analysis was used to reveal PGC-1Î± effects on the whole transcriptome, and the possible impact on fuel metabolism reprogramming was examined. Fifty-three different genes displayed changed expression levels in response to PGC-1Î±: 42 upregulated and 11 downregulated. Main associations of gene ontologies (GO) for the upregulated genes were mitochondrial components and processes and this correlated with an increase in COX activity, an indicator of mitochondrial content. Palmitate and lactate oxidation to CO2 was enhanced, but not glucose oxidation. The other most significant GO associations of upregulated genes were chemotaxis and cytokine activity, and accordingly, several cytokines, including IL8, CXCL6, CCL5 and CCL8, were within top induced genes. Among the most regulated genes were also potential metabolic regulators of fatty acid and glucose storage. FITM1/FIT1 induction was associated with an increased number of lipid droplets with smaller area, while triglyceride levels were modestly increased in oleate-incubated cells. Downregulation of CALM1, the calcium-modulated Î´ subunit of phosphorylase kinase, was linked to inactivation of glycogen phosphorylase and greater accumulation of glycogen. The most upregulated gene was PVALB, which is also related to calcium signaling. In conclusion, only the deficient mitochondrial transcriptional program of cultured myotubes is rescued by PGC-1Î±. New PGC-1Î± gene targets and pathways arise, some of which may mediate its activating effects in processes such as lipid and carbohydrate storage and angiogenesis. 6 samples from 3 different skeletal muscle cell cultures were used: 3 were transfected with adenovirus containing PGC-1aplha and 3 with adenovirus containing GFP (control). The 3 PGC-1alpha samples were compared against the control samples.

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.

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Analysis of PGC-1alpha overexpression effects on the whole transcriptome in cultured skeletal muscle cells

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