PGC-1α induces mitochondrial and myokine transcriptional programs and lipid droplet and glycogen accumulation in cultured human skeletal muscle cells

The transcriptional coactivator peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1α) is a chief activator of mitochondrial and metabolic programs and protects against atrophy in skeletal muscle (skm). Here we tested whether PGC-1α overexpression could restructure the transcr...

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Published in:PloS one 2012, Vol.7 (1), p.e29985-e29985
Main Authors: Mormeneo, Emma, Jimenez-Mallebrera, Cecilia, Palomer, Xavier, De Nigris, Valeria, Vázquez-Carrera, Manuel, Orozco, Anna, Nascimento, Andrés, Colomer, Jaume, Lerín, Carles, Gómez-Foix, Anna M
Format: Article
Language:English
Subjects:
Atrophy
Bayesian analysis
Bioaccumulation
Bioinformatics
Biology
Biomedical research
Biosynthesis
Blotting, Western
Calcium
Calcium signalling
Calmodulin - genetics
Calmodulin - metabolism
Carbon dioxide
Cells, Cultured
Chemokine CCL5 - genetics
Chemokine CCL5 - metabolism
Chemokine CCL8 - genetics
Chemokine CCL8 - metabolism
Chemokine CXCL6 - genetics
Chemokine CXCL6 - metabolism
Chemotaxis
Cytokines
Cytokines - genetics
Cytokines - metabolism
Diabetes
Disorders of metabolism
DNA microarrays
Droplets
Electron Transport Complex IV - genetics
Electron Transport Complex IV - metabolism
Fasting
Fatty acids
Fisiologia patològica
Gene expression
Genes
Genomes
Genètica molecular
Glucose
Glycogen
Glycogen - metabolism
Glycogen phosphorylase
Heat-Shock Proteins - genetics
Heat-Shock Proteins - metabolism
Humans
Interleukin 8
Interleukin-8 - genetics
Interleukin-8 - metabolism
Laboratories
Lactic acid
Lipids
Lipids - analysis
Membrane Proteins - genetics
Membrane Proteins - metabolism
Metabolism
Mitochondria
Mitochondrial Proteins - genetics
Mitochondrial Proteins - metabolism
Molecular genetics
Muscle Cells - cytology
Muscle Cells - metabolism
Muscle, Skeletal - cytology
Muscle, Skeletal - metabolism
Muscles
Musculoskeletal system
Oligonucleotide Array Sequence Analysis
Oligonucleotides
Oxidation
Palmitic acid
Parvalbumins - genetics
Parvalbumins - metabolism
Pathological physiology
Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
Phosphorylase
Phosphorylase kinase
Phosphorylation
Primary Cell Culture
Proteins
Regulators
Reverse Transcriptase Polymerase Chain Reaction
Rodents
Skeletal muscle
Storage
Trans-Activators - genetics
Trans-Activators - metabolism
Transcription
Transcription Factors - genetics
Transcription Factors - metabolism
Transcriptome
Transgenic animals
Trastorns del metabolisme
Triglycerides
Triglycerides - metabolism
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Summary:The transcriptional coactivator peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1α) is a chief activator of mitochondrial and metabolic programs and protects against atrophy in skeletal muscle (skm). Here we tested whether PGC-1α overexpression could restructure the transcriptome and metabolism of primary cultured human skm cells, which display a phenotype that resembles the atrophic phenotype. An oligonucleotide microarray analysis was used to reveal the effects of PGC-1α on the whole transcriptome. Fifty-three different genes showed altered expression in response to PGC-1α: 42 upregulated and 11 downregulated. The main gene ontologies (GO) associated with the upregulated genes were mitochondrial components and processes and this was linked with an increase in COX activity, an indicator of mitochondrial content. Furthermore, PGC-1α enhanced mitochondrial oxidation of palmitate and lactate to CO(2), but not glucose oxidation. The other most significantly associated GOs for the upregulated genes were chemotaxis and cytokine activity, and several cytokines, including IL-8/CXCL8, CXCL6, CCL5 and CCL8, were within the most highly induced genes. Indeed, PGC-1α highly increased IL-8 cell protein content. The most upregulated gene was PVALB, which is related to calcium signaling. Potential metabolic regulators of fatty acid and glucose storage were among mainly regulated genes. The mRNA and protein level of FITM1/FIT1, which enhances the formation of lipid droplets, was raised by PGC-1α, while in oleate-incubated cells PGC-1α increased the number of smaller lipid droplets and modestly triglyceride levels, compared to controls. CALM1, the calcium-modulated δ subunit of phosphorylase kinase, was downregulated by PGC-1α, while glycogen phosphorylase was inactivated and glycogen storage was increased by PGC-1α. In conclusion, of the metabolic transcriptome deficiencies of cultured skm cells, PGC-1α rescued the expression of genes encoding mitochondrial proteins and FITM1. Several myokine genes, including IL-8 and CCL5, which are known to be constitutively expressed in human skm cells, were induced by PGC-1α.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0029985