title: New gene targets of PGC-1α and ERRα co-regulation in C2C12 myotubes.
abstract: As a transcriptional coactivator, PGC-1α contributes to the regulation of a broad range of metabolic processes in skeletal muscle health and disease; however, there is limited information about the genes it transcriptionally regulates. To identify new potential gene targets of PGC-1α regulation, mouse C2C12 myotubes were screened by microarray analysis following PGC-1α overexpression. Genes with an mRNA expression of 2.5-fold or more (P < 0.001) were identified. From these, further genes were singled out if they had no previous connection to PGC-1α regulation or characterization in skeletal muscle, or were unannotated with no known function. Following confirmation of their regulation by PGC-1α using qPCR analysis, eight genes were focused on for further investigation (Akr1b10, Rmnd1, 1110008P14Rik, 1700021F05Rik, Mtfp1, Mrm1, Oxnad1 and Cluh). Bioinformatics indicated a number of the genes were linked to a range of metabolic-related functions including fatty acid oxidation, oxido-reductase activity, and mitochondrial remodeling and transport. Treating C2C12 myotubes for 6 h with AICAR, a known activator of AMP kinase and inducer of Pgc-1α gene expression, increased the mRNA levels of both Pgc-1α (P < 0.001) and of Mtfp1, Mrm1, Oxnad1 and Cluh (P < 0.05). Screening of the promoter and intron 1 regions also revealed all genes to contain either a consensus or near consensus response elements for the estrogen-related receptor α (ERRα), a key transcription factor-binding partner of PGC-1α in skeletal muscle. Furthermore, knockdown of endogenous ERRα levels partially or completely blocked the induction of gene expression of all genes by PGC-1α, while each gene was significantly upregulated in the presence of a constitutively active form of ERRα (P < 0.05) except for Akr1b10. These findings provide preliminary evidence for the novel regulation of these genes by PGC-1α and its signaling pathway in skeletal muscle.
authors.affiliation: Centre for Physical Activity and Nutrition Research (C-PAN), School of Exercise and Nutrition Sciences, Faculty of Health, Deakin University, Melbourne, Australia.
authors.forename: Abena
authors.initials: A
authors.lastname: Nsiah-Sefaa
authors.forename: Erin L
authors.initials: EL
authors.lastname: Brown
authors.forename: Aaron P
authors.initials: AP
authors.lastname: Russell
authors.forename: Victoria C
authors.initials: VC
authors.lastname: Foletta
mesh_terms: D000818:Animals; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D046228:Microarray Analysis; D018485:Muscle Fibers, Skeletal / Q000378:metabolism*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism*; D020218:Response Elements; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D019076:Transgenes; D015854:Up-Regulation; D000097983:ERRalpha Estrogen-Related Receptor
chemical_list: D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D011960:Receptors, Estrogen; D014157:Transcription Factors; D000097983:ERRalpha Estrogen-Related Receptor; C486497:PPARGC1A protein, human