title: Metabolomic Analysis of the Skeletal Muscle of Mice Overexpressing PGC-1α.
abstract: Peroxisome proliferator-activated receptor (PPAR) γ coactivator 1α (PGC-1α) is a coactivator of various nuclear receptors and other transcription factors whose expression increases in the skeletal muscle during exercise. We have previously made transgenic mice overexpressing PGC-1α in the skeletal muscle (PGC-1α-Tg mice). PGC-1α upregulates the expression of genes associated with red fibers, mitochondrial function, fatty acid oxidation, and branched chain amino acid (BCAA) degradation. However, global analyses of the actual metabolic products have not been investigated. In this study, we conducted metabolomic analysis of the skeletal muscle in PGC-1α-Tg mice by capillary electrophoresis with electrospray ionization time-of-flight mass spectrometry. Principal component analysis and hierarchical cluster analysis showed clearly distinguishable changes in the metabolites between PGC-1α-Tg and wild-type control mice. Changes were observed in metabolite levels of various metabolic pathways such as the TCA cycle, pentose phosphate pathway, nucleotide synthesis, purine nucleotide cycle, and amino acid metabolism, including BCAA and β-alanine. Namely, metabolic products of the TCA cycle increased in PGC-1α-Tg mice, with increased levels of citrate (2.3-fold), succinate (2.2-fold), fumarate (2.8-fold), and malate (2.3-fold) observed. Metabolic products associated with the pentose phosphate pathway and nucleotide biosynthesis also increased in PGC-1α-Tg mice. Meanwhile, BCAA levels decreased (Val, 0.7-fold; Leu, 0.8-fold; and Ile, 0.7-fold), and Glu (3.1-fold) and Asp (2.2-fold) levels increased. Levels of β-alanine and related metabolites were markedly decreased in PGC-1α-Tg mice. Coordinated regulation of the TCA cycle and amino acid metabolism, including BCAA, suggests that PGC-1α plays important roles in energy metabolism. Moreover, our metabolomics data showing the activation of the purine nucleotide pathway, malate-aspartate shuttle, as well as creatine metabolism, which are known to be active during exercise, further suggests that PGC-1α regulates metabolism in exercise. Thus, we demonstrated the roles of PGC-1α in the skeletal muscle at the metabolite level.
authors.affiliation: Department of Molecular Endocrinology and Metabolism, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan; Laboratory of Molecular Nutrition, Graduate School of Environmental and Life Science, Kyoto Prefectural University, Kyoto, Japan.
authors.forename: Yukino
authors.initials: Y
authors.lastname: Hatazawa
authors.affiliation: Laboratory of Nutritional Biochemistry, Graduate School of Nutritional and Environmental Sciences, University of Shizuoka, Shizuoka, Japan.
authors.forename: Nanami
authors.initials: N
authors.lastname: Senoo
authors.affiliation: Department of Nutritional Science, Faculty of Applied Bio-Science, Tokyo University of Agriculture, Tokyo, Japan.
authors.forename: Miki
authors.initials: M
authors.lastname: Tadaishi
authors.affiliation: Department of Molecular Endocrinology and Metabolism, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Ogawa
authors.affiliation: Department of Human Health and Design, Showa Women's University, Tokyo, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Ezaki
authors.affiliation: Laboratory of Molecular Nutrition, Graduate School of Environmental and Life Science, Kyoto Prefectural University, Kyoto, Japan.
authors.forename: Yasutomi
authors.initials: Y
authors.lastname: Kamei
authors.affiliation: Laboratory of Nutritional Biochemistry, Graduate School of Nutritional and Environmental Sciences, University of Shizuoka, Shizuoka, Japan.
authors.forename: Shinji
authors.initials: S
authors.lastname: Miura
mesh_terms: D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D002952:Citric Acid Cycle; D016000:Cluster Analysis; D004734:Energy Metabolism; D005260:Female; D015870:Gene Expression; D008297:Male; D055442:Metabolome; D055432:Metabolomics / Q000379:methods; D051379:Mice; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000378:metabolism*; D009711:Nucleotides / Q000096:biosynthesis; D010427:Pentose Phosphate Pathway; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D000596:Amino Acids; D009711:Nucleotides; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D014157:Transcription Factors