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Metabolomic Analysis of the Skeletal Muscle of Mice Overexpressing PGC-1α.

Hatazawa Y, Senoo N, Tadaishi M, Ogawa Y, Ezaki O, Kamei Y, Miura S - PLoS ONE (2015)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

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.

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.

No MeSH data available.


Schematic representation of metabolic pathway changes in PGC-1α-Tg mice.The levels of many metabolic products are changed in the skeletal muscle of PGC-1α-Tg mice. Many of these changes are associated with mitochondrial metabolism, in particular the TCA cycle. Increased mitochondrial content due to PGC-1α-overexpression appears to activate the TCA cycle (Fig 3); therefore, there must be more substrates available for the TCA cycle. For instance, the activated pentose phosphate pathway (Fig 4) stimulates nucleotide synthesis (Fig 5), which is followed by activation of the purine nucleotide cycle (Fig 6), supplying fumarate for the TCA cycle. Meanwhile, activation of the malate-aspartate shuttle supplies other substrates (Fig 7). In addition, amino acids are also likely to be used as substrates (Figs 7, 8 and 9). Increased coordinated regulation of the TCA cycle and amino acid metabolism, including BCAA, suggests that PGC-1α plays important roles in energy metabolism. Moreover, activation of the purine nucleotide pathway and malate–aspartate shuttle, which are known to be active during exercise, further suggests that PGC-1α regulates metabolism in exercise.
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pone.0129084.g010: Schematic representation of metabolic pathway changes in PGC-1α-Tg mice.The levels of many metabolic products are changed in the skeletal muscle of PGC-1α-Tg mice. Many of these changes are associated with mitochondrial metabolism, in particular the TCA cycle. Increased mitochondrial content due to PGC-1α-overexpression appears to activate the TCA cycle (Fig 3); therefore, there must be more substrates available for the TCA cycle. For instance, the activated pentose phosphate pathway (Fig 4) stimulates nucleotide synthesis (Fig 5), which is followed by activation of the purine nucleotide cycle (Fig 6), supplying fumarate for the TCA cycle. Meanwhile, activation of the malate-aspartate shuttle supplies other substrates (Fig 7). In addition, amino acids are also likely to be used as substrates (Figs 7, 8 and 9). Increased coordinated regulation of the TCA cycle and amino acid metabolism, including BCAA, suggests that PGC-1α plays important roles in energy metabolism. Moreover, activation of the purine nucleotide pathway and malate–aspartate shuttle, which are known to be active during exercise, further suggests that PGC-1α regulates metabolism in exercise.

Mentions: In this study, it was observed that many metabolic product levels changed in the skeletal muscle of PGC-1α-Tg mice (Fig 10). Many of these changes are related to mitochondrial metabolism. Increased coordinal regulation of the TCA cycle and amino acid metabolism, including BCAA, suggests that PGC-1α plays important roles in energy metabolism. Moreover, 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. In this study, we evaluated the role of PGC-1α in the skeletal muscle at the metabolic level.


Metabolomic Analysis of the Skeletal Muscle of Mice Overexpressing PGC-1α.

Hatazawa Y, Senoo N, Tadaishi M, Ogawa Y, Ezaki O, Kamei Y, Miura S - PLoS ONE (2015)

Schematic representation of metabolic pathway changes in PGC-1α-Tg mice.The levels of many metabolic products are changed in the skeletal muscle of PGC-1α-Tg mice. Many of these changes are associated with mitochondrial metabolism, in particular the TCA cycle. Increased mitochondrial content due to PGC-1α-overexpression appears to activate the TCA cycle (Fig 3); therefore, there must be more substrates available for the TCA cycle. For instance, the activated pentose phosphate pathway (Fig 4) stimulates nucleotide synthesis (Fig 5), which is followed by activation of the purine nucleotide cycle (Fig 6), supplying fumarate for the TCA cycle. Meanwhile, activation of the malate-aspartate shuttle supplies other substrates (Fig 7). In addition, amino acids are also likely to be used as substrates (Figs 7, 8 and 9). Increased coordinated regulation of the TCA cycle and amino acid metabolism, including BCAA, suggests that PGC-1α plays important roles in energy metabolism. Moreover, activation of the purine nucleotide pathway and malate–aspartate shuttle, which are known to be active during exercise, further suggests that PGC-1α regulates metabolism in exercise.
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Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4482640&req=5

pone.0129084.g010: Schematic representation of metabolic pathway changes in PGC-1α-Tg mice.The levels of many metabolic products are changed in the skeletal muscle of PGC-1α-Tg mice. Many of these changes are associated with mitochondrial metabolism, in particular the TCA cycle. Increased mitochondrial content due to PGC-1α-overexpression appears to activate the TCA cycle (Fig 3); therefore, there must be more substrates available for the TCA cycle. For instance, the activated pentose phosphate pathway (Fig 4) stimulates nucleotide synthesis (Fig 5), which is followed by activation of the purine nucleotide cycle (Fig 6), supplying fumarate for the TCA cycle. Meanwhile, activation of the malate-aspartate shuttle supplies other substrates (Fig 7). In addition, amino acids are also likely to be used as substrates (Figs 7, 8 and 9). Increased coordinated regulation of the TCA cycle and amino acid metabolism, including BCAA, suggests that PGC-1α plays important roles in energy metabolism. Moreover, activation of the purine nucleotide pathway and malate–aspartate shuttle, which are known to be active during exercise, further suggests that PGC-1α regulates metabolism in exercise.
Mentions: In this study, it was observed that many metabolic product levels changed in the skeletal muscle of PGC-1α-Tg mice (Fig 10). Many of these changes are related to mitochondrial metabolism. Increased coordinal regulation of the TCA cycle and amino acid metabolism, including BCAA, suggests that PGC-1α plays important roles in energy metabolism. Moreover, 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. In this study, we evaluated the role of PGC-1α in the skeletal muscle at the metabolic level.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

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.

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.

No MeSH data available.