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Skeletal Muscle-specific PGC-1α Overexpression Suppresses Atherosclerosis in Apolipoprotein E-Knockout Mice.

ABSTRACT: Endurance exercise training prevents atherosclerosis. Peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) increases myokine secretion from the skeletal muscle, and these myokines have been shown to affect the function of multiple organs. Since endurance exercise training increases PGC-1α expression in skeletal muscles, we investigated whether skeletal muscle-specific PGC-1α overexpression suppresses atherosclerosis. Apolipoprotein E-knockout (ApoE-KO)/PGC-1α mice, which overexpress PGC-1α in the skeletal muscle of ApoE-KO mice, were sacrificed, and the atherosclerotic plaque area, spontaneous activity, plasma lipid profile, and aortic gene expression were measured. Immunohistochemical analyses were also performed. The atherosclerotic lesions in ApoE-KO/PGC-1α mice were 40% smaller than those in ApoE-KO mice, concomitant with the reduction in vascular cell adhesion molecule-1 (VCAM-1) and monocyte chemoattractant protein-1 (MCP-1) mRNA and protein levels in the aorta. Spontaneous activity and plasma lipid profiles were not changed by the overexpression of PGC-1α in the skeletal muscle. In human umbilical vein endothelial cells, Irisin and β-aminoisobutyric acid (BAIBA), PGC-1α-dependent myokines, inhibited the tumor necrosis factor α-induced VCAM-1 gene and protein expression. BAIBA also inhibited TNFα-induced MCP-1 gene expression. These results showed that the skeletal muscle-specific overexpression of PGC-1α suppresses atherosclerosis and that PGC-1α-dependent myokines may be involved in the preventive effects observed.

SUBMITTER: Shimba Y

PROVIDER: S-EPMC6411944 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description: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.

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Skeletal Muscle-specific PGC-1α Overexpression Suppresses Atherosclerosis in Apolipoprotein E-Knockout Mice.

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