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.