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.
Highlights
Endurance exercise training upregulates peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) in the skeletal muscle[10,11]
Since plasma triglyceride (TG) and total cholesterol (TC) levels are increased greatly and atherosclerosis is initiated in Apolipoprotein E-knockout (ApoE-KO) mice fed with normal chow[24], we fed ApoE-KO mice normal chow
The present study shows that skeletal muscle-specific PGC-1α overexpression suppressed the progression of atherosclerosis in ApoE-KO mice without changing spontaneous activity and plasma lipid profiles
Summary
Endurance exercise training upregulates peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) in the skeletal muscle[10,11]. It has been reported that myokines, hormone-like peptides and cytokines which are secreted from skeletal muscle, are involved in the beneficial effects of exercise[15]. Skeletal muscle-specific overexpression of PGC-1α has been shown to stimulate the secretion of myokines, such as Irisin[20] and β-aminoisobutyric acid (BAIBA)[21]. PGC-1α overexpression in skeletal muscle increased production of FNDC5, a precursor form of Irisin, and Irisin stimulated transformation of white adipose tissue to brown adipose tissue-like characteristics[20]. We hypothesized that overexpression of PGC-1α in skeletal muscles may suppress atherosclerosis via increased secretion of myokines into the blood stream. We investigated whether skeletal muscle-specific PGC-1α overexpression suppresses atherosclerosis using a murine ApoE-KO model
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