Daidzein promotes the expression of oxidative phosphorylation- and fatty acid oxidation-related genes via an estrogen-related receptor α pathway to decrease lipid accumulation in muscle cells

Estrogen-related receptor (ERR)alpha regulates genes involved in fatty acid oxidation (FAO) and oxidative phosphorylation (OXPHOS) in muscle. The soy isoflavone daidzein was reported to be a putative ERR alpha activator, but little is known about its effects on gene expression and FA metabolism. This study aimed to clarify whether daidzein affects FAO- and OXPHOS-related genes thereby modulating intracellular FA metabolism in muscle cells. For this purpose, we used the C2C12 murine muscle cell line. ERR alpha-expressing C2C12 myotubes were treated with 50 mu M daidzein, and gene expression was examined. The expression of FAO genes such as pyruvate dehydrogenase kinase 4 (Pdk4) and acyl-coenzyme A dehydrogenase (Acadm) and that of OXPHOS genes such as ATP synthase F1 subunit beta (Atp5b) and cytochrome c (Cycs) was significantly increased by daidzein, and these effects were partially blocked by an ERR alpha inhibitor. Using a reporter assay, we showed that daidzein enhanced the promoter activity of these genes and that ERR alpha responsive elements in the promoter region were necessary for the action of daidzein. Finally, daidzein significantly decreased lipid accumulation in C2C12 myotubes associated with increased oxygen consumption. In conclusion, daidzein decreases lipid deposition in muscle cells by regulating the expression of genes related to FAO and OXPHOS via an ERR alpha-associated pathway at least in part. These results suggest that daidzein would be a beneficial tool to protect against various diseases caused by muscle lipotoxicity. (C) 2019 Elsevier Inc. All rights reserved.