Quantitative recovery of IRS1 by RXRα activation in mitochondrial dysfunction-induced myotubes

Abstract

Mitochondrion is a well-known organelle generating energy via metabolic pathway of nutrients, glucose and lipid. Mitochondrial dysfunction leads to impairment of insulin secretion in pancreatic beta cells and insulin resistance in liver and skeletal muscles. Our previous study on the cybrids carrying mtDNA A3243G mutation discovered that the activation of retinoid X receptor α (RXRα), a ligand dependent transcription factor, had restored mitochondrial function, therefore in this study the effect of RXRα activation on insulin signaling pathway impaired by mitochondrial dysfunction was investigated. RXRα as well as insulin receptor substrate 1 (IRS1) were decreased in the myotubes treated with mitochondrial OXPHOS complex inhibitors and in skeletal muscle of high fat/high sucrose-dieted mice. However, RXRα activation by its ligands restored IRS1 expression levels which were down-regulated by mitochondrial OXPHOS complex inhibitors in C2C12 myotubes. In addition, this was accompanied by the recovery of cellular ATP production. RXRα over-expression or activation increased the promoter activity of IRS1 in the transient transfection and luciferase assay system, indicating the possibility that RXRα regulates expression of IRS1 by directly binding to the promoter region. Therefore, these results suggest that RXRα might be a potential therapeutic target to improve insulin signaling in mitochondrial dysfunction-induced insulin resistance.