Loss of NOR-1 represses muscle metabolism through mTORC1-mediated signaling and mitochondrial gene expression in C2C12 myotubes.

Abstract

Gene expression of the NR4A nuclear orphan receptor NOR-1 is reduced in obesity and in human skeletal muscle during disuse. It has been well established that NOR-1 is highly responsive to both aerobic and resistance exercise and NOR-1 overexpression is coincident with a plethora of metabolic benefits. However, it is unclear whether loss of NOR-1 contributes to inappropriate metabolic signaling in skeletal muscle that could lead to insulin resistance. The purpose of this study was to elucidate the impact of NOR-1 deficiency on C2C12 metabolic signaling. Changes in gene expression after siRNA-mediated NOR-1 knockdown in C2C12 myotubes were determined by qPCR and bioinformatic analysis of RNA-Seq data. Our RNA-Seq data identified several metabolic targets regulated by NOR-1 and implicates NOR-1 as a modulator of mTORC1 signaling via Akt-independent mechanisms. Furthermore, pathway analysis revealed NOR-1 knockdown perturbs the insulin resistance and insulin sensitivity pathways. Taken together, these data suggest skeletal muscle NOR-1 deficiency may contribute to altered metabolic signaling that is consistent with metabolic disease. We postulate that strategies that improve NOR-1 may be important to offset the negative impact that inactivity, obesity, and type 2 diabetes have on mitochondria and muscle metabolism.