The role of c-Myc dependent pathway in insulin resistance uncovered by integrative analysis of skeletal muscle transcriptome

Abstract

I aim to identify a novel pathway to regulate insulin resistance from transcriptional profiles of skeletal muscles from patients with diabetes and to demonstrate its role in experimental models of insulin resistance. I performed transcriptional profiling of skeletal muscles from subjects with or without diabetes. Through an integrative analysis of the dataset with four previous datasets, I identified the core gene sets associated with insulin resistance. Among the 46 core gene sets for transcriptional regulators, I focused on c-Myc with the highest regulatory power in the network of the core gene sets. c-Myc expression decreased in skeletal muscle from diet-induced obesity rodent model. In C2C12 myotubes, c-Myc transcriptional activity was decreased by palmitate or TNFα treatment inducing insulin resistance. Knockdown of c-Myc decreased expression of oxidative phosphorylation (OXPHOS) genes and PGC-1-related coactivator, but showed no change in PGC1α. ERK regulated c-Myc induction by insulin, and palmitate abrogated insulin-induced c-Myc expression by modulating ERK activation. These data demonstrate that ERK-c-Myc pathway regulates OXPHOS gene expression in skeletal muscle insulin resistance, independent of PGC1α. The unbiased integrative approach of transcriptional profiles revealed ERK-c-Myc pathway as a novel pathway for skeletal muscle insulin resistance.