MicroRNAs role on mitochondrial function in skeletal muscle during insulin resistance

Abstract

A diminished mitochondrial oxidative capacity in skeletal muscle tissue has frequently been reported in human type 2 diabetes mellitus (T2DM) and insulin resistance. Moreover, interventions improving muscle oxidative capacity, such as exercise training and caloric restriction, are among the most potent strategies to revert the insulin resistant state. However, a sustained increase in physical activity or restriction of caloric intake is not easily achieved in a generally obese population and additional strategies are needed to improve mitochondrial oxidative capacity. In this context, Dr. Hoeks recently published the involvement of specific microRNAs - post-transcriptional regulators of gene expression - in the regulation of mitochondrial capacity in cardiac tissue. If and how microRNAs also affect mitochondrial metabolism in skeletal muscle has however not been studied so far. Dr. Hoeks group have previously screened >700 microRNA candidates in C2C12 myoblasts as well as myotubes for their involvement in the regulation of skeletal muscle mitochondrial capacity. During the intership, we will study ~2 of the primary microRNA candidates in detail, establishing their mechanism of action, their effects on functional outcomes of mitochondrial capacity and subsequently, insulin sensitivity. Initially, this will be studied in C2C12 muscle cells and in readily available human primary myotubes, derived from both T2DM patients and BMI- and age-matched controls. This project will reveal novel microRNAs that are involved in the regulation of skeletal muscle mitochondrial oxidative capacity and may uncover novel drug targets to improve metabolic health. (AU)