HuR Influences Metabolic Flexibility in Skeletal Muscle

Abstract

Metabolic Flexibility allows for the oxidation of fuels based on their availability. Respiratory Quotient (RQ) values from subjects with type 2 diabetes mellitus in both basal and insulin stimulated states remain consistent, indicating a decreased ability to switch between available substrates. The molecular mechanisms governing defects in this switching ability are unclear at present. We therefore compared global gene expression in skeletal muscle between obese subjects classified by their sleep and 24 hour RQ as either metabolically flexible or inflexible. From this data we identified a number of transcripts stabilized by the RNA binding protein, HuR, which were enriched in metabolically flexible subjects. This finding prompted us to generate mice with a skeletal muscle specific knockout of Elavl1, the gene encoding HuR (HuRm-/-). HuRm-/- mice have a metabolically inflexible phenotype with mild obesity and impaired glucose tolerance compared to control littermates. HuRm-/- mice have an increase in RER; and decreased expression of genes involved in oxidative phosphorylation, fatty acid transport, and mitochondrial fatty acid metabolism, suggesting a decreased ability to use fats as an energy source. HuRm-/- mouse skeletal muscle also shows decreases in protein levels of important modulators of the mTOR signaling pathway, and compensatory increases in transcript levels of HuR target mRNAs. These data highlight the importance of HuR function in skeletal muscle metabolism; and suggest HuR as a mediator of metabolite selection. Disclosure J.D. Warfel: None.