The RNA binding protein HuR influences skeletal muscle metabolic flexibility in rodents and humans

• Published in: Metabolism, clinical and experimental Vol. 97; pp. 40 - 49
• Main Authors: Mynatt, Randall L., Noland, Robert C., Elks, Carrie M., Vandanmagsar, Bolormaa, Bayless, David S., Stone, Allison C., Ghosh, Sujoy, Ravussin, Eric, Warfel, Jaycob D.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.08.2019
• Subjects: Adult; Animals; Diabetes Mellitus, Type 2 - metabolism; ELAV-Like Protein 1 - metabolism; Fasting - metabolism; Fatty Acids - metabolism; Female; Glucose Intolerance - metabolism; Humans; Lipid Metabolism - physiology; Male; Metabolic flexibility; Mice; Mice, Inbred C57BL; Mice, Knockout; Mitochondria - metabolism; Muscle, Skeletal - metabolism; Obesity - metabolism; Oxidation-Reduction; Oxidative Phosphorylation; Pulmonary Gas Exchange - physiology; RNA homeostasis; RNA-Binding Proteins - metabolism; Rodentia - metabolism; Skeletal muscle; RBP; RNA homeostasis; ARE; GDR; GTT; ITT; SAGE; IPA; Metabolic flexibility; RER; Skeletal muscle
• ISSN: 0026-0495; 1532-8600; 1532-8600
• DOI: 10.1016/j.metabol.2019.05.010

Metabolic flexibility can be assessed by changes in respiratory exchange ratio (RER) following feeding. Though metabolic flexibility (difference in RER between fasted and fed state) is often impaired in individuals with obesity or type 2 diabetes, the cellular processes contributing to this impairment are unclear. From several clinical studies we identified the 16 most and 14 least metabolically flexible male and female subjects out of >100 participants based on differences between 24-hour and sleep RER measured in a whole-room indirect calorimeter. Global skeletal muscle gene expression profiles revealed that, in metabolically flexible subjects, transcripts regulated by the RNA binding protein, HuR, are enriched. We generated and characterized mice with a skeletal muscle-specific knockout of the HuR encoding gene, Elavl1 (HuRm−/−). Male, but not female, HuRm−/− mice exhibit metabolic inflexibility, with mild obesity, impaired glucose tolerance, impaired fat oxidation and decreased in vitro palmitate oxidation compared to HuRfl/fl littermates. Expression levels of genes involved in mitochondrial fatty acid oxidation and oxidative phosphorylation are decreased in both mouse and human muscle when HuR is inhibited. HuR inhibition results in impaired metabolic flexibility and decreased lipid oxidation, suggesting a role for HuR as an important regulator of skeletal muscle metabolism. •HuR contributes to the mechanistic control of metabolic flexibility.•This is a translational research study using samples from clinical trials.•HuR controls cellular RNA and its removal results in impaired lipid oxidation.•The decrease in lipid oxidation may be more detrimental for males than females.