Activated ER alpha as compensation for HuR controlled lipid oxidation in skeletal muscle

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PROJECT SUMMARY/ABSTRACT Metabolic flexibility is the capacity for an organism to adapt fuel oxidation to fuel availability. We have shown that mice lacking the RNA binding protein HuR in skeletal muscle are less metabolically flexible than controls, with a decreased ability to oxidize lipids in skeletal muscle. Our recently published findings show that this phenotype is specific to male animals, and that female animals lacking HuR in skeletal muscle do not have decreased lipid oxidation relative to controls. The mechanistic underpinnings of this sexual dimorphism are unknown. This proposal tests the overarching hypothesis that activated ERα can promote lipid oxidation through the PPAR transcription factors, allowing females to bypass HuR-controlled lipid oxidation due to higher levels of circulating estrogen. Two specific aims are proposed: 1) Investigate HuR and ERα regulated skeletal muscle fatty acid oxidation; and 2) Test the ability of 17β-estradiol to stimulate fatty acid oxidation in HuR-deficient muscle. The completion of these aims will provide insights into sex-specific control of skeletal muscle lipid oxidation, which may facilitate development of sex-specific strategies for treatment of metabolic disease. Importantly, these studies will build upon data and experience obtained from my K01 award while also providing a novel extension of my previous training and current knowledge regarding HuR control of metabolic flexibility. The data generated from this proposal will provide a foundation for R01 proposals designed to investigate the molecular mechanisms controlling metabolic flexibility in mice and humans, which is consistent with my long- term research goals.