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

项目总结/摘要 代谢灵活性是生物体使燃料氧化适应燃料可用性的能力。我们已经表明 在骨骼肌中缺乏RNA结合蛋白HuR的小鼠比对照组的代谢灵活性更低， 骨骼肌中脂质氧化能力降低。我们最近发表的研究结果表明， 表型是雄性动物特有的，而骨骼肌中缺乏HuR的雌性动物没有 相对于对照，脂质氧化减少。这种两性异形的机械基础是 未知该提案测试了激活的ERα可以通过以下方式促进脂质氧化的总体假设 过氧化物酶体增殖物激活受体转录因子，使女性绕过HuR控制的脂质氧化，由于更高的水平， 循环雌激素本研究的目的有两个：1）研究HuR和ERα对骨骼肌的调节作用 脂肪酸氧化;和2）测试17β-雌二醇刺激HuR缺乏的小鼠中脂肪酸氧化的能力。 肌肉.这些目标的完成将为骨骼肌脂质的性别特异性调控提供新的见解 氧化，这可能有助于发展性别特异性的策略，用于治疗代谢疾病。 重要的是，这些研究将建立在从我的K 01奖获得的数据和经验的基础上，同时也提供了 我以前的训练和目前的知识关于代谢灵活性的HuR控制的一个新的扩展。 本提案生成的数据将为R 01提案提供基础，该提案旨在调查 控制小鼠和人类代谢灵活性的分子机制，这与我长期以来的研究一致， 长期研究目标。

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.