Glucocorticoid regulation of NAD+ and energy metabolism in skeletal muscle ageing

糖皮质激素对骨骼肌衰老中 NAD 和能量代谢的调节

• 批准号: 2389191
• 金额: --
• 依托单位: University of Birmingham
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2019
• 资助国家: 英国
• 起止时间: 2019 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2389191
• 关键词: Glucocorticoid; regulation; NAD+; energy; metabolism

Background and need for the projectGlucocorticoid hormones are regulators of muscle energy homeostasis, and in mild excess or deficiency lead to metabolic disease, particularly in muscle, contributing to age-related frailty and cardiovascular disease. The role of NAD+ as a metabolic cofactor in redox reactions is well understood, and impaired NAD+ synthesis or increased consumption is proposed to drive aspects of age-related functional deficits, particularly in muscle. It has been shown that using NAD+ precursors to augment the NAD+ metabolome can modify metabolism and positively impact on mitochondrial function and inflammation. Glucocorticoids interact with the NAD+ metabolome and synthetic pathways in muscle, but the nature and impact of this interaction on age-related metabolic dysregulation has not been studied. It is proposed that interrogation of this new axis of metabolic regulation will illuminate novel muscle biology and therapies in a range of age-related disease processes.HypothesisGlucocorticoid hormone and NAD+ synthesis and consumption pathways interact to modulate energy metabolism in ageing muscle through metabolic and transcriptional control of networks important to health.Aims and objectives1) Define muscle metabolic network dynamics and pathway signalling in response to glucocorticoid and NAD+.2) Investigate this network and its modulation with ageing in mouse models of altered NAD and glucocorticoid metabolism.3) Examine NAD dynamics, sensitivity and interactions with glucocorticoid in young and aged humans.Brief experimental planAim-1 and 2- To investigate glucocorticoid interaction with NAD+ pathways using primary mouse myotubes, mice with and without mild and chronic excess or deficiency e.g. CRH KO, young and aged mouse models with genetic modifications of NAD+ synthetic pathways (NMRK1/2KO, NAMPTKO, NMR2.Tg overexpression) in combination with state-of-the-art methodologies [e.g. NAD+ metabolome; expression and activity of the NAD+ biosynthetic programme; targeted proteomics; high resolution mitochondrial respiration; metabolomics; stable isotope (C13 glucose and palmitate, N15 glutamine) tracing of nutrient metabolism.Aim 3- To test whether metabolism deteriorates in response to glucocorticoid more readily in ageing humans and examine the role of NAD in this process, young and aged humans will be exposed to conditions of mild glucocorticoid excess (using oral prednisolone) with and without supplementation with NR to assess its effects on fasting, postprandial and exercise metabolism. This will be carried by examining muscle and adipose biopsy, adipose micro-dialysis, blood and urine samples. This aim will benefit from close collaboration with Professor Jeremy Tomlinson at the University of Oxford- a world renowned steroid biologist and clinician with expertise in the metabolic understanding of glucocorticoid hormone action in health and disease.Expected outcome- Mechanistic and physiological knowledge of glucocorticoid interactions with the NAD+ metabolic network in muscle in young and aged mice and humans.- Insight into the therapeutic potential of nutritional NAD+ boosting to augment muscle metabolic responses and function in young and aged mice and humans.- Student to receive advanced training in state-of-the-art integrative physiology in laboratories with reputations for strong mentorship, onward career development and impactful contributions to the literature.

研究背景和课题需求糖皮质激素是肌肉能量平衡的调节因子，轻度过量或不足会导致代谢性疾病，尤其是肌肉代谢性疾病，导致与年龄相关的虚弱和心血管疾病。NAD+作为氧化还原反应中的代谢辅因子的作用已被充分理解，并且提出NAD+合成受损或消耗增加会导致年龄相关的功能缺陷，特别是在肌肉中。已经表明，使用NAD+前体来增加NAD+代谢组可以改变代谢并对线粒体功能和炎症产生积极影响。糖皮质激素与肌肉中的NAD+代谢组和合成途径相互作用，但这种相互作用对年龄相关的代谢失调的性质和影响尚未研究。有人提出，这一新的代谢调节轴的审讯将阐明新的肌肉生物学和治疗在一系列与年龄有关的疾病processes.HypothesisGlucocorticoid激素和NAD+的合成和消耗途径相互作用，以调节能量代谢在衰老肌肉通过代谢和转录控制网络的重要健康。定义响应糖皮质激素和NAD+的肌肉代谢网络动力学和通路信号传导。2）在改变的NAD和糖皮质激素代谢的小鼠模型中研究该网络及其随衰老的调节。3）检查NAD动力学，目的-1和2-为了研究糖皮质激素与NAD+途径的相互作用，使用原代小鼠肌管，具有和不具有轻度和慢性过量或缺乏例如CRH KO的小鼠，具有NAD+合成途径的遗传修饰的年轻和老年小鼠模型（NMRK 1/2KO、NAMPTKO、NMR2.Tg过表达）与最先进的方法学[例如NAD+代谢组学; NAD+生物合成程序的表达和活性;靶向蛋白质组学;高分辨率线粒体呼吸;代谢组学;稳定同位素（C13葡萄糖和棕榈酸盐，N15谷氨酰胺）追踪营养代谢目的3-为了测试在老年人中代谢是否更容易响应于糖皮质激素而恶化，并检查NAD在该过程中的作用，将年轻人和老年人暴露于轻度糖皮质激素过量（使用口服泼尼松龙）的条件下，补充和不补充NR，以评估其对空腹、餐后和运动代谢的影响。这将通过检查肌肉和脂肪活检，脂肪微透析，血液和尿液样本进行。这一目标将受益于与牛津大学Jeremy Tomlinson教授的密切合作。Jeremy Tomlinson教授是世界著名的类固醇生物学家和临床医生，擅长了解糖皮质激素在健康和疾病中的代谢作用。预期成果-糖皮质激素与年轻和老年小鼠和人类肌肉中NAD+代谢网络相互作用的机制和生理知识。深入了解营养NAD+增强的治疗潜力，以增强年轻和老年小鼠和人类的肌肉代谢反应和功能。学生在实验室接受最先进的综合生理学的高级培训，以强大的指导，向前的职业发展和对文献的有影响力的贡献而闻名。