LAT1 and the development of anabolic resistance

LAT1 和合成代谢抵抗的发展

• 批准号: 9052680
• 负责人: Keith Baar
• 金额: $ 39.37万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9052680
• 关键词: Address; Aging; American; Americas; Animals; Area; Biogenesis; Biology; Clinical; Coronary Arteriosclerosis; Data; Development; Direct Costs; Disease; Drug Design; Elderly; Event; Exercise; FRAP1 gene; Fatigue; Goals; Growth; Health; Intervention; Knockout Mice; Laboratories; Lead; Leucine; Longevity; Maintenance; Measures; Metabolism; Moderate Exercise; Molecular; Muscle; Muscle Proteins; Non-Insulin-Dependent Diabetes Mellitus; Obesity; One-Step dentin bonding system; Pharmacotherapy; Population; Process; Protein Biosynthesis; Protein Kinase; Proteins; Public Health; Publishing; Quality of life; Rennie; Research; Resistance; Resistance development; Ribosomes; Role; Skeletal Muscle; Techniques; Testing; Time; Work; age-related muscle loss; aged; drug development; economic cost; effective therapy; feeding; fighting; frailty; improved; innovation; men; mortality; muscle form; muscle hypertrophy; muscle strength; novel; nutrition; overexpression; prevent; research study; resistance exercise; response; sarcopenia; treatment strategy; uptake; young adult

DESCRIPTION (provided by applicant): Sarcopenia, the loss of muscle mass due to aging, causes or aggravates a range of debilitating conditions including coronary artery disease, obesity, type 2 diabetes, and frailty. Even though muscle mass is essential for health and quality of life, the molecular chain of events that lead from nutrition and activity to a change in muscle protein synthesis, mass and strength remains poorly understood. This study aims to examine critical factors that contribute to muscle strength, with the ultimate goal of improving the longevity and quality of life in millions of Americans. Specifically, we will look at the role playd by the primary leucine transporter in muscle, LAT1, in the development of sarcopenia. Since leucine uptake is required for the anabolic response to both resistance exercise and protein feeding, the objective of this work is to determine the role of LAT1 in anabolic resistance and develop a pharmacological strategy to maintain muscle mass and strength. Building on our previously published research in this area, and strong preliminary data, we have developed the working hypothesis that decreased mTOR activation and ribosome biogenesis in muscle results in anabolic resistance. We will test this hypothesis by examining these three specific aims: 1) Determine whether aging or loss of LAT1 imparts anabolic resistance to loading; 2) Determine whether loss of LAT1 imparts anabolic resistance to protein feeding; and 3) Determine whether increasing ribosome mass reverses anabolic resistance. This highly innovative proposal explores this essential question in muscle biology using novel techniques to measure ribosome biogenesis at multiple levels for the first time. The significance of this research is two-fold: 1)It will contribute to a basic understanding of the molecular events leading to sarcopenia, and 2) It will validate a simple drug treatment strategy that can increase muscle mass and thus improve quality of life and reduce mortality in the population. Successful completion of this application i one step towards the long-term objective of our laboratory: to create bigger, stronger, and more fatigue resistant muscles without the need for exercise.

描述（由申请人提供）：肌肉减少症，衰老引起的肌肉质量损失，导致或加剧了一系列令人衰弱的疾病，包括冠状动脉疾病，肥胖，2型糖尿病和脆弱。即使肌肉质量对于健康和生活质量至关重要，但从营养和活性到肌肉蛋白质合成的变化，质量和力量的变化的分子链仍然知之甚少。这项研究旨在检查有助于肌肉力量的关键因素，其最终目标是改善数百万美国人的寿命和生活质量。具体而言，我们将研究主要亮氨酸转运蛋白在LAT1中的角色扮演。由于对抗性运动和蛋白质喂养的合成代谢反应需要亮氨酸摄取，因此这项工作的目的是确定LAT1在合成代谢抗性中的作用，并制定一种药理策略来维持肌肉质量和力量。在我们先前在该领域发表的研究以及强大的初步数据的基础上，我们开发了这样的假设，即在肌肉中降低MTOR激活和核糖体生物发生会导致合成代谢性。我们将通过检查以下三个特定目的来检验这一假设：1）确定衰老或LAT1的损失是否赋予合成代谢的载荷能力； 2）确定LAT1的损失是否赋予合成代谢抗蛋白质的抗性； 3）确定增加核糖体质量是否会逆转合成代谢性。这项高度创新的建议使用新颖的技术探索了肌肉生物学中的这个基本问题，以首次测量多个层次的核糖体生物发生。这项研究的意义是两个方面：1）它将有助于对导致肌肉减少症的分子事件的基本了解，以及2）它将验证一种简单的药物治疗策略，该策略可以增加肌肉质量，从而提高生活质量并降低人群的死亡率。成功完成本应用程序，我朝着实验室的长期目标迈出了一步：创造更大，更强壮，更抗疲劳的肌肉而无需运动。