LAT1 and the development of anabolic resistance

描述(申请人提供)：骨骼减少，肌肉质量的损失，由于年龄的增长，导致或加重一系列衰弱的情况，包括冠状动脉疾病，肥胖，2型糖尿病，和虚弱。尽管肌肉质量对健康和生活质量至关重要，但从营养和活动到肌肉蛋白质合成、质量和力量的变化的分子链仍然知之甚少。这项研究旨在研究影响肌肉力量的关键因素，最终目的是提高数百万美国人的寿命和生活质量。具体地说，我们将研究肌肉中主要的亮氨酸转运体LAT1在石棺减少症发展中所扮演的角色。由于亮氨酸摄取是抵抗运动和蛋白质喂养的合成代谢反应所必需的，因此本研究的目的是确定LAT1在合成代谢抵抗中的作用，并开发一种维持肌肉质量和力量的药理学策略。基于我们之前在这一领域发表的研究，以及强有力的初步数据，我们提出了一个工作假说，即肌肉中mTOR激活和核糖体生物生成减少会导致合成代谢抵抗。我们将通过检验以下三个具体目标来检验这一假说：1)确定LAT1的老化或丢失是否会带来对负荷的合成抵抗；2)确定LAT1的丢失是否会使蛋白质摄取产生合成抵抗；以及3)确定核糖体质量增加是否会逆转合成抵抗。这一极具创新性的建议首次使用新技术在多个水平上测量核糖体生物发生，探索了肌肉生物学中的这一基本问题。这项研究的意义有两方面：1)它将有助于基本了解导致骨质疏松症的分子事件；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，从而改善生活质量并降低人口死亡率。这项应用的成功完成向我们实验室的长期目标又迈进了一步：在不需要锻炼的情况下创造更大、更强壮和更耐疲劳的肌肉。

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.