LAT1 and the development of anabolic resistance

描述（由申请人提供）：肌肉减少症，由于衰老导致的肌肉量减少，导致或加重一系列衰弱性疾病，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，最终目标是提高数百万美国人的寿命和生活质量。具体来说，我们将研究肌肉中的主要亮氨酸转运蛋白LAT1在肌肉减少症的发展中所起的作用。由于亮氨酸的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，并制定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，我们已经提出了一个工作假设，即肌肉中mTOR激活和核糖体生物生成的减少会导致合成代谢抵抗。我们将通过以下三个具体目标来检验这一假设：1)确定老化或LAT1的丧失是否会影响对负荷的合成代谢抗性；2)确定LAT1的缺失是否会增加对蛋白质饲养的合成代谢抗性；3)确定核糖体质量的增加是否能逆转合成代谢抵抗。这一高度创新的提议首次利用新技术在多个水平上测量核糖体的生物发生，探索了肌肉生物学中的这个基本问题。这项研究的意义是双重的：1)它将有助于对导致肌肉减少症的分子事件的基本理解，2)它将验证一种简单的药物治疗策略，可以增加肌肉质量，从而提高生活质量，降低人群死亡率。这项应用的成功完成是我们实验室实现长期目标的一步：在不需要锻炼的情况下，创造出更大、更强壮、更抗疲劳的肌肉。

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.