LAT1 and the development of anabolic resistance

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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.