Nutrient regulation of amino acid transporters in aging human skeletal muscle

描述（由申请人提供）：本K01申请的目的是促进候选人在衰老临床和转化研究方面的职业发展。他的长期职业目标是成为老年人功能衰退和康复的独立翻译研究者。在接受了基础人类骨骼肌研究的博士后培训后，申请人通过与UTMB Claude D. Pepper老年美国人独立中心（OAIC）的互动，对衰老的转化研究产生了兴趣。他现在寻求额外的培训，以更好地了解老年人功能衰退和康复的潜在问题。职业发展计划包括正式和非正式培训以及学徒式学习活动。一个由博士组成的多元化指导团队。沃尔皮、奥滕巴赫和帕顿-琼斯将指导这一发展。UTMB特别适合培养候选人的职业发展，因为它为多学科研究提供了一个非常协作的环境。具体而言，候选人将继续得到UTMB OAIC和CTSA的教育和核心资源支持。该研究项目的目标是确定衰老和不活动如何降低营养物质的肌肉合成代谢作用，并导致肌肉和功能丧失。核心假设是衰老降低了mTORC1信号和骨骼肌氨基酸转运蛋白的表达，以响应合成代谢刺激，导致肌肉对增加的细胞内氨基酸需求的适应性降低。我们进一步假设，不运动加剧了这种影响，导致显著的肌肉和功能丧失，而康复可以使肌肉信号、代谢和功能恢复到基线值。控制卧床休息是通过减少肌肉蛋白质合成来加速肌肉损失和功能障碍的一个非常有力的模型。随着年龄的增长，卧床休息造成的肌肉和功能损失的程度显著增加。我们将在健康受试者中进行以下测试：1)确定衰老是否会减弱mTORC1信号和骨骼肌氨基酸转运蛋白对氨基酸摄入的生理上调，并降低细胞内氨基酸可用性和肌肉蛋白质合成代谢。2)确定不运动（卧床休息）是否进一步加剧了年龄诱导的mTORC1信号和氨基酸转运蛋白表达的减少，以响应氨基酸摄入，并导致老年人比年轻人更大的肌肉和功能损失。3)确定物理康复是否能使肌肉信号、代谢和功能恢复到与睡前休息状态无差异的水平。收集的试点数据将用于未来的R01提交，以确定改善老年人肌肉功能和保持身体独立性的干预机制和新目标。

DESCRIPTION (provided by applicant): The purpose of this K01 application is to foster the candidate's career development in clinical and translational research on aging. His long term career goal is to become an independent translational investigator in functional decline and rehabilitation of older adults. After postdoctoral training in basic human skeletal muscle research, the applicant became interested in translational research on aging through his interactions with the UTMB Claude D. Pepper Older Americans Independence Center (OAIC). He now seeks additional training to gather a better understanding of the issues underlying functional decline and rehabilitation in older adults. The career development plan includes both formal and informal training combined with apprentice-style learning activities. A diverse mentoring team comprised of Drs. Volpi, Ottenbacher and Paddon-Jones will guide this development. UTMB is exceptionally well suited to foster the candidate's career development, as it provides a very collaborative environment for multidisciplinary research. Specifically, the candidate will continue to receive educational and core resource support from the UTMB OAIC and CTSA. The goal of the research project is to determine how aging and inactivity reduce the muscle anabolic effect of nutrients and lead to muscle and functional loss. The central hypothesis is that aging reduces mTORC1 signaling and the expression of skeletal muscle amino acid transporters in response to anabolic stimulation leading to reduced muscle adaptation to increased intracellular amino acid requirements. We further hypothesize that inactivity exacerbates this effect with significant muscle and functional loss, and rehabilitation restores muscle signaling, metabolism and function to baseline values. Controlled bed rest is a very powerful model of accelerated muscle loss and dysfunction via a reduction in muscle protein synthesis. The degree of muscle and functional loss achieved with bed rest significantly increases with aging. We will test in healthy subjects the following specific aims: 1) To determine if aging blunts the physiological upregulation of mTORC1 signaling and skeletal muscle amino acid transporters to amino acid ingestion and decreases intracellular amino acid availability and muscle protein anabolism. 2) To determine if physical inactivity (bed rest) further exacerbates the age-induced reduction in mTORC1 signaling and amino acid transporter expression in response to amino acid ingestion and induces a larger muscle and functional loss in older as compared to younger subjects. 3) To determine if physical rehabilitation can restore muscle signaling, metabolism and function to levels not different from the pre-bed rest condition. The pilot data collected will be used for future R01 submissions to identify mechanisms and novel targets for interventions to improve muscle function and preserve physical independence in older adults.