Nutrient regulation of amino acid transporters in aging human skeletal muscle

衰老人体骨骼肌中氨基酸转运蛋白的营养调节

基本信息

批准号：
8324211
负责人：
Micah J Drummond
金额：
$ 12.31万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-01 至 2015-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8324211
关键词：
Acute Address Age Aging American Amino Acid Transporter Amino Acids Anabolism Bed rest Biology Boxing Clinical Research Complex Data Development Development Plans Disease Elderly Environment Essential Amino Acids Fostering Functional disorder Future Gene Expression Gene Proteins Genetic Transcription Goals Growth Hospitalization Human Individual Ingestion Interdisciplinary Study Intervention Lead Learning Measures Mentors Metabolism Methods Microdialysis Modeling Molecular Biology Monitor Muscle Muscle Cells Muscle Proteins Muscle function Nutrient Outcome Perfusion Physical Function Physical therapy Physiological Protein Biosynthesis Proteins Publications Regulation Rehabilitation therapy Research Research Personnel Research Project Grants Resistance Resources Signal Transduction Signaling Protein Skeletal Muscle Skilled Nursing Facilities Societies Stimulus Techniques Testing Training Translational Research Ultrasonography United States National Institutes of Health Up-Regulation career career development combat design evidence base feeding functional decline functional loss improved interest mTOR protein muscle form novel post-doctoral training research study response skill acquisition stable isotope synthetic protein tool young adult

项目摘要

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.

描述（由申请人提供）：该K01申请的目的是促进候选人在衰老的临床和转化研究中的职业发展。他的长期职业目标是成为职能下降和老年人康复的独立翻译调查员。经过基本人类骨骼肌研究的博士后培训后，申请人通过与UTMB Claude D. Peper D. Pepper D. Pepper D. Pepper D. Peper D. Peper D. Peper D. Peper D. Pepper D. Pepper D. Peper D. Peper D. Peper D. Peper D. pepper Uniped Center（OAIC）的互动感兴趣。他现在寻求额外的培训，以更好地了解老年人功能下降和康复的问题。职业发展计划包括正式和非正式培训以及学徒风格的学习活动。由DRS组成的多元化指导团队。 Volpi，Ottenbacher和Paddon-Jones将指导这一发展。 UTMB非常适合促进候选人的职业发展，因为它为多学科研究提供了非常协作的环境。具体来说，候选人将继续获得UTMB OAIC和CTSA的教育和核心资源支持。研究项目的目的是确定衰老和不活动如何减少营养的肌肉合成代谢作用，并导致肌肉和功能损失。中心假设是，衰老降低了MTORC1信号传导和骨骼肌氨基酸转运蛋白的表达，这是对合成代谢刺激的响应，从而减少了肌肉适应增加细胞内氨基酸的需求。我们进一步假设，不活动会加剧这种效果，而肌肉和功能损失很大，而康复则恢复了肌肉信号传导，代谢和功能对基线值。受控床休息是通过减少肌肉蛋白质合成的肌肉丧失和功能障碍的非常强大的模型。随着床的休息，肌肉和功能损失的程度随着衰老而显着增加。我们将在健康受试者中测试以下特定目的：1）确定衰老是否会钝化MTORC1信号传导和骨骼肌氨基酸转运蛋白的生理上调，以摄入氨基酸并降低细胞内氨基酸的可利用性和肌肉蛋白质蛋白合物。 2）确定物理不活跃（床休息）是否进一步加剧了年龄引起的MTORC1信号传导和氨基酸转运蛋白表达的减少，响应于氨基酸摄取，并诱导与年轻受试者相比，老年人的肌肉和功能损失更大。 3）确定身体康复是否可以恢复肌肉信号传导，代谢和功能至与预床预休息条件没有不同的水平。收集的试点数据将用于未来的R01提交，以确定改善肌肉功能并保留老年人身体独立性的干预措施的机制和新目标。