Identifying therapeutic targets of accelerated sarcopenia

确定加速肌少症的治疗靶点

基本信息

批准号：
9056065
负责人：
Elena Volpi
金额：
$ 54.12万
依托单位：
UNIVERSITY OF TEXAS MED BR GALVESTON
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-08-15 至 2021-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9056065
关键词：
Acceleration Acids Acute Age Aging American Amino Acid Transporter Amino Acids Anabolism Bed rest Biology Carrier Proteins Cell membrane Cells Chronic Chronic Disease Clinical Trials Complex Data Development Diet Disease Elderly Exercise FRAP1 gene Goals Health Hospitalization Injury Insulin Intervention Knowledge Lead Measures Methodology Mission Modeling Muscle Muscle Proteins Muscle function Muscular Atrophy Non-Insulin-Dependent Diabetes Mellitus Outcome Persons Physical Dependence Physical Function Process Protein Biosynthesis Proteins Public Health Research Resistance Risk Signal Transduction Signaling Protein Skeletal Muscle Societies Stimulus Testing Work base disability disability burden evidence base extracellular fall risk frailty functional disability functional loss healthy aging human old age (65+)improved innovation molecular imaging mortality muscle form new therapeutic target novel nutrition prevent programs protein metabolism public health relevance resistance exercise response sarcopenia stable isotope therapeutic target

项目摘要

DESCRIPTION (provided by applicant): Sarcopenia is a major contributor to frailty and increases the risk of falls, physical dependence, disability and mortality in older adults. It advances slowly with healthy aging. However, diseases or other insults and injuries can accelerate sarcopenia and lead to catastrophic declines in mobility and independence. For example, chronic diseases such as Type 2 Diabetes Mellitus (T2DM) are associated with accelerated loss of muscle mass and function in seniors; hospitalization with bed rest inactivity acutely accelerates sarcopenia. What we do not know is how concurrent diseases, inactivity or other insults and injuries accelerate sarcopenia in older adults. This knowledge gap hinders the development of innovative, targeted treatments for this disabling condition. Our objective is to examine the basic mechanisms that underlie accelerated sarcopenia in older adults and identify potential targets for interventions. The central hypothesis, based on our preliminary data, is that a global and fundamental mechanism of acute or chronic acceleration of sarcopenia is a reduction in skeletal muscle amino acid transport, which decreases muscle protein anabolism, and can be reversed by activation of the mammalian/mechanistic Target of Rapamycin Complex 1 (mTORC1) signaling with a non- amino acid stimulus such as exercise. Amino acid transport is an active process that controls intracellular amino acid availability and the activation of protin synthesis in skeletal muscle. It is regulated by amino acid concentrations and non-amino acid stimuli that activate mTORC1 signaling, such as resistance exercise and insulin. We will test our central hypothesis with the following specific aims: 1) Determine the effect of T2DM on the sensitivity of skeletal muscle amino acid transport to dietary amino acids. 2) Determine the effect of short-term bed rest inactivity on the sensitivity of skeletal muscle amino acid transport to dietary amino acids. 3) Determine the effect of resistance exercise on the sensitivity of amino acid transport to dietary amino acids in acute and chronic accelerated sarcopenia induced by inactivity and T2DM. Using integrative molecular, imaging and stable isotope methodologies we will measure amino acid transport and protein metabolism in muscle, identifying specific upstream regulators involved in the anabolic resistance of accelerated sarcopenia that can be targeted with novel treatments to reduce sarcopenia and improve independence in older adults.

描述（由适用提供）：肌肉减少症是脆弱的主要因素，并增加了老年人跌倒，身体依赖，残疾和死亡率的风险。随着健康的衰老，它会缓慢发展。然而，疾病或其他伤害和伤害会加速肌肉减少症，并导致流动性和独立性的灾难性下降。例如，诸如2型糖尿病（T2DM）之类的慢性疾病与老年人的肌肉质量和功能的加速丧失有关。床休息不活动的住院急性加速肌肉减少症。我们不知道的是同时发生的疾病，无活跃或其他伤害以及老年人加速肌肉减少症。这种知识差距阻碍了针对这种残疾状况的创新，有针对性治疗的发展。我们的目标是检查基本的基本机制，这些机制是老年人加速肌肉减少症的基础，并确定了干预措施的潜在靶标。基于我们的初步数据的中心假设是肌肉减少症的急性或慢性加速的全球和基本机制是骨骼肌氨基酸转运的减少，可降低肌肉蛋白质合成蛋白，并且可以通过激活Rapamycin复合物1（MTORC1）信号（MTORC1）信号的哺乳动物/机械靶标（例如非氨基酸刺激刺激）的哺乳动物/机械靶标的逆转。氨基酸转运是一个控制细胞内氨基酸的可用性和骨骼肌中蛋白质合成的激活。它受氨基酸浓度和非氨基酸刺激的调节，可激活MTORC1信号传导，例如耐药性运动和胰岛素。我们将通过以下特定目的测试中心假设：1）确定T2DM对骨骼肌氨基酸对饮食氨基酸的敏感性的影响。 2）确定短期床休息不活动对骨骼肌氨基酸转运的灵敏度的影响 3）确定耐药性运动对氨基酸转运至急性和慢性加速肌肉减少症在不活动和T2DM引起的肌肉症中的敏感性。使用集成的分子，成像和稳定的同位素方法，我们将测量肌肉中的氨基酸转运和蛋白质代谢，确定参与加速肌肉减少合成代谢性抗性的特定上游调节剂，这些调节剂可以用新的治疗方法来靶向以减少肌肉减少症并改善老年人的独立性。