Identifying therapeutic targets of accelerated sarcopenia

确定加速肌少症的治疗靶点

• 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
• 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

 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(由申请人提供)：骨质疏松症是导致身体虚弱的主要因素，并增加老年人跌倒、身体依赖、残疾和死亡的风险。随着健康的衰老，它的进展缓慢。然而，疾病或其他侮辱和伤害会加速骨骼减少，并导致行动能力和独立性的灾难性下降。例如，像2型糖尿病(T2 DM)这样的慢性病与老年人肌肉质量和功能的加速丧失有关；卧床休息不活动的住院会急剧加速骨骼减少。我们不知道的是，并发的疾病、不活动或其他侮辱和伤害是如何加速老年人的骨质疏松症的。这种知识差距阻碍了针对这种致残性疾病的创新、有针对性的治疗方法的开发。我们的目标是研究老年人加速石棺减少的基本机制，并确定干预的潜在靶点。根据我们的初步数据，中心假设是 骨骼肌急性或慢性加速的一个全球性和基本的机制是骨骼肌氨基酸运输减少，从而减少肌肉蛋白质的合成代谢，并可以通过激活哺乳动物/机械雷帕霉素复合体1靶点(MTORC1)信号与非氨基酸刺激(如运动)来逆转。氨基酸转运是一个主动的过程，它控制细胞内氨基酸的可获得性和骨骼肌中蛋白质合成的激活。它受氨基酸浓度和激活mTORC1信号的非氨基酸刺激的调节，如抵抗运动和胰岛素。我们将通过以下具体目标来验证我们的中心假设：1)确定T2 DM对骨骼肌氨基酸运输对饮食氨基酸的敏感性的影响。2)测定短期卧床不活动对骨骼肌氨基酸转运敏感性的影响 到饮食中的氨基酸。3)探讨抗阻运动对急、慢性运动缺乏和2型糖尿病所致的急性和慢性加速性骨质疏松症患者氨基酸转运对膳食氨基酸敏感性的影响。使用整合的分子、成像和稳定同位素方法，我们将测量肌肉中的氨基酸运输和蛋白质代谢，确定特定的上游调节因子，这些调节因子参与加速的骨质疏松症的合成代谢抵抗，可以通过新的治疗方法来减少骨质疏松症，提高老年人的独立性。