Nutrient Sensing & Signaling in Aging Muscle

营养感应

• 批准号: 9137155
• 负责人: Blake B Rasmussen
• 金额: $ 46.79万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-30 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9137155
• 关键词: Acute; Aerobic Exercise; Aging; Amino Acid Transporter; Amino Acids; Amino Acids Activation; Anabolism; Area; Bed rest; Blood; Burn Trauma; Cells; Clinical; Complex; Data; Dependency; Development; Elderly; Endothelium; Equilibrium; Etiology; Evidence based intervention; Exercise; Fall prevention; Goals; Health; Hospitalization; Human; Ingestion; Intervention; Kinetics; Knowledge; Lead; Measures; Mission; Modeling; Molecular Analysis; Molecular Target; Morbidity - disease rate; Muscle; Muscle Cells; Muscle Proteins; Muscle function; Muscular Atrophy; Nutrient; Outcome; Patients; Perfusion; Phosphotransferases; Physical Dependence; Physical Function; Physical activity; Physiological; Play; Population; Protein Biosynthesis; Public Health; Quality of life; Research; Resistance; Resistance development; Role; Signal Pathway; Signal Transduction; Signaling Protein; Sirolimus; Skeletal Muscle; Societies; Testing; Time; Translating; Vasodilation; Work; base; cancer cachexia; detection of nutrient; disability burden; endothelial dysfunction; evidence base; fall risk; feeding; human subject; improved; innovation; muscle aging; muscle form; muscle strength; novel; nutrition; protein metabolism; response; sarcopenia; wasting

 DESCRIPTION (provided by applicant): Anabolic resistance to nutrition is the reduced ability of skeletal muscle to increase protein synthesis in response to feeding. It is a major contributor to muscle atrophy in aging, inactivity, burns, trauma, and cancer cachexia. The effects of anabolic resistance on health and physical function are important. For example, the loss of muscle mass and strength with aging (sarcopenia) increases the risk for falls, physical dependency and morbidity in older adults. A major determinant of muscle size is muscle protein content, which is controlled by the fine balance between protein synthesis and breakdown. Recently, we have found that amino acids and exercise independently increase muscle protein synthesis and overall anabolism by activating the mammalian/mechanistic target of rapamycin complex 1 (mTORC1) signaling pathway in humans. Aging and inactivity reduce these anabolic effects, but the underlying mechanisms of anabolic resistance are not known. The purpose of our application is to better understand how anabolic resistance develops in skeletal muscle. Our long-term goal is to identify specific molecular targets for the development of evidence-based clinical interventions to counteract anabolic resistance and muscle wasting in clinical populations. Here, we will focus on the three potential mechanisms underlying anabolic resistance to amino acids: a) endothelial function (i.e., amino acid-induced endothelium dependent vasodilation and consequent muscle perfusion); b) amino acid transport capacity and function; c) activation of mTORC1 in human muscle cells. Our central hypothesis is that the physical activity level regulates endothelial function which is the primary contributor to anabolic resistance in human skeletal muscle. We will test this hypothesis in healthy subjects with the following specific aims: 1) Determine how physical inactivity reduces the sensitivity of muscle to amino acids. 2) Determine how exercise improves the muscle sensitivity to amino acids. 3) Determine the effect of increasing habitual physical activity on anabolic resistance. We will study human subjects utilizing a novel 4-pool stables isotopic model to measure amino acid kinetics and muscle protein metabolism in combination with molecular analysis of muscle to determine the regulatory role of amino acids, physical inactivity, and amino acid transporter functional activity on mTORC1. The proposed approach is innovative because it represents a new and substantial departure from the status quo as we will examine the underlying mechanisms of anabolic resistance to nutrition using novel methodological approaches. The proposed research is significant because it will lead to the development of evidence-based interventions to treat sarcopenia and muscle wasting.

 描述（由申请方提供）：对营养的合成代谢抗性是骨骼肌响应进食增加蛋白质合成的能力降低。它是衰老、不活动、烧伤、创伤和癌症恶病质中肌肉萎缩的主要原因。合成代谢抵抗对健康和身体功能的影响是重要的。例如，随着年龄的增长，肌肉质量和力量的损失（肌肉减少症）增加了老年人福尔斯、身体依赖和发病的风险。肌肉大小的一个主要决定因素是肌肉蛋白质含量，这是由蛋白质合成和分解之间的精细平衡控制的。最近，我们发现，氨基酸和运动独立地增加肌肉蛋白质合成和整体anastomia通过激活哺乳动物/机械靶雷帕霉素复合物1（mTORC 1）信号通路在人类。衰老和不活动减少了这些合成代谢作用，但合成代谢抵抗的潜在机制尚不清楚。我们应用的目的是更好地了解骨骼肌中合成代谢抵抗是如何发展的。我们的长期目标是确定特定的分子靶点，用于开发循证临床干预措施，以对抗临床人群中的合成代谢抵抗和肌肉萎缩。在这里，我们将重点关注对氨基酸的合成代谢抗性的三种潜在机制：a）内皮功能（即，氨基酸诱导的内皮依赖性血管舒张和随后的肌肉灌注）; B）氨基酸转运能力和功能; c）人肌肉细胞中mTORC 1的活化。我们的中心假设是，体力活动水平调节内皮功能，这是合成代谢的主要贡献者。 人体骨骼肌的抵抗力。我们将在健康受试者中测试这一假设，具体目标如下：1）确定身体不活动如何降低肌肉对氨基酸的敏感性。2)确定运动如何提高肌肉对氨基酸的敏感性。3)确定增加习惯性体力活动对合成代谢抵抗力的影响。我们将研究人类受试者，利用一种新的4池稳定同位素模型来测量氨基酸动力学和肌肉蛋白质代谢，结合肌肉的分子分析来确定氨基酸、体力活动和氨基酸转运蛋白功能活性对mTORC 1的调节作用。所提出的方法是创新的，因为它代表了一个新的和实质性的偏离现状，因为我们将使用新的方法学方法来研究合成代谢抵抗营养的潜在机制。这项研究意义重大，因为它将导致开发基于证据的干预措施来治疗肌肉减少症和肌肉萎缩。