Nutrient Sensing & Signaling in Aging Muscle

 说明(申请人提供)：合成代谢抵抗是指骨骼肌对摄食反应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机能的影响很重要。例如，随着年龄的增长，肌肉质量和力量的丧失(骨骼减少)会增加老年人跌倒、身体依赖和发病率的风险。肌肉大小的一个主要决定因素是肌肉蛋白质含量，它由蛋白质合成和分解之间的微妙平衡所控制。最近，我们发现氨基酸和运动通过激活哺乳动物/机械目标雷帕霉素复合体1(MTORC1)信号通路，独立地增加肌肉蛋白质合成和整体合成代谢。衰老和不活动减少了这些合成代谢的影响，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，以抵消临床人群中的合成代谢抵抗和肌肉萎缩。在这里，我们将集中讨论氨基酸合成代谢抵抗的三个潜在机制：a)内皮功能(即氨基酸诱导的内皮依赖性血管扩张和随后的肌肉灌流)；b)氨基酸运输能力和功能；c)人肌肉细胞中mTORC1的激活。我们的中心假设是，身体活动水平调节内皮功能，内皮功能是合成代谢的主要贡献者 人类骨骼肌中的抵抗力。我们将在健康受试者中测试这一假设，具体目的如下：1)确定不运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阻力的影响。我们将利用一种新的四池马厩同位素模型来研究人类受试者，以测量氨基酸动力学和肌肉蛋白质代谢，并结合肌肉的分子分析来确定氨基酸、身体活动不足和氨基酸转运体功能活性对mTORC1的调节作用。拟议的方法是创新的，因为它代表着与现状的新的和实质性的偏离，因为我们将使用新的方法方法来研究合成代谢抵抗营养的潜在机制。这项拟议的研究意义重大，因为它将导致循证干预措施的发展，以治疗石棺减少和肌肉萎缩。

 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.