Insulin and Sarcopenia in the Elderly

描述（由申请人提供）：我们的一般假设是肌肉蛋白质合成代谢对胰岛素的反应降低在随着年龄增长的肌肉质量损失中起重要作用。我们的目标是确定与年龄相关的肌肉蛋白胰岛素抵抗的机制，这将使我们能够确定针对这种缺陷的特定干预措施，并为预防和治疗肌肉减少症提供科学依据。我们之前的研究表明，与年轻对照组相比，健康老年人肌肉蛋白对胰岛素合成代谢作用的反应受损，这阻碍了混合喂养对肌肉蛋白的合成代谢作用。这些变化与年龄相关的胰岛素血管舒张反应的减少有关，从我们的数据来看，这似乎是胰岛素对肌肉蛋白生理合成代谢作用的潜在重要介质。我们实验室的初步数据还表明，在老年受试者中，单次有氧运动可以恢复血液流动、肌肉蛋白质合成和胰岛素合成代谢的正常反应。因此，我们将在健康受试者中测试以下具体假设：1)胰岛素引起的血流量和肌肉灌注的增加是胰岛素对肌肉蛋白质合成和合成代谢的生理刺激所必需的。2)衰老降低了血管对胰岛素的敏感性，阻止了血流量和肌肉灌注对胰岛素的生理增加，从而降低了肌肉蛋白质合成和净平衡对胰岛素和混合饲养的合成代谢作用的反应。3)有氧运动可以使老年人胰岛素引起的血流量和肌肉灌注增加恢复到年轻时的水平，从而使胰岛素和混合喂养对肌肉蛋白质合成和净肌肉蛋白质平衡的合成代谢作用正常化。我们将使用最先进的稳定同位素示踪技术来测量肌肉蛋白质转换，以及一种新开发的方法来测量年轻人和老年人的肌肉灌注。这些研究结果将使我们更好地定义胰岛素对肌肉蛋白合成代谢的生理作用机制，提高我们对肌肉减少症病理生理的认识，并为老年肌肉损失的行为和/或药物治疗提供科学依据。

DESCRIPTION (provided by applicant): Our general hypothesis is that a reduced response of muscle protein anabolism to insulin plays an important role in the loss of muscle mass with aging. Our goal is to determine the mechanisms underlying the age-related insulin resistance of muscle proteins, which will allow us to define specific interventions to target this defect and provide the scientific basis for the prevention and treatment of sarcopenia. Our previous studies indicate that the response of muscle proteins to the anabolic action of insulin is impaired in healthy older adults as compared to younger controls, which hampers the anabolic effect of mixed feeding on muscle proteins. These changes are associated with an age-related reduction in the vasodilatory response to insulin, which, from our data, appears to be a potentially important mediator of the physiological anabolic effect of insulin on muscle proteins. Preliminary data from our laboratory also suggest that in older subjects a single bout of aerobic exercise may restore the normal response of blood flow, muscle protein synthesis and anabolism to insulin. Therefore, we will test in healthy subjects the following specific hypotheses: 1) Insulin-induced increases in blood flow and muscle perfusion are necessary for the physiological stimulation of muscle protein synthesis and anabolism by insulin. 2) Aging reduces the vascular sensitivity to insulin, which prevents the physiological increase in blood flow and muscle perfusion in response to insulin, thereby decreasing the response of muscle protein synthesis and net balance to the anabolic action of insulin and mixed feeding. 3) Aerobic exercise can restore, in older subjects, the insulin-induced increase in blood flow and muscle perfusion to youthful levels, thus normalizing the anabolic effect of insulin and mixed feeding on muscle protein synthesis and net muscle protein balance. We will use state-of the art stable isotope tracer techniques to measure muscle protein turnover, and a newly developed method to measure muscle perfusion in young and older subjects. The results of these studies will allow us to better define the physiological mechanisms of action of insulin on muscle protein anabolism, advance our knowledge on the pathophysiology of sarcopenia, and provide the scientific basis for the behavioral and/or pharmacological treatment of muscle loss with aging.