Nutritional and Contractile Regulation of Muscle Growth

描述(由申请人提供)：本项目的重点是研究调节人类骨骼肌生长的生理和细胞机制。保持足够的肌肉质量不仅对活动能力和能量/蛋白质代谢至关重要，而且对生存也至关重要。只有当足够的合成代谢刺激抵消了以基础状态和许多导致肌肉萎缩的条件为特征的蛋白质分解代谢时，肌肉质量才能保持或增加。我们的初步研究表明，营养和耐力运动是骨骼肌合成代谢的两个主要刺激因素。在之前的资助周期中，我们已经证明mTOR信号通路似乎参与了人类肌肉蛋白质合成的抗阻运动和营养刺激。我们还表明，mTOR通路在一种新的治疗方法(低强度阻力运动中限制血流)后被激活。这一发现在患者群体中具有潜在的用途(例如，在手术后接受物理治疗的患者、虚弱的老年人、骨科患者等)。不能以诱导肌肉生长所需的强度进行阻力运动。因此，根据我们的初步数据，我们的一般假设是，合成代谢营养、代谢应激/反应性充血和年龄是调节阻力运动后合成信号、合成和分解代谢基因表达以及肌肉蛋白质合成的独立因素。具体地说，我们假设在健康受试者中：(1)mTOR信号通路的激活是阻力运动和/或合成代谢营养摄入后刺激肌肉蛋白质合成的主要细胞机制。(2)低强度抗阻运动中的血流受限会导致肌肉代谢应激和反应性充血，激活合成代谢途径。(3)衰老与抵抗运动的合成代谢反应降低有关，这一缺陷可以通过运动后摄入合成营养物质和/或血流受限的新疗法来克服。这些尖锐的研究将提供对调节人类肌肉蛋白质平衡的生理和细胞机制的洞察，并将被用作开发基于科学的干预措施的基础，以改善衰老、康复、创伤、癌症和艾滋病等条件下的肌肉蛋白质平衡。与公共健康相关：该项目的重点是研究营养素和抵抗力运动如何调节人体肌肉生长。在这项应用中，我们提出了几项人体研究：1)确定关键细胞通路(MTOR)是否负责控制肌肉生长；2)研究一种具有潜在临床意义的新型运动疗法如何促进肌肉生长的机制；3)确定运动后使用营养补充是否可以改善老年人的肌肉生长反应。这些研究将提供对调节人类肌肉生长的机制的洞察，并将被用作开发基于科学的干预措施的基础，以改善衰老、康复、创伤、癌症和艾滋病等条件下的肌肉生长和功能。

DESCRIPTION (provided by applicant): The focus of this project is to examine physiological and cellular mechanisms that regulate human skeletal muscle growth. Maintenance of an adequate muscle mass is critical not only for mobility and energy/protein metabolism, but also for survival. Muscle mass is maintained or increased only when adequate anabolic stimuli counteract the protein catabolism that characterizes the basal state and many of the conditions that lead to muscle wasting. Our preliminary studies have shown that nutrition and resistance exercise are two major anabolic stimuli for skeletal muscle. During the previous grant cycle we have shown that the mTOR signaling pathway appears to be an involved in both the resistance exercise and nutrient stimulation of muscle protein synthesis in humans. We have also shown that the mTOR pathway is activated following a novel treatment (blood flow restriction during low-intensity resistance exercise). This finding has potential use in patient populations (e.g., in patients undergoing physical therapy following surgery, frail elderly, orthopedic patients, etc.) that cannot perform resistance exercise at the intensity level needed to induce muscle growth. Therefore, based on our preliminary data, our general hypothesis is that anabolic nutrients, metabolic stress/reactive hyperemia, and age are independent factors that can regulate anabolic signaling, anabolic and catabolic gene expression, and muscle protein synthesis following a bout of resistance exercise. Specifically, we hypothesize that in healthy human subjects: (1) Activation of the mTOR signaling pathway is the primary cellular mechanism responsible for the stimulation of muscle protein synthesis following resistance exercise and/or anabolic nutrient ingestion. (2) Blood flow restriction during low-intensity resistance exercise induces muscle metabolic stress and reactive hyperemia which activates anabolic pathways. (3) Aging is associated with a reduced anabolic response to resistance exercise, and this defect can be overcome by post-exercise ingestion of anabolic nutrients and/or the novel treatment of blood flow restriction. These acute studies will provide insight into physiological and cellular mechanisms that regulate human muscle protein balance, and will be utilized as a basis from which to develop scientifically-based interventions for improving muscle protein balance in conditions such as aging, rehabilitation, trauma, cancer, and AIDS. PUBLIC HEALTH RELEVANCE: The focus of this project is to examine how nutrients and resistance exercise regulate human muscle growth. In this application we propose several human studies to: 1) determine whether a key cellular pathway (mTOR) is responsible for controlling muscle growth; 2) examine the mechanisms of how a novel exercise treatment with potential clinical significance can promote muscle growth; 3) determine whether the muscle growth response can be improved in the elderly with the use of nutrient supplementation following exercise. These studies will provide insight into the mechanisms that regulate human muscle growth, and will be used as a basis from which to develop scientifically-based interventions for improving muscle growth and function in conditions such as aging, rehabilitation, trauma, cancer, and AIDS.