Mechanisms Involved in Age-Related Loss of Muscle Mass and Growth Response

描述(由申请人提供)： 骨骼肌是一种高度适应性的组织，它对各种信号做出反应，以改变其大小和功能能力。随着年龄的增长，所有个体都会不同程度地出现骨骼肌质量和功能的丧失，这是导致虚弱程度增加、活动能力丧失和死亡率增加的主要原因。在衰老过程中，骨骼肌也对生长(或肥大)产生抵抗力，以应对增长刺激，如增加负荷和营养。在长时间卧床或不活动后，无法对增加的负荷和营养摄入量做出反应以恢复肌肉大小，可能会加速与年龄相关的肌肉损失的进展，并导致老年人经常观察到的功能活动能力、独立性的丧失和开始虚弱。虽然许多研究已经调查了 尽管衰老对原本健康的肌肉在抵抗运动后生长的能力有影响，但很少有人研究衰老对肌肉在固定和卧床后一段时间内发生的负荷诱导生长的影响。由于随着年龄的增长，强制卧床休息的时间变得越来越普遍，肌肉质量和功能的受损恢复是一个重要的临床问题，可能会影响患者的长期健康和福祉。因此，这项建议的具体目标是了解肌肉抵抗生长的细胞和分子机制，以响应废弃诱导的萎缩后增加的负荷和营养。我们的工作假设是，与年龄相关的负荷诱导的肌肉生长丧失是代谢应激增加的结果，导致蛋白质降解的激活，以及伴随而来的翻译起始和核糖体生物发生的抑制，从而导致蛋白质负平衡。在这个方案中，我们将利用我们已经证明接近复制人类情况的啮齿动物模型，即尾部悬吊卸载后的后肢重新加载，来研究年龄对骨骼肌萎缩和萎缩后肌肉质量恢复的影响。卸载/再负荷对年轻(9月龄)和老年(28月龄)Fisher 344-Brown挪威大鼠骨骼肌质量和收缩功能的影响将被研究，Fisher 344-Brown挪威鼠是一个成熟的啮齿动物衰老模型。这项建议的具体目的是：(1)确定活动减少和代谢应激增加是否是老年大鼠重新负荷后观察到的肌肉生长减少的原因。(2)测定老年大鼠负荷后蛋白质降解途径(泛素蛋白酶体系统、钙蛋白酶、溶酶体蛋白水解酶)是否被更大程度地激活。(3)确定老年大鼠在负荷增加后，蛋白质合成是否由于氨基酸摄取受损和通过mTORC1(雷帕霉素的哺乳动物靶标)翻译起始受抑而减少。在可能的情况下，将在我们的动物模型中测试特定的营养(蛋白质补充)和药物(激活SIRT1)干预措施以逆转衰老的影响 在转化为临床人群之前。这项建议中概述的研究将提供关于随着年龄增长而调节肌肉萎缩后肌肉生长的细胞机制的基础知识，并确定可能的移植到人类的治疗方法。 这项研究与退伍军人管理局特别相关，因为该系统中的老年退伍军人人数正在上升，而骨骼肌萎缩对老年人的影响更大，成本更高。这项研究概述的长期目标是开发有效的治疗方法，以促进老年人萎缩后的肌肉恢复，这是一个重大的问题和未得到满足的临床需求。

DESCRIPTION (provided by applicant): Skeletal muscle is a highly adaptable tissue that responds to a variety of signals to modify its size and functional capacity. Loss of skeletal muscle mass and function occurs to varying degrees in all individuals with age and is a major contributor to increased frailty, loss of mobiliy, and increased mortality. During the aging process, skeletal muscle also develops a resistance to grow (or hypertrophy) in response to growth stimuli such as increased loading and nutrition. An inability to respond to increased loading and nutritional intake to restore muscle size following extended periods of bed rest or inactivity could accelerate the progression of age-associated muscle loss, and contribute to the loss of functional mobility, independence and the onset of frailty often observed in the elderly. While many studies have investigated the effects of aging on the ability of otherwise healthy muscle to grow in response to resistance exercise, few have studied the effects of aging on load-induced growth following a period of muscle wasting as occurs following immobilization and bed rest. Since periods of enforced bed rest become more common with age, the impaired recovery of muscle mass and function is a significant clinical concern that can affect the long-term health and well-being of patients. Consequently, the specific objective of this proposal is to understand the cellular and molecular mechanisms underlying the resistance of muscle to grow in response to increased loading and nutrition following disuse-induced atrophy. Our working hypothesis is that the age-associated loss of load-induced muscle growth is the result of increased metabolic stress resulting in the activation of protein degradation and a concomitant inhibition of translation initiation and ribosome biogenesis resulting in negative protein balance. In this proposal we will utilize a rodent model that we have shown to closely replicate the human condition, i.e., hindlimb reloading following tail suspension unloading, to study the effect of age on both skeletal muscle atrophy and the recovery of muscle mass following atrophy. The effects of unloading/reloading on skeletal muscle mass and contractile function will be studied in young (9 month old) and old (28 month old) Fisher 344-Brown Norway rats, a well-established rodent aging model. The specific aims for this proposal are to: (1) Determine whether decreased activity and increased metabolic stress underlie the reduced muscle growth observed following reloading in aged rats. (2) Determine whether protein degradation pathways (ubiquitin proteasome system, calpain, lysosomal proteases) are activated to a greater extent in aged rats following reloading. (3) Determine whether protein synthesis is decreased in aged rats following increased loading due to impaired amino acid uptake and inhibition of translation initiation through mTORC1 (mammalian target of rapamycin). Where possible, specific nutritional (protein supplementation) and pharmaceutical (SIRT1 activation) interventions to reverse the effects of aging will be tested in our animal model before translation into a clinical population. The studies outlined in this proposal will provide fundamental knowledge about the cellular mechanism regulating muscle growth following atrophy as a function of age, as well as identify potential treatments for translation into humans. This research is of particular relevance to the Veteran's Administration since the population of older veterans in the system is rising, and the effects of skeletal muscle atrophy are more debilitating and costly in the elderly. The long-term goal of the research outlined in this proposa is the development of effective therapies for the enhancement of muscle recovery following atrophy in the elderly, which represents a significant problem and unmet clinical need.