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

与年龄相关的肌肉质量损失和生长反应的机制

• 批准号: 8277635
• 负责人: Sue C Bodine
• 金额: --
• 依托单位: VA NORTHERN CALIFORNIA HEALTH CARE SYS
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8277635
• 关键词: 26S proteasome; Acetylation; Activities of Daily Living; Adult; Affect; Age; Age-Months; Aged, 80 and over; Aging; Aging-Related Process; Amino Acids; Animal Model; Animals; Atrophic; Bed rest; Biogenesis; Biological Assay; Calpain; Cathepsins B; Cell Respiration; Clinical; Cues; Degradation Pathway; Development; Diet; Elderly; Equilibrium; Exercise; Genes; Goals; Growth; Growth Factor; HDAC4 gene; Harvest; Health; High Pressure Liquid Chromatography; Hindlimb; Hormones; Human; Hypertrophy; Immobilization; Individual; Injury; Intake; Intervention; Knowledge; Leucine; Measurement; Measures; Mechanics; Medical; Metabolic stress; Metabolism; Methods; Milk; Modeling; Molecular; Monitor; Motor; Movement; Mus; Muscle; Muscle function; Muscular Atrophy; Natural regeneration; Norway; Nutrient; Nutritional; Older Population; Oxygen Consumption; Pathway interactions; Patients; Peptide Hydrolases; Personal Satisfaction; Pharmacologic Substance; Phosphotransferases; Population; Process; Production; Protein Biosynthesis; Proteins; Rattus; Rattus norvegicus; Recovery; Rehabilitation therapy; Research; Resistance; Ribosomes; Rodent; Rodent Model; Role; Signal Transduction; Skeletal Muscle; Stimulus; Supplementation; System; Tail Suspension; Testing; Therapeutic; Thermogenesis; Tissues; Transcriptional Activation; Translation Initiation; Translations; Trauma; Ubiquitin; United States Department of Veterans Affairs; Veterans; Western Blotting; Work; age effect; age related; aged; aging population; blood glucose regulation; effective therapy; endoplasmic reticulum stress; feeding; frailty; functional loss; improved; mTOR protein; mortality; multicatalytic endopeptidase complex; muscle form; muscle strength; nutrition; prevent; protein degradation; relating to nervous system; repaired; response; sarcopenia; skeletal muscle growth; stable isotope; uptake; wasting

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. PUBLIC HEALTH RELEVANCE: To date there are no effective therapeutic treatments for preventing age-related loss of muscle mass and function, or to enhance recovery of muscle following atrophy and injury. The studies outlined in this proposal will provide fundamental knowledge about the cellular and molecular mechanisms 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 a significant number of patients in the system will require rehabilitation to recover skeletal muscle mass following atrophy induced by bed rest, immobilization, or neural trauma. The aging population represents a growing medical and monetary concern for the VA, since the elderly will suffer greater consequences of atrophy due to poor recovery. The development of effective therapies for the enhancement of muscle recovery following atrophy in the elderly is an unmet clinical need, and is the long-term goal of the research outlined in this proposal.

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，骨骼肌质量和功能的丧失在所有个体中都不同程度地发生，并且是增加虚弱、丧失活动性和增加死亡率的主要原因。在衰老过程中，骨骼肌也会对生长刺激（如增加的负荷和营养）产生生长阻力（或肥大）。在长时间卧床休息或不活动后，无法对增加的负荷和营养摄入做出反应以恢复肌肉大小，这可能会加速与年龄相关的肌肉损失的进展，并导致功能性移动性、独立性的丧失和老年人经常观察到的虚弱发作。虽然许多研究已经调查了 衰老对健康肌肉响应抗阻运动而生长的能力的影响，很少有人研究衰老对在固定和卧床休息后发生的肌肉消耗一段时间后负荷诱导的生长的影响。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，肌肉质量和功能的恢复受损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，本提案的具体目标是了解废用性萎缩后肌肉抵抗负荷和营养增加而生长的细胞和分子机制。我们的工作假设是，与年龄相关的负荷诱导的肌肉生长的损失是代谢应激增加的结果，导致蛋白质降解的激活和伴随的翻译起始和核糖体生物合成的抑制，导致负蛋白质平衡。在这个提议中，我们将利用一种啮齿动物模型，我们已经证明它可以近似地复制人类的状况，即，尾部悬吊卸载后后肢再加载，以研究年龄对骨骼肌萎缩和萎缩后肌肉质量恢复的影响。将在年轻（9月龄）和老年（28月龄）Fisher 344-Brown Norway大鼠（一种成熟的啮齿动物衰老模型）中研究卸载/重新加载对骨骼肌质量和收缩功能的影响。该建议的具体目标是：（1）确定活动减少和代谢应激增加是否是老年大鼠再负荷后观察到的肌肉生长减少的基础。(2)确定蛋白质降解途径（泛素蛋白酶体系统、钙蛋白酶、溶酶体蛋白酶）在老年大鼠中是否在重新加载后被更大程度地激活。(3)确定老年大鼠在增加负荷后，由于氨基酸摄取受损和通过mTORC 1（雷帕霉素的哺乳动物靶标）抑制翻译起始，蛋白质合成是否减少。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（SIRT 1激活）干预以逆转衰老的影响 在转化为临床人群之前。本提案中概述的研究将提供有关细胞机制的基本知识，这些细胞机制调节萎缩后肌肉生长作为年龄的函数，并确定潜在的治疗方法。 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增加，骨骼肌萎缩的影响在老年人中更加虚弱和昂贵。本提案中概述的研究的长期目标是开发有效的治疗方法，以增强老年人萎缩后的肌肉恢复，这是一个重大问题和未满足的临床需求。 公共卫生关系： 迄今为止，还没有有效的治疗方法来预防与年龄相关的肌肉质量和功能损失，或增强肌肉萎缩和损伤后的恢复。本提案中概述的研究将提供有关调节肌肉萎缩后肌肉生长的细胞和分子机制的基础知识，并确定潜在的治疗方法。这项研究与退伍军人管理局特别相关，因为系统中有相当数量的患者在卧床休息、固定或神经创伤引起的萎缩后需要康复以恢复骨骼肌质量。人口老龄化代表了VA日益增长的医疗和经济问题，因为老年人将因恢复不佳而遭受更大的萎缩后果。开发有效的治疗方法来增强老年人萎缩后的肌肉恢复是一个尚未满足的临床需求，也是本提案中概述的研究的长期目标。