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; 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，它响应各种信号，以改变其大小和功能能力。在所有年龄的个体中，骨骼肌质量和功能的丧失均在不同程度上发生，这是增加脆弱，动员丧失和死亡率增加的主要因素。在衰老过程中，骨骼肌还会发展出对生长刺激（例如增加负荷和营养）的抗性（或肥大）。在延长床休息或不活动的延长后，无法响应增加的负荷和营养摄入以恢复肌肉大小，这可能会加速与年龄相关的肌肉损失的进展，并有助于在老年人中经常观察到的功能迁移，独立性和脆弱性的丧失。尽管许多研究都研究了 衰老的健康肌肉在抗药性运动中成长的能力，很少有人研究衰老对肌肉浪费后载荷引起的生长的影响，因为固定和床休息后发生的那样。由于强制床休息的时期随着年龄的增长而变得越来越普遍，因此肌肉质量和功能的恢复受损是一个重要的临床关注，可能会影响患者的长期健康和福祉。因此，该提案的具体目标是了解肌肉耐药性生长的细胞和分子机制，以响应废除诱导的萎缩后的负荷和营养增加。我们的工作假设是，与年龄相关的负荷诱导的肌肉生长的丧失是代谢应激增加的结果，导致蛋白质降解的激活以及对翻译起始和核糖体生物发生的随之抑制，导致蛋白质平衡。在此提案中，我们将利用一种啮齿动物模型，我们已证明，该模型密切复制了人类状况，即，在尾悬浮后的后肢重新加载，以研究年龄对骨骼肌萎缩的影响和萎缩后的神经质量的恢复。将在年轻人（9个月大）和老年（28个月大的）Fisher 344-Brown挪威大鼠（一种鲜艳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。该提案的具体目的是：（1）确定活性减少和代谢压力是否构成了老年大鼠重新加载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）是否在重新加载后更大程度地激活年龄大鼠。 （3）确定由于氨基酸摄取受损而增加负荷后，老年大鼠的蛋白质合成是否会降低，并通过MTORC1（Rapamycin的哺乳动物靶标）抑制了翻译起始。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（SIRT1激活）干预措施以扭转衰老的影响 在转化为临床人群之前。该提案中概述的研究将提供有关调节萎缩后调节肌肉生长的细胞机制的基本知识，并确定了将转化为人类转化的潜在治疗方法。 这项研究与退伍军人的管理特别相关，因为系统中老年退伍军人的人口正在上升，并且骨骼肌萎缩的影响在老年人中更具令人衰弱和昂贵。该提议中概述的研究的长期目标是开发有效的疗法，以增强老年人萎缩后肌肉恢复，这代表了一个重大的问题和未满足的临床需求。 公共卫生相关性： 迄今为止，还没有有效的治疗治疗方法可以预防与年龄相关的肌肉质量和功能的损失，或者在萎缩和损伤后增强肌肉的恢复。该提案中概述的研究将提供有关调节萎缩后调节肌肉生长的细胞和分子机制的基本知识，并确定潜在的治疗方法将转化为人类。这项研究与退伍军人的管理特别相关，因为该系统中的大量患者需要康复才能在床休息，固定或神经创伤引起的萎缩后恢复骨骼肌质量。老龄化的人口代表了弗吉尼亚州日益增长的医疗和货币关注，因为老年人由于恢复不良而遭受萎缩的影响更大。在老年人萎缩后增强肌肉恢复的有效疗法的发展是未满足的临床需求，这是该提案中概述的研究的长期目标。