Impact of Exercise on Sarcopenia

运动对肌肉减少症的影响

基本信息

批准号：
8299939
负责人：
JUDD M. AIKEN
金额：
$ 39.49万
依托单位：
UNIVERSITY OF ALBERTA
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-05-15 至 2013-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8299939
关键词：
Aerobic Aerobic Exercise Affect Age Age-Months Aging Animals Apoptotic Area Atrophic Attenuated Benefits and Risks Biological Models Complex Contractile Proteins Contralateral Cytochrome c Reductase Data Deletion Mutation Elderly Electron Transport Etiology Event Exercise Exhibits Fiber Genome Genotype Goals Health Human Hybrids Infiltration Intervention Link Literature Mammals Mechanics Mitochondria Mitochondrial DNA Modeling Moderate Exercise Molecular Morphology Muscle Muscle Fibers Muscle function Mutation Necrosis Norway Outcome Study Oxidases Phenotype Play Prevalence Process Property Rattus Regimen Role Skeletal Muscle Soleus Muscle Succinate Dehydrogenase System Testing Time Training age related aged base combat cytochrome c oxidase design disability enzyme activity healthy aging male mature animal mitochondrial DNA mutation muscle aging muscle form rectus femoris research study sarcopenia sedentary tool vastus lateralis

项目摘要

Sarcopenia, the loss of muscle mass and function due to muscle fiber loss and atrophy, is a prominent and debilitating age-related consequence in humans. There is a need for a healthy aging model system to efficiently evaluate potential interventions that delay or reduce sarcopenia of the aged. We defined the onset of significant muscle mass and fiber loss in the Fischer 344 x Brown Norway hybrid rat (FBN) at 30 months of age. Our studies have demonstrated that mitochondrial DNA (mtDNA) abnormalities play a causal role in muscle fiber loss. We have shown that age-dependent mtDNA deletion mutations clonally accumulate to high levels in aged skeletal muscle fibers. Concomitant with this increase in aberrant genomes is a loss of complex IV (cytochrome c oxidase; COX-) activity of the electron transport system (ETS) and the hyper-reactivity of complex II (succinate dehydrogenase; SDH++). These COX-/SDH++ regions of abnormal fibers are prone to atrophy and breakage, linking a molecular event, mtDNA deletion mutations, with an aging phenotype, muscle fiber loss. Endurance training is a common intervention employed by the elderly to combat the loss of muscle mass and function that occurs with age. Very little, however, is known of the impact of this intervention in very old humans or animals. We have recently completed a study showing that 3 months of high intensity endurance training, initiated at 30 months of age in the male FBN rat, increased the prevalence of ETS abnormal fibers, a detrimental process that leads to fiber loss. Our data is consistent with a rapidly growing body of literature that indicates the level of exercise necessary for beneficial adaptation declines with age. We hypothesize that the benefits/risks of aerobic exercise is dependent on i) the age at which aerobic exercise is initiated and ii) the intensity level of the exercise. To test this hypothesis, we will initiate two levels of exercise (moderate and high) prior to (24-month-old rats; SA1) and at the onset (30-month-old rats; SA2) of significant accumulation of mitochondrial abnormalities, muscle mass loss and fiber loss in male FBN rats. The sarcopenic profiles (muscle morphology and fiber fate) will be determined in control rats (sedentary at 24-. 30 and 36 months) and experimental rats at 36-months of age. These analyses will define muscle mass, muscle cross-sectional area, fiber number, fiber cross-sectional area, fiber type and fibrotic infiltration, as well as the number of fibers exhibiting necrotic and apoptotic changes. The impact of exercise on the abundance and progression and mtDNA deletion load will be determined in affected fibers (SA 3). We will also ascertain if single fibers with high mtDNA deletion loads have altered contractile function and whether exercise alters the mechanical properties of affected single fibers (SA4). This exercise model will serve as a means of testing our proposed mechanism of age-related fiber loss as well as further our understanding of the impact of aerobic exercise in aged skeletal muscle. An important outcome of these studies is to determine if endurance training, a commonly employed intervention of sarcopenia, can be beneficial to muscle health in old mammals. 1

肌肉减少症是由于肌肉纤维丧失和萎缩而导致的肌肉质量和功能的丧失，是一个突出的，并且人类与年龄相关的后果。需要健康的老化模型系统有效评估延迟或减少老年肌肉减少症的潜在干预措施。我们定义了发作 Fischer 344 x棕色挪威杂种大鼠（FBN）的肌肉质量和纤维损失在30个月时年龄。我们的研究表明，线粒体DNA（mtDNA）异常在肌肉纤维损失。我们已经表明，年龄依赖性mtDNA缺失突变在克隆中积累到高老年骨骼肌纤维的水平。与异常基因组增加的同时，是复合物的丧失电子传输系统（ETS）的IV（细胞色素C氧化酶； COX-）活性和超反应性复合物II（琥珀酸脱氢酶； SDH ++）。这些异常纤维的COX-/SDH ++区域容易萎缩和破裂，将分子事件，mtDNA缺失突变与衰老表型，肌肉联系起来纤维损失。耐力训练是老年人采取的常见干预措施来打击肌肉的丧失随着年龄的增长而发生的质量和功能。然而，很少有人知道这种干预措施对老人或动物。我们最近完成了一项研究，表明3个月的高强度雄性FBN大鼠以30个月大的耐力训练增加了ETS的患病率异常纤维，这是导致纤维损失的有害过程。我们的数据与迅速增长的文学体系表明，随着年龄的增长，有益适应所必需的锻炼水平。我们假设有氧运动的益处/风险取决于i）有氧运动的年龄启动和ii）练习的强度水平。为了检验这一假设，我们将启动两个级别的练习（24个月大的大鼠； SA1）和一开始（30个月大的大鼠; SA2）之前（中等和高）雄性FBN大鼠的线粒体异常，肌肉质量损失和纤维损失的积累。这肌肉减少型（肌肉形态和纤维命运）将在对照大鼠中确定（久坐于24-。30 和36个月的实验大鼠在36个月的年龄。这些分析将定义肌肉质量，肌肉横截面区域，纤维数，纤维横截面区域，纤维类型和纤维化浸润以及表现出坏死和凋亡变化的纤维数量。运动对丰度和进展和mtDNA缺失负荷将在受影响的纤维中确定（SA 3）。我们还将确定是否具有高mtDNA缺失载荷的单纤维已改变收缩功能，并且运动是否改变受影响的单纤维的机械性能（SA4）。这种锻炼模型将作为测试我们的一种手段提出的与年龄相关纤维损失的机制，以及我们对有氧恐怖的影响的理解运动骨骼肌。这些研究的重要结果是确定耐力训练是否，通常采用肌肉减少症的干预措施，对旧哺乳动物的肌肉健康有益。 1