Impact of Exercise on Sarcopenia

运动对肌肉减少症的影响

• 批准号: 7580241
• 负责人: JUDD M. AIKEN
• 金额: $ 43.31万
• 依托单位: UNIVERSITY OF ALBERTA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-15 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7580241
• 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; Mutation; Necrosis; Norway; Outcome Study; Oxidases; Phenotype; Play; Prevalence; Process; Property; Rattus; Role; Skeletal Muscle; Soleus Muscle; Succinate Dehydrogenase; System; Testing; Time; Training; Treatment Protocols; age related; aged; base; combat; cytochrome c oxidase; design; disability; enzyme activity; healthy aging; male; mature animal; mitochondrial DNA mutation; muscle aging; muscle form; public health relevance; research study; sarcopenia; sedentary; tool

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: 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. Although endurance training is a commonly applied intervention in the elderly, the benefits/risks are not well delineated and its impact is normally studied in young. By quantifying the molecular, cellular and functional effects of different regimens of endurance training on skeletal muscle in old and very old rats, we will determine whether endurance training attenuates sarcopenia.

描述（由申请人提供）：肌肉减少症，由于肌肉纤维损失和萎缩而导致的肌肉质量和功能的丧失，是人类中与年龄相关的显着后果。健康的老化模型系统需要有效评估延迟或减少老年肌肉减少症的潜在干预措施。我们在30个月大时定义了Fischer 344 x棕色挪威杂种大鼠（FBN）的肌肉质量和纤维损失的发作。我们的研究表明，线粒体DNA（mtDNA）异常在肌肉纤维损失中起因果作用。我们已经表明，年龄依赖性的mtDNA缺失突变在老年骨骼肌纤维中克隆积聚至高水平。与异常基因组增加的同时，电子传输系统（ETS）的复合体IV（​​细胞色素C氧化酶； Cox-）活性的丧失和复合物II的高反应性（琥珀酸脱氢酶； SDH ++）。这些异常纤维的COX-/SDH ++区域易于萎缩和破裂，将分子事件，mtDNA缺失突变与衰老表型，肌肉纤维丧失联系起来。耐力训练是老年人采取的一种常见干预措施来应对随着年龄的增长而发生的肌肉质量和功能。然而，很少有人知道这种干预对非常老的人或动物的影响。我们最近完成了一项研究，该研究表明，男性FBN大鼠在30个月大的30个月大的高强度耐力训练增加了ETS异常纤维的患病率，这是导致纤维损失的有害过程。我们的数据与快速增长的文献一致，这表明随着年龄的增长，有益适应所必需的运动水平。我们假设有氧运动的益处/风险取决于i）启动有氧运动的年龄以及ii）运动的强度水平。为了检验这一假设，我们将在（24个月大的大鼠； SA1）和雄性FBN大鼠的线粒体异常，肌肉质量损失和纤维损失的显着积累开始之前（24个月大的大鼠； SA1）和在一开始（30个月大的大鼠; SA2）之前开始进行两种级别的运动（中和高）。肌肉减少型（肌肉形态和纤维命运）将在对照大鼠（24-.30和36个月的久坐大鼠）中确定，并在36个月大时进行实验大鼠。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。运动对受影响的纤维中的丰度和进展和mtDNA缺失负荷的影响（SA 3）。我们还将确定具有高mtDNA缺失载荷的单纤维是否改变了收缩功能，并且运动是否会改变受影响的单纤维的机械性能（SA4）。该运动模型将作为测试我们提出的与年龄相关的纤维损失机制的一种手段，并进一步了解有氧运动对老年骨骼肌的影响。这些研究的一个重要结果是确定耐力训练是一种通常采用的肌肉减少症干预措施，对旧哺乳动物的肌肉健康是否有益。 公共卫生相关性：肌肉减少症，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，是人类与年龄相关的显着后果。尽管耐力训练是老年人通常采用的干预措施，但效益/风险尚未得到很好的描述，通常在Young中研究其影响。通过量化耐力训练的不同方案对旧大鼠骨骼肌的分子，细胞和功能作用，我们将确定耐力训练是否会减轻肌肉减少症。