Impact of Exercise on Sarcopenia

运动对肌肉减少症的影响

• 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
• 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

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

骨质疏松症是由于肌肉纤维丢失和萎缩而导致的肌肉质量和功能的丧失，是一种突出的 对人类造成衰弱的与年龄相关的后果。需要一个健康的老龄化模型系统来 有效评估延缓或减少老年人骨质疏松症的潜在干预措施。我们定义了起病时间 Fischer 344×Brown挪威杂交大鼠(FBN)在30个月龄时显著的肌肉质量和纤维丢失 年龄。我们的研究表明，线粒体DNA(MtDNA)异常在糖尿病的发病中起着一定的作用。 肌肉纤维丢失。我们已经证明了依赖于年龄的mtdna缺失突变克隆性累积到高。 老化的骨骼肌纤维中的水平。伴随着这种异常基因组的增加的是复合体的丢失 电子传递系统(ETS)的IV(细胞色素C氧化酶；COX-)活性及其高反应性 复合体II(琥珀酸脱氢酶；SDH++)。这些异常纤维的COX-/SDH++区域容易发生 萎缩和断裂，将分子事件mtDNA缺失突变与衰老表型肌肉联系起来 纤维损耗。耐力训练是老年人对抗肌肉丧失的一种常见干预措施 随着年龄增长而产生的质量和功能。然而，人们对这种干预的影响知之甚少。 年老的人类或动物。我们最近完成的一项研究表明，3个月的高强度运动 在雄性FBN大鼠30个月龄时开始的耐力训练增加了ETS的患病率 纤维异常，这是一种导致纤维丢失的有害过程。我们的数据与快速增长的 表明有益适应所需的运动水平随着年龄的增长而下降的文献。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)练习的强度级别。为了验证这一假设，我们将开始两个级别的锻炼 (中度和高度)在(24月龄大鼠；SA1)之前和(30月龄大鼠；SA2)开始时 雄性FBN大鼠线粒体异常堆积、肌肉质量丢失和纤维丢失。这个 将在对照组大鼠(24小时久坐)中测定骨骼肌生肌谱(肌肉形态和纤维命运)。30 和36个月龄的实验大鼠。这些分析将定义肌肉质量、肌肉 纤维横截面积、纤维数目、纤维横截面积、纤维类型和纤维浸润，以及 呈现坏死性和凋亡性改变的纤维数量。运动对人体的丰富性和 进展和线粒体DNA缺失负荷将在受影响的纤维(SA 3)中确定。我们还将确定是否 线粒体DNA缺失负荷高的单一纤维改变了收缩功能，以及运动是否改变了 受影响的单纤维的机械性能(SA4)。此练习模型将作为测试我们的 提出了与年龄相关的纤维丢失的机制以及加深了我们对有氧运动影响的理解 老年骨骼肌中的运动。这些研究的一个重要结果是确定耐力训练是否， 一种常用的干预骨质疏松症的方法，对老年哺乳动物的肌肉健康是有益的。 1