Impact of Exercise on 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损失，是人类与年龄相关的一种突出和衰弱的后果。需要一个健康的衰老模型系统来有效地评估延缓或减少老年人肌肉减少症的潜在干预措施。我们定义了Fischer 344 x Brown Norway杂交大鼠（FBN）在30月龄时显著肌肉质量和纤维损失的开始。我们的研究表明，线粒体DNA （mtDNA）异常在肌纤维损失中起因果作用。我们已经表明，年龄依赖性mtDNA缺失突变在老年骨骼肌纤维中克隆积累到高水平。伴随异常基因组增加的是电子传递系统（ETS）复合物IV（细胞色素c氧化酶；COX-）活性的丧失和复合物II（琥珀酸脱氢酶；SDH++）的高反应性。这些异常纤维的COX-/SDH++区域容易萎缩和断裂，将分子事件（mtDNA缺失突变）与衰老表型（肌纤维损失）联系起来。耐力训练是老年人常用的干预措施，以对抗随着年龄增长而出现的肌肉质量和功能的丧失。然而，人们对这种干预对高龄人类或动物的影响知之甚少。我们最近完成的一项研究表明，雄性FBN大鼠在30月龄时开始进行3个月的高强度耐力训练，增加了ETS异常纤维的患病率，这是一个导致纤维丢失的有害过程。我们的数据与快速增长的文献一致，表明有益适应所需的运动水平随着年龄的增长而下降。我们假设有氧运动的益处/风险取决于i)开始有氧运动的年龄和ii)运动的强度水平。为了验证这一假设，我们将在雄性FBN大鼠线粒体异常、肌肉质量损失和纤维损失显著积累之前（24个月大鼠；SA1）和开始时（30个月大鼠；SA2）启动两种水平的运动（中度和高强度）。对照大鼠（24岁时久坐不动）的肌肉减少特征（肌肉形态和纤维命运）将被确定。30和36个月)和36个月大的实验大鼠。这些分析将定义肌肉质量、肌肉横截面积、纤维数量、纤维横截面积、纤维类型和纤维化浸润，以及显示坏死和凋亡变化的纤维数量。运动对受影响纤维的丰度、进展和mtDNA缺失负荷的影响将被确定（SA 3）。我们还将确定具有高mtDNA缺失负荷的单纤维是否改变了收缩功能，以及运动是否改变了受影响的单纤维的机械性能（SA4）。这个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否有益于老年哺乳动物的肌肉健康，耐力训练是一种常用的肌肉减少症干预方法。公共卫生相关性：肌肉减少症是由于肌肉纤维损失和萎缩导致的肌肉质量和功能的损失，是人类与年龄相关的一个突出和衰弱的后果。虽然耐力训练在老年人中是一种常用的干预措施，但其益处/风险并没有很好地描述，其影响通常在年轻人中研究。通过量化不同耐力训练方案对老年和超龄大鼠骨骼肌的分子、细胞和功能影响，我们将确定耐力训练是否能减轻肌肉减少症。

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.