Impact of Exercise on Sarcopenia

描述(申请人提供)：骨质疏松症，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，是人类的一种与年龄相关的显著和衰弱的后果。需要一种健康的衰老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30个月大的Fischer 344×Brown挪威杂交大鼠(FBN)的显著肌肉质量和纤维丢失的开始。我们的研究表明，线粒体DNA(MtDNA)异常在肌肉纤维丢失中起着因果作用。我们已经证明，年龄相关的mtDNA缺失突变在衰老的骨骼肌纤维中克隆性积累到高水平。伴随着异常基因组增加的是电子传递系统(ETS)的复合体IV(细胞色素c氧化酶；COX-)活性的丧失和复合体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，将一个分子事件mtDNA缺失突变与衰老表型肌肉纤维丢失联系在一起。耐力训练是老年人用来对抗随着年龄增长而出现的肌肉质量和功能丧失的一种常见干预措施。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，在30个月大的雄性FBN大鼠中开始3个月的高强度耐力训练，会增加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相一致，这些文献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(24个月龄大鼠；SA1)和开始(30个月龄大鼠；SA2)雄性FBN大鼠线粒体异常显著积累、肌肉质量丧失和纤维丢失之前启动两种水平的运动(中等和高强度)。将在对照组大鼠(24小时久坐不动)中测定骨骼肌生肌谱(肌肉形态和纤维命运)。30和36月龄)和36月龄实验大鼠。这些分析将确定肌肉质量、肌肉横截面积、纤维数量、纤维横截面积、纤维类型和纤维渗透，以及呈现坏死和凋亡变化的纤维数量。运动对受累纤维中线粒体DNA的丰度和进程以及线粒体DNA缺失负荷的影响将被确定(SA3)。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单纤维的机械性能(SA4)。这个运动模型将作为一种测试我们提出的与年龄相关的纤维丢失机制的手段，以及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对老年哺乳动物的肌肉健康有利，耐力训练是一种常见的石棺减少干预措施。与公共卫生相关：骨质疏松症，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，是人类与年龄相关的显著和衰弱的后果。虽然耐力训练是老年人常用的干预措施，但其益处/风险并未得到很好的描述，其影响通常在年轻人中进行研究。通过量化不同耐力训练方案对老年和高龄大鼠骨骼肌的分子、细胞和功能的影响，我们将确定耐力训练是否可以减轻骨骼肌减少症。

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.