Impact of Exercise on Sarcopenia

肌肉减少症，即由于肌纤维损失和萎缩而导致的肌肉质量和功能的损失，是一种突出的， 与年龄相关的衰弱性后果。需要一种健康的老龄化模型系统， 有效地评估延迟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个月时的显著肌肉质量和纤维损失 年龄我们的研究已经证明，线粒体DNA（mtDNA）异常发挥因果作用， 肌肉纤维损失我们已经证明，年龄依赖性mtDNA缺失突变克隆积累到高水平， 老年骨骼肌纤维中的水平。伴随着异常基因组的增加， IV（细胞色素c氧化酶;考克斯-）活性的电子传递系统（ETS）和高反应性的 复合物II（琥珀酸脱氢酶; SDH++）。这些异常纤维的考克斯-/SDH++区域易于发生 萎缩和断裂，将分子事件、mtDNA缺失突变与衰老表型、肌肉 光纤损耗耐力训练是一种常见的干预雇用的老年人，以打击损失的肌肉 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的影响， 老年人或动物我们最近完成的一项研究表明，3个月的高强度 在30个月大的雄性FBN大鼠中开始耐力训练，增加了ETS的患病率 异常纤维，导致纤维损失的有害过程。我们的数据显示 大量文献表明，有益的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）有氧运动的年龄 （1）运动强度;（2）运动强度。为了验证这一假设，我们将启动两个级别的运动 （中度和高度）之前（24月龄大鼠; SA 1）和开始时（30月龄大鼠; SA 2）的显著性 线粒体异常的积累、肌肉质量损失和纤维损失。的 将在对照大鼠（24小时久坐不动）中确定肌肉减少特征（肌肉形态和纤维命运）。30 和36月龄）和36月龄的实验大鼠。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。运动对丰富和 将在受影响的纤维中确定进展和mtDNA缺失负荷（SA 3）。我们还将确定， 高mtDNA缺失负荷的单纤维改变了收缩功能，运动是否改变了收缩功能， 受影响的单纤维的机械性能（SA 4）。这个练习模型将作为测试我们的 提出了与年龄相关的纤维损失的机制，以及进一步了解有氧运动的影响， 老年骨骼肌的锻炼。这些研究的一个重要成果是确定耐力训练， 一种通常采用的肌肉减少症的干预，可有益于老年哺乳动物的肌肉健康。 1

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