Impact of Exercise on Sarcopenia

运动对肌肉减少症的影响

基本信息

批准号：
8082609
负责人：
JUDD M. AIKEN
金额：
$ 41.94万
依托单位：
UNIVERSITY OF ALBERTA
依托单位国家：
美国
项目类别：
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/8082609
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

项目摘要

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丧失，是人类与年龄相关的一个突出且令人衰弱的后果。需要一种健康老龄化模型系统来有效评估延迟或减少老年人肌少症的潜在干预措施。我们定义了 Fischer 344 x 挪威棕色杂交大鼠 (FBN) 在 30 个月龄时出现显着肌肉质量和纤维损失的情况。我们的研究表明，线粒体 DNA (mtDNA) 异常在肌纤维损失中起着因果作用。我们已经证明，年龄依赖性 mtDNA 缺失突变在衰老的骨骼肌纤维中克隆地积累到高水平。与异常基因组的增加相伴的是电子传递系统（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。耐力训练是老年人用来对抗随年龄增长而出现的肌肉质量和功能丧失的常见干预措施。然而，人们对这种干预措施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 个月大时开始进行 3 个月的高强度耐力训练，会增加 ETS 异常纤维的患病率，这是一个导致纤维损失的有害过程。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。为了检验这一假设，我们将在线粒体异常显着积累之前（24 个月大的大鼠；SA1）和开始时（30 个月大的大鼠；SA2）启动两个级别的运动（中度和高），雄性 FBN 大鼠的肌肉质量损失和纤维损失。将在对照大鼠（24-30和36个月久坐）和36个月龄的实验大鼠中测定肌肉减少特征（肌肉形态和纤维命运）。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，以及表现出坏死和凋亡变化的纤维数量。运动对丰度和进展以及 mtDNA 缺失负荷的影响将在受影响的纤维中确定 (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方法，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（肌肉减少症的常用干预措施）是否有益于老年哺乳动物的肌肉健康。公共卫生相关性：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丧失，是人类与年龄相关的一个突出且令人衰弱的后果。尽管耐力训练是老年人中常用的干预措施，但其益处/风险尚不清楚，并且通常在年轻人中研究其影响。通过量化不同耐力训练方案对老年和非常老年大鼠骨骼肌的分子、细胞和功能影响，我们将确定耐力训练是否可以减轻肌肉减少症。