Ceramide Mediated Oxidative Stress in Muscle Loss with Aging and Disuse

神经酰胺介导的氧化应激导致衰老和废用性肌肉损失

基本信息

批准号：
8486746
负责人：
Paul Martin Coen
金额：
$ 12.92万
依托单位：
ADVENTHEALTH ORLANDO
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-01 至 2017-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8486746
关键词：
Age Aging Animals Antioxidants Apoptotic Atrophic Attenuated Autophagocytosis Bed rest Bioenergetics Biopsy Buffers Ceramides Comorbidity Disuse Atrophy Elderly Electron Transport Experimental Models Fatigue Functional disorder Goals Healthcare Hospitalization Human Hydrogen Peroxide In Situ Individual Inflammatory Knockout Mice Limb structure Link Lipids Lysosomes Measures Mediating Mediator of activation protein Metabolism Methods Mitochondria Mitochondrial DNA Modeling Morbidity - disease rate Mus Muscle Muscle Fibers Muscle Weakness Muscle function Muscular Atrophy Oxidative Stress Pathway interactions Performance Physical Function Play Population Prevalence Production Protein Biosynthesis Proteins Public Health Reactive Oxygen Species Recruitment Activity Resistance Respiration Role Signal Pathway Signal Transduction Skeletal Muscle Source Sphingolipids Stress System Techniques Testing Therapeutic Studies Time Transgenic Organisms Ubiquitin Western Blotting age related aged catalase defined contribution dihydroceramide desaturase frailty indexing innovation lipid metabolism loss of function mitochondrial dysfunction mortality multicatalytic endopeptidase complex muscle form novel overexpression oxidative damage prevent protein degradation public health relevance response sarcopenia theories thermozymocidin translational approach translational study

项目摘要

DESCRIPTION (provided by applicant): Background: Sarcopenia is characterized by loss of muscle mass and weakness, leading to frailty, and impaired mobility. Prolonged muscle disuse, as occurs during hospitalization and bed rest, can accelerate the progression sarcopenia. Sarcopenia and its related co-morbidities are an enormous public health problem in the U.S. However, the mechanisms underlying sarcopenia have not been elucidated. Elevated muscle oxidative stress inhibits protein synthesis and increases protein breakdown, and has been identified as a mediator of muscle atrophy during disuse. While the source of oxidative stress during muscle atrophy has not been identified, reactive oxygen species (ROS) produced by mitochondria may play a role. The regulators of ROS production during prolonged muscle inactivity remains largely unknown. However, evidence suggests that the muscle lipid ceramide may play a role. Aim: The aim of this study is to determine the role of ceramide in mitochondrial ROS production and muscle atrophy in the context of aging and disuse. Methods: A hind limb model will be used to induce muscle atrophy in young and old mice. By specifically manipulating either ceramide content (myriocin treatment, DES-1 KO) or H2O2 (mCAT over-expression) within skeletal muscle using different experimental paradigms, we will be able to more carefully discern their roles in disuse atrophy. Muscle performance, including fatigability and maximal strength will be determined, as ceramide has also been shown to mediate fatigue and loss of strength. We will recruit sarcopenic low physically functioning and non-sarcopenic high physically functioning elderly individuals to define the relationships between muscle mass, function and muscle biopsy-derived ceramide species, and mitochondrial bioenergetics. Significance: The proposed studies will provide, for the first time, novel translational evidence i both animals and humans that intramyocellular ceramides contribute to mitochondrial ROS production, sarcopenia and loss of physical function.

描述（由申请人提供）：背景：肌肉减少症的特点是肌肉质量损失和虚弱，导致虚弱和活动能力受损。住院和卧床期间发生的长期肌肉废用会加速肌肉减少症的进展。肌肉减少症及其相关并发症在美国是一个巨大的公共卫生问题。然而，肌肉减少症的潜在机制尚未阐明。肌肉氧化应激升高会抑制蛋白质合成并增加蛋白质分解，并已被确定为废用期间肌肉萎缩的介质。虽然肌肉萎缩期间氧化应激的来源尚未确定，但线粒体产生的活性氧（ROS）可能发挥了作用。长时间肌肉不活动期间 ROS 产生的调节因素仍然很大程度上未知。然而，有证据表明肌肉脂质神经酰胺可能发挥作用。目的：本研究的目的是确定神经酰胺在衰老和废用背景下线粒体 ROS 产生和肌肉萎缩中的作用。方法：使用后肢模型来诱导年轻和年老小鼠的肌肉萎缩。通过使用不同的实验范例专门控制骨骼肌内的神经酰胺含量（多球菌素处理，DES-1 KO）或H2O2（mCAT过表达），我们将能够更仔细地辨别它们在废用性萎缩中的作用。将确定肌肉性能，包括疲劳性和最大力量，因为神经酰胺也被证明可以调节疲劳和力量损失。我们将招募肌肉减少症低身体功能和非肌肉减少症高身体功能老年人来定义肌肉质量、功能和肌肉活检衍生的神经酰胺种类以及线粒体生物能学之间的关系。意义：拟议的研究将首次为动物和人类提供新的转化证据，证明肌细胞内神经酰胺有助于线粒体 ROS 产生、肌肉减少症和身体功能丧失。