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：肌肉减少症的特征是肌肉质量和无力丧失，导致脆弱和流动性受损。如住院和床休息期间发生的长时间肌肉消失可以加速肌肉减少症的进展。肌肉减少症及其相关的合并症在美国是一个巨大的公共卫生问题，但是，尚未阐明肌肉减少症的机制。升高的肌肉氧化应激会抑制蛋白质的合成并增加蛋白质分解，并被确定为废弃过程中肌肉萎缩的介体。尽管尚未鉴定出肌肉萎缩期间的氧化应激来源，但线粒体产生的活性氧（ROS）可能起作用。长时间肌肉不活跃期间，ROS产生的调节剂在很大程度上未知。但是，有证据表明肌肉脂质神经酰胺可能起作用。目的：这项研究的目的是确定神经酰胺在衰老和废弃的背景下在线粒体ROS产生和肌肉萎缩中的作用。方法：后肢模型将用于诱导年轻小鼠和老鼠的肌肉萎缩。通过使用不同的实验范式在骨骼肌内特异性操纵神经酰胺含量（Myriocin处理，DES-1 KO）或H2O2（MCAT过表达），我们将能够更加仔细地识别它们在废弃萎缩中的作用。将确定肌肉性能，包括疲劳性和最大强度，因为神经酰胺也已显示可介导疲劳和强度损失。我们将招募肌肉减少型在身体功能低下和非肌肉减少型高身体功能的老年人，以定义肌肉质量，功能和肌肉活检衍生的神经酰胺物种与线粒体生物能学之间的关系。意义：拟议的研究将首次提供新的翻译证据我既有动物和人类又是细胞内神经酰胺有助于线粒体ROS的产生，肌肉细胞减少症和身体功能丧失。