Ceramide Mediated Oxidative Stress in Muscle Loss with Aging and Disuse

描述（由申请人提供）：背景：肌肉减少症的特征是肌肉质量损失和无力，导致虚弱和活动能力受损。长期肌肉废用，如住院和卧床休息期间发生的，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是美国的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。升高的肌肉氧化应激抑制蛋白质合成并增加蛋白质分解，并且已被鉴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）可能起作用。长期肌肉不活动期间ROS产生的调节剂在很大程度上仍然未知。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：采用后肢肌萎缩动物模型，对青年和老年小鼠进行肌肉萎缩实验。通过使用不同的实验范例在骨骼肌内特异性地操纵神经酰胺含量（多球菌素处理，DES-1 KO）或H2 O2（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介导疲劳和力量损失。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，以确定肌肉质量，功能和肌肉活检衍生的神经酰胺种类和线粒体生物能量学之间的关系。重要性：拟议的研究将首次在动物和人类中提供新的翻译证据，即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。

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.