Sestrin1-knockout mice as a model of facilitated muscle aging

Sestrin1 敲除小鼠作为促进肌肉衰老的模型

• 批准号: 8700296
• 负责人: Jun Hee Lee
• 金额: $ 23.33万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-15 至 2015-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8700296
• 关键词: Accounting; Adipose tissue; Age; Aging; Animal Model; Animals; Antioxidants; Apoptosis; Arrhythmia; Atrophic; Attenuated; Autophagocytosis; Biochemical; Biological Preservation; Blood Glucose; Caenorhabditis elegans; Cardiac; Cardiovascular Diseases; Cell Death; Clinical; Data; Defect; Development; Diabetes Mellitus; Disease; Drosophila genus; Elderly; Exhibits; Family; Fatigue; Goals; Health; Homologous Gene; Human; Individual; Insecta; Insulin; Insulin Resistance; Intervention; Intramuscular; Knockout Mice; Lead; Lipids; Liver; Maintenance; Mammals; Mediating; Mental Health; Metabolic; Methods; Mitochondria; Modeling; Molecular; Molecular Target; Mus; Muscle; Muscle Cells; Muscle Weakness; Muscle function; Muscle hypotonia; Myocardium; Myopathy; Names; Obese Mice; Obesity; Output; Pathology; Patients; Pharmaceutical Preparations; Phenotype; Physiological; Physiology; Population; Prevention; Process; Proteins; Proto-Oncogene Proteins c-akt; Public Health; Quality of life; Reactive Oxygen Species; Regulation; Rejuvenation; Research; Research Project Grants; Role; Signal Transduction; Skeletal Muscle; Staging; Stress; Testing; Tissues; Transgenic Mice; Viral; Work; adeno-associated viral vector; age related; aged; anti aging; attenuation; base; blood glucose regulation; cell injury; cell type; combat; cost effective; design; effective therapy; fall risk; fly; functional decline; human disease; inhibitor/antagonist; innovation; insulin sensitivity; mitochondrial dysfunction; mouse model; muscle aging; muscle degeneration; muscle form; muscular structure; mutant; normal aging; overexpression; oxidative damage; physical conditioning; prevent; protein aggregate; public health relevance; research study; response; restoration; sarcopenia; skeletal; small molecule; wasting

DESCRIPTION (provided by applicant): Sarcopenia, a loss of muscle mass and function, is a common feature of aging which is associated with oxidative damage and apoptosis. Autophagy, a process for degradation of unnecessary cellular constituents, is considered to be a mechanism to combat muscle cell damage and death. We recently found that Drosophila Sestrin is an endogenous suppressor of the age-related muscle degeneration. Sestrins form a family of stress-inducible proteins that have antioxidant, AMPK-activating, TOR-inhibiting and autophagy- inducing functions. Mammals have three Sestrins (Sesn1-3), while Drosophila has a single Sestrin homologue (dSesn). In Drosophila, dSesn expression is highly enriched in skeletal muscles. dSesn-null mutant flies exhibit accelerated age-related skeletal and cardiac muscle degeneration that is preceded by accumulation of dysfunctional mitochondria, ubiquitinated protein aggregates and reactive oxygen species (ROS), all caused by defective autophagy. Conversely, muscle-specific overexpression of dSesn in aged flies enhances intramuscular autophagy, prevents age-dependent mobility decline and increases fatigue tolerance. These results suggest that Sestrin is an important homeostatic regulator of muscle physiology that promotes autophagy and attenuates age-associated myopathies. However, in order to overcome the physiological differences between insects and mammals, we need to develop and utilize mammalian animal models to investigate the role of Sestrins in age-associated muscle pathologies. Among the three Sestrins in mammals, Sesn1 is most highly expressed in skeletal and cardiac muscles. Interestingly, the expression of Sesn1 is downregulated in degenerating muscles of human patients. Reduced Sesn1 expression is also observed in atrophying mouse muscle in response to obesity or inactivity. Reintroduction of Sesn1 through adeno-associated viral vector into the degenerating mouse muscle partially restores the functional decline. Therefore, here we propose to generate and characterize the Sesn1-knockout mice to investigate more about endogenous Sesn1, which is expected to have critical myoprotective functions. Through this model, we will evaluate the role of Sesn1 in skeletal muscles in (i) preserving structural integrity and muscle functionality (mobility output) and (ii) maintaining insulin sensitivity (metabolic output) during normal aging. The proposed experiments will clarify if Sesn1 in mammals indeed is essential for the prevention of age- associated muscle degeneration and metabolic derangements, similar to dSesn in Drosophila cardiac and indirect flight muscle. In addition to being served as a relevant animal model for assessing Sesn1 function, the Sesn1-knockout mice can be also used as a valuable model of facilitated muscle aging. As Sesn1 is generally downregulated during muscle pathology in humans, supplementing Sesn1 activity through viral or pharmacological means may offer innovative rejuvenation methods for degenerating muscle in elderly population.

描述（由申请人提供）：肌肉减少症是肌肉质量和功能的损失，是衰老的常见特征，与氧化损伤和凋亡有关。自噬是不必要的细胞成分降解的过程，被认为是对抗肌肉细胞损伤和死亡的一种机制。我们最近发现，果蝇sestrin是与年龄相关的肌肉变性的内源性抑制剂。 Sestrins形成了具有抗氧化剂，AMPK激活，抑制和自噬诱导功能的胁迫诱导蛋白家族。哺乳动物有三个sestrins（SESN1-3），而果蝇具有单个sestrin同源物（DSESN）。在果蝇中，DSESN表达在骨骼肌中高度富集。 DSESN-NULL突变蝇表现出与年龄相关的骨骼和心脏肌肉变性的加速，这是由功能障碍的线粒体，泛素化蛋白质聚集体和活性氧（ROS）的积累，所有这些物种都是由自噬引起的。相反，老年蝇中DSESN的肌肉特异性过表达增强了肌内自噬，可防止依赖年龄的迁移率下降并增加疲劳耐受性。这些结果表明，Sestrin是肌肉生理的重要稳态调节剂，可促进自噬并减弱与年龄相关的肌病。但是，为了克服昆虫和哺乳动物之间的生理差异，我们需要开发和利用哺乳动物模型来研究sestrins在与年龄相关的肌肉病理学中的作用。在哺乳动物中的三个sestrins中，SESN1在骨骼和心脏肌肉中表现最高。有趣的是，在人类患者的肌肉中，SESN1的表达被下调。响应肥胖或不活动的小鼠肌肉中也观察到SESN1表达降低。通过腺体相关的病毒载体重新引入SESN1进入退化的小鼠肌肉，部分恢复了功能下降。因此，我们在这里建议生成和表征SESN1敲除小鼠，以便更多有关内源性SESN1的研究，后者有望具有关键的体温功能。通过该模型，我们将评估SESN1在（i）保存结构完整性和肌肉功能（迁移率输出）和（ii）在正常衰老过程中维持胰岛素敏感性（代谢输出）的作用。提出的实验将阐明哺乳动物中的SESN1是否确实对于预防与年龄相关的肌肉变性和代谢扰动至关重要，类似于果蝇心脏和间接飞行肌肉中的DSESN。除了作为评估SESN1功能的相关动物模型外，SESN1敲除小鼠还可以用作促进肌肉衰老的宝贵模型。由于SESN1通常在人类的肌肉病理学期间被下调，因此通过病毒或药理手段补充SESN1活性可能会提供创新的复兴方法，用于使老年人群中的肌肉退化。