CELLULAR ENERGETICS AS A REGULATOR OF MUSCLE MASS AND MITOCHONDRIAL CONTENT DURING MUSCLE ATROPHY

细胞能量作为肌肉萎缩期间肌肉质量和线粒体含量的调节剂

基本信息

批准号：
10088076
负责人：
JEFFREY J BRAULT
金额：
$ 34.24万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-07-24 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10088076
关键词：
5&apos -AMP-activated protein kinase AMP Deaminase Address Adenine Nucleotides Adult Aging Anabolism Area Atrophic Binding Bioenergetics Biogenesis Body Weight decreased Cells Cessation of life Chemicals Chronic Chronic Disease Chronic Wasting Disease Complication Data Deaminase Denervation Depressed mood Diabetes Mellitus Energy Supply Etiology FDA approved Food deprivation (experimental)Functional disorder Gene Targeting Genetic Transcription Glucocorticoids Goals Heart failure Hindlimb Impairment Lead Link Malignant Neoplasms Measurable Mediator of activation protein Messenger RNA Metabolic Metabolism Mission Mitochondria Molecular Mus Muscle Muscle Fibers Muscle Mitochondria Muscle Proteins Muscular Atrophy National Institute of Arthritis and Musculoskeletal and Skin Diseases Nerve Operative Surgical Procedures Pathology Pathway interactions Pharmacologic Substance Phosphotransferases Physiological Positioning Attribute Process Production Protein Degradation Induction Protein Isoforms Protein Kinase Proteins Proteolysis Public Health Research Role Signal Transduction Skeletal Muscle Testing Thermodynamics Time base disability falls fiber cell improved improved functioning insight knock-down multicatalytic endopeptidase complex muscle form new therapeutic target novel overexpression prevent protein activation protein complex protein degradation response skeletal muscle wasting treatment strategy

项目摘要

Project Summary Skeletal muscle atrophy is a major cause of disability and death in many chronic diseases, e.g. cancer, diabe- tes, and heart failure. Despite diverse etiology, atrophying muscles share many common features, like loss of mitochondrial content and depressed energetic state. One probable regulator of muscle mass and mitochon- dria during atrophy is the metabolic enzyme AMP deaminase (AMPD), which isoform 3 is increased up to 100- fold during atrophy. AMPD catalyzes the thermodynamically irreversible degradation of AMP and thereby also controls the size of the adenine nucleotide (ATP ↔ ADP ↔ AMP) pool. Binding or degrading AMP is particu- larly important since its free, cytosolic levels are detected by the energy sensing enzyme AMP-activated pro- tein kinase (AMPK), a well-described inducer of mitochondrial content. Thus, AMPD3 is uniquely positioned to modulate a major intracellular energetic signal, [AMP]/[ATP] ratio. To date, the molecular mechanisms that link muscle atrophy, cellular energetics, and mitochondria biogenesis are largely unknown. The long-term goal of this project is to identify new targets to increase muscle mass, mitochondrial content and perhaps improve the energetic state and function of atrophic muscle. The objective of this application is to determine whether during muscle atrophy AMPD3 decreases mitochondrial production and accelerates muscle protein loss. The central hypothesis is that high levels of AMPD3, which degrades the adenine nucleotide pool, triggers loss of mito- chondria and increases the rate of protein degradation. This is based, in part, on exciting preliminary data from cultured muscle showing that overexpression of AMPD3 mimics the energy deficit of atrophy, increases prote- olysis rate, and decreases protein content; while knockdown of AMDP3 in adult muscle protects against mus- cle weight loss of denervation atrophy. To test the central hypothesis, we propose to knockdown or remove AMPD3 in skeletal muscle fibers/cells that are non-atrophying or atrophying due to various energetic insults: either surgical denervation of one hindlimb (decreased energy demand), food deprivation (decreased energy supply), and glucocorticoid treatment (increase in demand and decrease in supply). The Aims of this proposal are to 1) To determine the role of AMP deaminase as a mediator of mitochondrial loss during skeletal muscle atrophy, and 2) determine the role of AMP deaminase as a mediator of protein loss during skeletal muscle at- rophy. The working hypotheses are that loss of AMPD3 during atrophy will increase [AMP], mitochondrial bio- genesis, and mitochondrial content. Conversely, overexpression of AMPD3, because of impairment in cellular energetics, will trigger accelerated protein degradation and muscle fiber size loss. The expected results of this proposal, demonstrating the energetic control of muscle atrophy, will not only provide novel insights into how energetics/metabolism and muscle mass are linked mechanistically, but will also be expected to reveal novel therapeutic targets to slow or stop muscle mass loss in most, if not all, atrophy conditions.

项目概要骨骼肌萎缩是许多慢性疾病（例如癌症、糖尿病）致残和死亡的主要原因。尽管病因多种多样，但肌肉萎缩有许多共同特征，例如肌肉萎缩。线粒体含量和低能量状态的一种可能的肌肉质量和线粒体调节剂。萎缩期间的干细胞是代谢酶 AMP 脱氨酶 (AMPD)，其异构体 3 增加至 100- AMPD 催化 AMP 的热力学不可逆降解。控制腺嘌呤核苷酸 (ATP ↔ ADP ↔ AMP) 池的大小结合或降解 AMP 是特别重要的。非常重要，因为它的游离胞质水平是由能量感应酶 AMP 激活的前体检测到的。 Tein 激酶 (AMPK) 是一种众所周知的线粒体内容物诱导剂，因此，AMPD3 具有独特的定位。调节主要的细胞内能量信号，[AMP]/[ATP] 比率迄今为止，连接的分子机制。肌肉萎缩、细胞能量学和线粒体生物发生的长期目标在很大程度上是未知的。该项目旨在确定新的目标，以增加肌肉质量、线粒体含量，并可能改善该应用程序的目的是确定萎缩肌肉的能量状态和功能。肌肉萎缩 AMPD3 减少线粒体生成并加速肌肉蛋白质流失。假设高水平的 AMPD3 会降解腺嘌呤核苷酸库，引发线粒体损失这在一定程度上是基于令人兴奋的初步数据。培养的肌肉显示 AMPD3 的过度表达模拟萎缩的能量不足，增加蛋白质分解率，并降低蛋白质含量；而成人肌肉中 AMDP3 的敲低可防止肌肉损伤；为了检验中心假设，我们建议敲除或去除。由于各种能量损伤而未萎缩或萎缩的骨骼肌纤维/细胞中的 AMPD3：一侧后肢手术去神经术（能量需求减少）、食物匮乏（能量需求减少）供应）和糖皮质激素治疗（需求增加和供应减少）。 1) 确定 AMP 脱氨酶作为骨骼肌过程中线粒体损失介体的作用萎缩，2) 确定 AMP 脱氨酶作为骨骼肌萎缩过程中蛋白质损失介体的作用可行的假设是，萎缩过程中 AMPD3 的损失会增加[AMP]，线粒体生物- 由于细胞受损，AMPD3 过度表达。能量学，将引发加速蛋白质降解和肌肉纤维尺寸损失。该提案展示了肌肉萎缩的能量控制，不仅将提供新的见解能量/代谢和肌肉质量是机械联系在一起的，但也有望揭示新的目标是在大多数（如果不是全部）萎缩情况下减缓或阻止肌肉质量的治疗性损失。