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Regulation of Nutrient Sensing and Muscle Wasting by Alcohol

酒精对营养感应和肌肉消耗的调节

基本信息

批准号：
9320058
负责人：
CHARLES H. LANG
金额：
$ 34.81万
依托单位：
PENNSYLVANIA STATE UNIV HERSHEY MED CTR
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：
2017-04-05 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9320058
关键词：
Acute Address Adult Alcohol abuse Alcoholic Intoxication Alcohols Amino Acids Area Autophagocytosis Binding Biochemical Cells Chronic Complex Data Degradation Pathway Development Doxycycline Electroporation Environment FRAP1 gene Face Female Funding Future Genetic Goals Growth Factor Guanosine Triphosphate Phosphohydrolases Health Hormones Impairment In Vitro Instruction Intoxication Knockout Mice Knowledge Laboratories Leucine Mediating Membrane Methods Modeling Molecular Mus Muscle Muscle Cells Muscle Fibers Muscle Proteins Muscular Atrophy Myopathy Nutrient Nutritional Outcome Pathology Pathway interactions Pharmacology Phase Phosphorylation Phosphotransferases Physiological Postdoctoral Fellow Protein Biosynthesis Protein Phosphatase 2A Regulatory Subunit PR53 Proteins Proteomics Public Health Publications Publishing Raptors Reagent Recruitment Activity Regulation Rehabilitation therapy Research Resistance Seminal Signal Transduction Skeletal Muscle Societies System Time Training Work alcohol availability alcohol effect alcohol research alcohol use disorder alcoholic myopathy base binge drinking chronic alcohol ingestion clinically significant detection of nutrient economic cost experimental study in vivo innovation insight knock-down male mortality mouse model novel overexpression premature protein complex response small hairpin RNA therapeutic target tool trafficking

项目摘要

Muscle wasting is a hallmark of sustained alcohol abuse and the associated weakness represents the most common form of skeletal muscle myopathy. Over the past 4 years we have used genetic, biochemical and pharmacological approaches, both in vivo and in vitro, to generate definitive evidence pertaining to the mechanisms by which acute alcohol intoxication (binge drinking) and chronic alcohol consumption impair muscle protein synthesis under basal postabsorptive conditions and antagonize the anabolic response to amino acids and growth factors. The original 3 aims remain valid with experiments in the first phase of the R37 elucidating the cellular mechanisms by which alcohol down-regulates nutritional signals transduced via mTORC1-dependent and -independent transduction networks producing skeletal muscle myopathy, and comparing these to hormone- and contraction-induced regulation. Exceptional progress was made (27 publications) and the research environment leveraged for the successful training and F32 funding of a post- doctoral fellow who will continue in alcohol-related research. Our publications attest that the original aims have been largely achieved; although our new data also open previously unrecognized avenues of exploration. Unique tools have been developed that will permit us to identify and explore novel mechanisms and thereby validate specific proteins as therapeutic targets. Specific Aim 1 determined whether alcohol-induced changes in Deptor are responsible for the decrease in basal and leucine-stimulated muscle protein synthesis. This aim is now extended to investigate the relative importance of alcohol-induced changes in Deptor under in vivo conditions using our newly developed muscle-specific Deptor knockout mouse. Further, our new data reveal alcohol decreases the previously unrecognized binding of REDD1 with Deptor, a finding that will be expanded upon. Specific Aim 2 delineated the mechanism by which alcohol alters mTOR endosomal trafficking thereby impairing mTORC1 and protein synthesis. This aim will be continued by assessing alcohol-induced changes, with and without leucine, on Sestrin2 phosphorylation and binding with proteins of the GATOR2 complex. The goal of these experiments is to identify new components and modifiers governing the topology of mTORC1. Specific Aim 3 elucidated whether altered MAP4K3 signaling is in part responsible for alcohol-induced decreases mTORC1. These studies will be extended to examine the MAP4K3-dependent phosphorylation of Raptor that can function by mTORC1-dependent and -independent mechanisms. This R37 extension exploits innovative approaches, made possible by the availability of novel reagents and supported by our strong track record. While in vitro studies permit us to define cellular mechanisms and prioritize future work, state-of-the-art in vivo approaches permit us to definitively assign physiological importance – thus filling knowledge gaps. The expected outcomes will contribute translational knowledge on nutrient regulation and provide seminal mechanistic insights into the clinically significant pathology of alcohol-induced muscle disease. RELEVANCE (See instructions): Alcohol excess, both chronic abuse and acute intoxication, exacts a staggering economic cost to society and remains a major public health problem. Alcohol use disorder is associated not only with increased mortality, but also with premature and preventable health concerns, and impaired rehabilitation. Our study focuses on the cellular and molecular mechanisms by which excess alcohol impairs basal skeletal muscle protein synthesis and produces a resistance to the normal beneficial effects of nutrients, thereby leading to the development of alcoholic myopathy, one of the most prominent muscle diseases.

肌肉萎缩是持续酗酒的一个标志，相关的无力代表了最严重的症状。骨骼肌肌病的常见形式。在过去的 4 年里，我们利用遗传、生化和体内和体外药理学方法，以产生有关的明确证据急性酒精中毒（酗酒）和慢性饮酒损害的机制基础吸收后条件下的肌肉蛋白质合成并拮抗合成代谢反应氨基酸和生长因子。最初的 3 个目标在 R37 第一阶段的实验中仍然有效阐明酒精下调营养信号的细胞机制 mTORC1 依赖性和非依赖性转导网络产生骨骼肌肌病，以及将这些与激素和收缩诱导的调节进行比较。取得了非凡的进展（27 出版物）以及用于成功培训和 F32 资助后的研究环境博士研究员，将继续从事与酒精相关的研究。我们的出版物证明了最初的目标已基本实现；尽管我们的新数据也开辟了以前未被认识的探索途径。独特的工具已经开发出来，使我们能够识别和探索新的机制，从而验证特定蛋白质作为治疗靶点。具体目标 1 确定酒精是否会引起变化 Deptor 中的蛋白质负责基础和亮氨酸刺激的肌肉蛋白质合成的减少。这个目标现在扩展到研究体内酒精诱导的 Deptor 变化的相对重要性使用我们新开发的肌肉特异性 Deptor 敲除小鼠的条件。此外，我们的新数据显示酒精会降低之前未被识别的 REDD1 与 Deptor 的结合，这一发现将得到扩展之上。具体目标 2 描述了酒精改变 mTOR 内体运输的机制损害 mTORC1 和蛋白质合成。我们将通过评估酒精引起的变化来继续这一目标，有和没有亮氨酸对 Sestrin2 磷酸化以及与 GATOR2 复合物蛋白结合的影响。这这些实验的目标是确定控制 mTORC1 拓扑的新组件和修饰剂。具体目标 3 阐明了 MAP4K3 信号传导的改变是否是酒精诱发的部分原因降低 mTORC1。这些研究将扩展到检查 MAP4K3 依赖性磷酸化 Raptor 可以通过 mTORC1 依赖和独立机制发挥作用。这个 R37 扩展利用了创新方法，通过新型试剂的可用性和我们强大的跟踪支持而成为可能记录。虽然体外研究使我们能够定义细胞机制并优先考虑未来的工作，但最先进的体内方法使我们能够明确地分配生理重要性，从而填补知识空白。这预期成果将贡献营养调节方面的转化知识，并提供开创性的成果对酒精引起的肌肉疾病的临床显着病理学的机制见解。相关性（参见说明）：酗酒，无论是长期滥用还是急性中毒，都会给社会带来惊人的经济成本，仍然是一个重大的公共卫生问题。酒精使用障碍不仅与死亡率增加有关，但也存在过早和可预防的健康问题以及康复受损。我们的研究重点是过量酒精损害基础骨骼肌蛋白的细胞和分子机制合成并对营养素的正常有益作用产生抵抗力，从而导致酒精性肌病的发展，这是最突出的肌肉疾病之一。