Modulation of Contraction-Induced Changes in Muscle mTOR Signaling by Alcohol

酒精调节收缩引起的肌肉 mTOR 信号变化

• 批准号: 8779998
• 负责人: Jennifer Lynn Steiner
• 金额: $ 4.99万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8779998
• 关键词: Abstinence; Activation Analysis; Activities of Daily Living; Acute; Alcohol abuse; Alcohol consumption; Alcoholic Intoxication; Alcoholism; Alcohols; Antibodies; Attenuated; Binding Proteins; Blood alcohol level measurement; Cessation of life; Chronic; Contracts; Data; Depressed mood; Disease; Equilibrium; Etiology; Exercise; Fast-Twitch Muscle Fibers; Fellowship; Functional disorder; Gastrocnemius Muscle; Genetic Translation; Goals; Growth; Health; Heavy Drinking; Hormones; Hypertrophy; Imagery; Individual; Intake; Intoxication; Knowledge; Label; Leg; Link; Lysosomes; Mass Spectrum Analysis; Mediating; Metabolic; Metabolism; Modality; Modeling; Molecular; Morbidity - disease rate; Mus; Muscle; Muscle Contraction; Muscle Fibers; Muscle Proteins; Muscle Weakness; Muscle function; Myopathy; Nutrient; Patients; Phosphorylation; Phosphotransferases; Physical Function; Positioning Attribute; Protein Biosynthesis; Proteins; Proteomics; Public Health; Puromycin; Reaction Time; Recovery; Recovery of Function; Reporting; Research; Resistance; Ribosomal Protein S6 Kinase; Ribosomes; Rodent Model; Role; Signal Transduction; Signal Transduction Pathway; Signaling Protein; Skeletal Muscle; Stimulus; Symptoms; TSC2 gene; Techniques; Testing; Therapeutic; Time; Tissues; Transcutaneous Electric Nerve Stimulation; alcohol abstinence; alcohol effect; alcoholic myopathy; base; binge drinking; body system; chronic alcohol ingestion; clinically relevant; effective therapy; feeding; high risk behavior; human FRAP1 protein; improved; in vivo; innovation; mTOR Signaling Pathway; mTOR protein; mortality; muscle form; muscle hypertrophy; muscle strength; novel; premature; prevent; problem drinker; protein complex; public health relevance; research study; response; ribosomal protein S6 kinase 1; social; therapy development; trafficking; treatment strategy

DESCRIPTION (provided by applicant): Binge drinking and chronic alcohol abuse (i.e. alcoholism) represent important public health issues as these are associated with high risk behaviors, multiple organ system dysfunction, impaired recovery from illness and even premature death. Habitual alcohol abuse leads to skeletal muscle myopathy characterized by muscle loss, weakness, and decreased physical function. These symptoms are associated with molecular changes including a depressed rate of mTOR-dependent protein synthesis in skeletal muscle. Few treatment strategies exist to aid in the recovery from this disease both in the continued presence of alcohol and under circumstances where abstinence is achieved. However, skeletal muscle contraction activates mTOR kinase activity and increases protein synthesis. Importantly, when an intermittent contractile stimulus is sustained over several weeks it induces significant muscle growth and a coordinate increase in muscle function. Therefore, stimulated muscle contraction, either voluntarily or via transcutaneous electrical stimulation, may represent a potential therapeutic modality for individuals with alcoholic muscle disease who have limited mobility and functional capacity. Our long term goal is to determine the effects of alcohol on skeletal muscle protein synthesis and mTOR activity that has been increased by stimulated muscle contraction, and to identify potential signaling changes and new proteins that mediate the observed response. Progression towards this goal will be achieved through the following specific aims: (1) Determine whether acute alcohol intoxication reverses the pre-existing increase in mTOR activity, protein synthesis and muscle hypertrophy induced by acute or chronic muscle contraction; (2) Establish the therapeutic relevance of acute and chronic muscle contraction in a model of chronic alcoholic myopathy with regards to changes in muscle mTOR activity, protein synthesis and muscle hypertrophy; (3) Define the role of endosomal/lysosomal targeting of TSC2 and mTOR following acute and chronic alcohol, and muscle contraction relevant to previously observed changes in hypertrophy, contractility and mTOR signaling; and (4) Identify skeletal muscle proteins whose synthetic rate is altered by alcohol and/or muscle contraction using puromycin-associated nascent chain proteomics (PUNCH- P). These aims represent a set of novel and comprehensive experiments utilizing several innovative in vivo and ex vivo techniques including rodent models of acute and chronic alcohol abuse, isolated muscle strength and fatigability testing, visualization of the molecular trafficking of mTOR and TSC2, as well as mass spectrometry to identify newly made proteins following alcohol and muscle contraction. Data garnered from these experiments will provide clinically relevant knowledge to significantly advance treatment strategies and contribute to the mechanistic understanding of the etiology of acute and chronic alcoholic muscle disease.

描述（由申请人提供）：暴饮暴食和慢性酒精滥用（即酒精中毒）代表了重要的公共卫生问题，因为这些问题与高风险行为，多器官系统功能障碍，疾病康复甚至过早死亡有关。习惯性酗酒导致骨骼肌肌病的特征是肌肉丧失，无力和身体机能减少。这些症状与分子变化有关，包括骨骼肌中MTOR依赖性蛋白质合成的降低。在持续存在酒精和禁欲的情况下，很少有治疗策略能够帮助从这种疾病中恢复这种疾病。然而，骨骼肌收缩激活MTOR激酶活性并增加蛋白质合成。重要的是，当间歇性收缩刺激持续数周内时，它会诱导肌肉的显着生长和肌肉功能的坐标增加。因此，刺激的肌肉收缩，无论是自愿还是通过经皮电刺激，可能代表对迁移率和功能能力有限的酒精肌肉疾病患者的潜在治疗方式。我们的长期目标是确定酒精对骨骼肌肉蛋白合成和MTOR活性的影响，这些影响已通过刺激的肌肉收缩增加，并确定潜在的信号传导变化和介导观察到的反应的新蛋白质。通过以下特定目的将实现向这一目标的发展：（1）确定急性酒精中毒是否会逆转急性或慢性肌肉收缩引起的MTOR活性，蛋白质合成和肌肉肥大的先前增加； （2）在慢性酒精性肌病模型中，在肌肉MTOR活性，蛋白质合成和肌肉肥大的变化方面建立了急性和慢性肌肉收缩的治疗相关性； （3）定义急性和慢性酒精后TSC2和MTOR的内体/溶酶体靶向的作用，以及与先前观察到的肥大，收缩力和MTOR信号传导的变化有关的肌肉收缩； （4）确定使用与呼毒素相关的新生链蛋白质组学（PUNCH-P）通过酒精和/或肌肉收缩改变合成速率的骨骼肌蛋白。这些目标代表了一套新颖而全面的实验，该实验利用了几种创新的体内和Ex Vivo技术，包括急性和慢性酒精滥用的啮齿动物模型，孤立的肌肉力量和疲劳性测试，MTOR和TSC2分子运输的可视化，以及质谱的分子运输，以及确定新成立的蛋白质和肌肉的蛋白质和肌肉构成的质量。从这些实验中获得的数据将提供临床上相关的知识，以显着提高治疗策略，并有助于对急性和慢性酒精性肌肉疾病病因的机械理解。