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）：酗酒和长期酗酒（即酗酒）是重要的公共卫生问题，因为这些问题与高危行为、多器官系统功能障碍、疾病恢复受损甚至过早死亡有关。习惯性酗酒会导致骨骼肌肌病，其特征是肌肉损失、虚弱和身体功能下降。这些症状与分子变化有关，包括骨骼肌中 mTOR 依赖性蛋白质合成率降低。在持续饮酒和戒酒的情况下，很少有治疗策略可以帮助从这种疾病中恢复。然而，骨骼肌收缩会激活 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时，它会引起显着的肌肉生长和肌肉功能的协调增强。因此，刺激肌肉收缩，无论是自愿还是通过经皮电刺激，对于活动能力和功能能力有限的酒精性肌肉疾病患者来说可能是一种潜在的治疗方式。我们的长期目标是确定酒精对骨骼肌蛋白质合成和 mTOR 活性（通过刺激肌肉收缩而增加）的影响，并确定潜在的信号变化和介导观察到的反应的新蛋白质。实现这一目标的进展将通过以下具体目标来实现：（1）确定急性酒精中毒是否逆转了预先存在的由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增加； (2) 建立慢性酒精性肌病模型中急性和慢性肌肉收缩与肌肉 mTOR 活性、蛋白质合成和肌肉肥大变化的治疗相关性； (3) 定义急性和慢性酒精后内体/溶酶体靶向 TSC2 和 mTOR 的作用，以及与先前观察到的肥大、收缩性和 mTOR 信号传导变化相关的肌肉收缩； (4)使用嘌呤霉素相关新生链蛋白质组学(PUNCH-P)鉴定其合成率因酒精和/或肌肉收缩而改变的骨骼肌蛋白。这些目标代表了一系列新颖而全面的实验，利用了多种创新的体内和离体技术，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量光谱测定法可识别酒精和肌肉收缩后新产生的蛋白质。从这些实验中获得的数据将提供临床相关知识，以显着推进治疗策略，并有助于对急性和慢性酒精性肌肉疾病病因学的机制理解。