Chronic alcohol-induced skeletal muscle myopathy: etiology & physiology

职业目标：我的研究职业目标是研究酒精滥用对骨骼肌结构和功能的影响，并开发临床有效的治疗酒精性肌病的方法。我计划在一个学术实验室里以PI的身份实现这些目标。通过这个建议，我将获得几个新技术的经验，包括，肌肉力学措施，HPLC，siRNA，荧光素酶测定和流式细胞术。 研究项目：2001年，美国国家酒精滥用和酒精中毒研究所估计，近1800万美国成年人滥用酒精或酗酒。慢性酒精滥用，定义为酒精摄入超过100克/天超过10年，可产生严重的，病理性紊乱的各种组织，包括肺，肝，心脏和骨骼肌。由于过量饮酒引起的骨骼肌肌病，称为酒精性肌病，发生在45-70%的酗酒者中，并且比肝硬化至少高五倍。骨骼肌结构和功能的这些紊乱可能是多因素的起源，但可能是受酒精诱导的氧化应激和抗氧化剂水平降低的部分调节。然而，酒精诱导的氧化应激刺激的分子机制及其对骨骼肌结构和功能的影响仍不清楚。因此，本申请的长期目标是确定酒精性肌病的根本原因，并提供可行且临床有效的治疗方法来对抗该疾病。我们最近发表的数据表明，慢性酒精滥用会增加氧化应激，并对大鼠骨骼肌中谷胱甘肽循环的组分产生特定的改变（39）。此外，atrogin-1和转化生长因子-<$（TGF-<$）（与骨骼肌萎缩相关的两种因子）的表达在这些骨骼肌中被强烈诱导。重要的是，谷胱甘肽补充减弱氧化应激和这些分解代谢因子的表达。因此，在三个综合的具体目标中，将使用不同的谷胱甘肽前体设计实验，试图减弱酒精诱导的氧化还原敏感性atrogin-1 /TGF β通路，并最终保留骨骼肌结构和功能。 公共卫生相关性：这些研究对于确定调节酒精性肌病的主要分子、生化和生理途径具有相关性。此外，鉴于谷胱甘肽替代疗法在其他酒精诱导的组织损伤中的临床有效性，K 01应用的结果可能会提供非常成功的预防这种疾病症状的治疗策略。

DESCRIPTION (provided by applicant): Career Goals: My research career goals are to study the effects of alcohol abuse on skeletal muscle structure and function, and to develop clinically effective treatments for alcoholic myopathy. I plan to obtain these goals as a PI in an academic laboratory. Through this proposal, I will gain experience in several new techniques, including, muscle mechanic measures, HPLC, siRNA, luciferase assays, and flow cytometry. Research Project: In 2001, the National Institute on Alcohol Abuse and Alcoholism estimated that nearly 18 million adult Americans abused alcohol or were alcoholics. Chronic alcohol abuse, defined as alcohol ingestion in excess of 100 g/d for more than 10 years, can produce severe, pathological derangements to various tissues, including lungs, liver, heart, and skeletal muscle. Skeletal muscle myopathy due to excessive alcohol ingestion, termed alcoholic myopathy, occurs in 45-70% of alcoholics and is at least five times more prevalent than cirrhosis. These derangements in skeletal muscle structure and function are likely multi-factorial in origin, but may be regulated, in part, by alcohol-induced oxidative stress and reduced antioxidant levels. Yet, the molecular mechanisms stimulated by alcohol-induced oxidative stress and their influence on skeletal muscle structure and function remain poorly defined. Therefore, the long-term objectives of this application are to identify a root cause of alcoholic myopathy and to provide feasible and clinically effective treatments to combat the disease. We have recently published data that show chronic alcohol abuse increases oxidative stress with specific alterations to components of the glutathione cycle in rat skeletal muscle (39). Further, expressions of atrogin-1 and Transforming Growth Factor-¿ (TGF-¿), two factors associated with skeletal muscle atrophy, are strongly induced in these skeletal muscles. Importantly, glutathione supplementation attenuated oxidant stress and expression of these catabolic factors. Therefore, in three integrated specific aims, experiments will be designed using distinct glutathione precursors in attempts to attenuate the alcohol-induced, redox-sensitive atrogin-1 /TGF¿ pathway and to ultimately preserve skeletal muscle structure and function. Public Health Relevance: These studies have relevance for defining major molecular, biochemical and physiological pathways that regulate alcoholic myopathy. Further, given the clinical effectiveness of glutathione replacement therapy in other alcohol-induced tissue injuries, the results from this K01 application will likely provide very successful therapeutic strategies that prevent symptoms of this disease.