Regulation of Exercise-Induced IL-6 Expression in Skeletal Muscle

运动诱导的骨骼肌 IL-6 表达的调节

• 批准号: 7364542
• 负责人: DAVID L ALLEN
• 金额: $ 7.58万
• 依托单位: UNIVERSITY OF COLORADO
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-06-01 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7364542
• 关键词: Acute; Adipose tissue; Affect; Animal Model; Biopsy; Blood; Burn injury; Condition; Contracts; Data; Defect; Development; Diabetes Mellitus; Diabetes prevention; Disease; End Point; Exercise; Fatty acid glycerol esters; Genes; Genetic; Genetic Polymorphism; Genetic Transcription; Genotype; Goals; Health; Heterogeneous Nuclear RNA; Hindlimb; Human; IL6 gene; Insulin; Interleukin-6; Knowledge; Link; Lipolysis; Liver; Luciferases; Measures; Messenger RNA; Metabolic; Metabolism; Modality; Molecular; Mus; Muscle; Muscle Fibers; Obesity; Personal Satisfaction; Persons; Promoter Regions; Protein Secretion; Purpose; Regulation; Reporter; Research; Role; Running; Serum; Signal Transduction; Skeletal Muscle; Testing; Training Programs; Transgenes; Treatment Protocols; cell type; cytokine; design; fatty acid oxidation; glycogenolysis; human study; human subject; improved; in vivo; insight; mRNA Expression; mRNA Precursor; mRNA Stability; mouse model; prevent; programs; promoter; response; sensor; sugar

DESCRIPTION (provided by applicant): Interleukin-6 (IL-6) is a cytokine secreted by many cell types, including skeletal muscle. Under basal conditions, skeletal muscle IL-6 expression is minimal, but its mRNA expression and secretion increase up to a hundredfold in response to a single bout of endurance exercise. Secreted IL-6 appears to act as a sensor linking increased muscle activity with mobilization of substrate stores from liver and fat, as it increases liver glycogenolysis and adipose lipolysis. Currently the molecular mechanisms governing exercise-induced IL-6 expression in skeletal muscle are poorly defined. The purpose of this proposal is to develop an integrative, translational program of research using animal models and human studies to elucidate the mechanisms underlying exercise-induced IL-6 expression in skeletal muscle. The major aims of this research are threefold: (1) to develop a mouse model of IL-6 exercise responsiveness with which we will test the effects of different exercise paradigms on IL-6 expression in vivo; (2) to examine whether increased transcription is responsible for the increase in IL-6 mRNA expression in mouse and human muscle in response to exercise; (3) to determine whether specific IL-6 promoter polymorphisms affect muscle IL-6 expression in human subjects undergoing a single bout of endurance exercise. IL-6 pre-mRNA, mature IL-6 mRNA, and luciferase activity will be quantified in response to a single bout of endurance exercise in mice containing an IL-6 promoter- reporter transgene. In addition, we will compare the effects of different exercise modalities (voluntary vs. forced running), different exercise variables (intensity and duration), and muscle fiber type on the exercise IL-6 response. Finally, human subjects will be genotyped for the IL-6 -174 G/C polymorphism and will be exercised to determine whether exercise-induced IL-6 transcription differs in subjects with different IL-6 genotypes. Together these data should provide insights into the mechanisms governing exercise-induced IL-6 expression in muscle that may assist in the development of optimally effective training programs for persons suffering from conditions such as obesity and diabetes which are characterized by defects in substrate mobilization. The proposed research seeks to understand how a gene called interleukin-6 (IL-6) is regulated in skeletal muscle in response to exercise. IL-6 released by skeletal muscle during exercise signals the fat and the liver to release their stores of sugars and fats for use by the contracting muscle, and thus understanding how IL-6 is regulated, and how this gene is turned on during exercise, may provide insights into how to design better exercise regimens to optimize fat and sugar utilization during exercise. This in turn may help prevent the development of disorders such as obesity and diabetes, and may help people who already have these conditions to improve their metabolism and reduce the negative effects of these conditions on their health and well-being.

描述（由申请人提供）：白细胞介素-6（IL-6）是一种由多种细胞类型（包括骨骼肌）分泌的细胞因子。在基础条件下，骨骼肌IL-6的表达是最小的，但其mRNA的表达和分泌增加高达一百倍，响应于一轮耐力运动。分泌的IL-6似乎作为一个传感器连接增加的肌肉活动与动员的底物储存从肝脏和脂肪，因为它增加肝糖原分解和脂肪分解。目前，运动诱导的骨骼肌IL-6表达的分子机制尚不清楚。该提案的目的是利用动物模型和人体研究开发一个综合的转化研究计划，以阐明骨骼肌中运动诱导的IL-6表达的机制。本研究的主要目的有三：（1）建立小鼠IL-6运动反应性模型，以检测不同运动模式对体内IL-6表达的影响;（2）检测运动后小鼠和人肌肉中IL-6 mRNA表达的增加是否与转录的增加有关;（3）确定特定的IL-6启动子多态性是否影响经受单次耐力运动的人类受试者的肌肉IL-6表达。在含有IL-6启动子-报告基因转基因的小鼠中，响应于单次耐力运动，对IL-6前mRNA、成熟IL-6 mRNA和荧光素酶活性进行定量。此外，我们将比较不同的运动方式（自愿与强迫运行），不同的运动变量（强度和持续时间）和肌肉纤维类型对运动IL-6反应的影响。最后，将对人类受试者的IL-6 - 174 G/C多态性进行基因分型，并进行锻炼以确定运动诱导的IL-6转录在具有不同IL-6基因型的受试者中是否不同。这些数据应提供深入了解运动诱导的IL-6在肌肉中表达的机制，这可能有助于开发最佳有效的训练计划，用于患有以底物动员缺陷为特征的疾病如肥胖和糖尿病的人。这项拟议中的研究旨在了解骨骼肌中一种名为白细胞介素-6（IL-6）的基因是如何对运动做出反应的。运动期间骨骼肌释放的IL-6向脂肪和肝脏发出信号，释放其储存的糖和脂肪，供收缩的肌肉使用，因此了解IL-6是如何调节的，以及该基因在运动期间是如何打开的，可以为如何设计更好的运动方案以优化运动期间的脂肪和糖利用提供见解。这反过来可能有助于预防肥胖和糖尿病等疾病的发展，并可能帮助已经患有这些疾病的人改善他们的新陈代谢，减少这些疾病对他们健康和福祉的负面影响。