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

描述(申请人提供)：白介素6(IL-6)是一种由多种细胞类型分泌的细胞因子，包括骨骼肌。在基础条件下，骨骼肌IL-6的表达很低，但其mRNA的表达和分泌在单轮耐力运动中增加了100倍。分泌的IL-6似乎作为一种传感器，将肌肉活动的增加与肝脏和脂肪底物储备的动员联系起来，因为它增加了肝脏糖原分解和脂肪脂肪分解。目前，运动诱导骨骼肌中IL-6表达的分子机制尚不清楚。这项建议的目的是开发一个整合的，翻译的研究计划，使用动物模型和人类研究来阐明运动诱导骨骼肌IL-6表达的潜在机制。这项研究的主要目的有三个：(1)建立IL-6运动反应性的小鼠模型，利用该模型，我们将测试不同运动范式对体内IL-6表达的影响；(2)检测转录增加是否导致运动反应中小鼠和人类肌肉中IL-6mRNA表达的增加；(3)确定特定的IL-6启动子基因多态性是否影响单次耐力运动受试者肌肉中IL-6的表达。在携带IL-6启动子-报告基因的小鼠中，IL-6前信使核糖核酸、成熟的白介素酶信使核糖核酸和荧光素酶活性将在单轮耐力运动中被量化。此外，我们将比较不同的运动方式(自愿跑步和强迫跑步)、不同的运动变量(强度和持续时间)以及肌肉纤维类型对运动IL-6反应的影响。最后，将对受试者进行IL-6-174G/C多态的基因分型，并将进行锻炼，以确定不同IL-6基因型的受试者在运动诱导的IL-6转录方面是否有所不同。总之，这些数据应该为控制运动诱导肌肉中IL-6表达的机制提供洞察，这可能有助于为患有肥胖症和糖尿病等以底物动员缺陷为特征的人制定最佳有效的训练计划。这项拟议的研究试图了解一种名为白细胞介素6(IL-6)的基因是如何在骨骼肌中调节的，以应对运动。骨骼肌在运动过程中释放的IL-6信号使脂肪和肝脏释放其储存的糖和脂肪，供收缩肌肉使用，从而了解IL-6是如何调节的，以及该基因在运动过程中是如何被激活的，这可能为如何设计更好的运动方案来优化运动期间脂肪和糖的利用提供见解。这反过来可能有助于防止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新陈代谢，减少这些疾病对他们健康和福祉的负面影响。

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.