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

描述（由申请人提供）：白细胞介素-6 （IL-6）是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的表达很少，但其mRNA的表达和分泌在单次耐力运动后增加了100倍。分泌的IL-6似乎作为一种传感器，将肌肉活动增加与肝脏和脂肪底物储存的动员联系起来，因为它增加了肝糖原分解和脂肪脂解。目前，运动诱导骨骼肌中IL-6表达的分子机制尚不明确。本提案的目的是通过动物模型和人体研究来开发一个综合的、可转化的研究项目，以阐明运动诱导骨骼肌中IL-6表达的机制。本研究的主要目的有三个：(1)建立小鼠IL-6运动反应性模型，通过该模型我们将测试不同运动模式对体内IL-6表达的影响；(2)研究运动后小鼠和人肌肉中IL-6 mRNA表达的增加是否与转录增加有关；(3)确定特异性IL-6启动子多态性是否影响单次耐力运动人体肌肉IL-6表达。IL-6前mRNA、成熟IL-6 mRNA和荧光素酶活性将在含有IL-6启动子报告基因的小鼠单次耐力运动后被量化。此外，我们将比较不同运动方式（自主与强制跑步）、不同运动变量（强度和持续时间）和肌纤维类型对运动IL-6反应的影响。最后，将对人类受试者进行IL-6 -174 G/C多态性基因分型，并进行锻炼以确定不同IL-6基因型受试者的运动诱导IL-6转录是否不同。总之，这些数据应该为运动诱导的肌肉中IL-6表达的调控机制提供见解，这可能有助于为患有肥胖和糖尿病等以底物动员缺陷为特征的疾病的人制定最有效的训练计划。这项拟议的研究旨在了解骨骼肌中一种名为白介素-6 （IL-6）的基因是如何在运动后受到调节的。运动过程中骨骼肌释放的IL-6向脂肪和肝脏发出信号，释放它们储存的糖和脂肪供收缩肌肉使用，从而了解IL-6是如何被调节的，以及该基因在运动过程中是如何开启的，可能为如何设计更好的运动方案提供见解，以优化运动过程中脂肪和糖的利用。反过来，这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.