Cellular signaling in muscle metabolic adaptation and energy metabolism

肌肉代谢适应和能量代谢中的细胞信号传导

• 批准号: 9403594
• 负责人: Chih-Hao Lee
• 金额: $ 42.91万
• 依托单位: HARVARD SCHOOL OF PUBLIC HEALTH
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-01 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9403594
• 关键词: Address; Animal Model; Cell Respiration; Cells; Cytokine Signaling; Data; Disease; Dyslipidemias; Energy Metabolism; Energy Supply; Exercise; Exercise Physiology; Exhibits; Health; Homeostasis; Human; IL-13Ralpha1; Insulin Resistance; Interleukin-13; Interleukin-6; Knock-out; Link; Lymphoid; Mediating; Metabolic; Metabolic Control; Metabolic Diseases; Metabolic syndrome; Mitochondria; Modernization; Mus; Muscle; Muscle Cells; Muscle Fibers; Muscle function; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Overnutrition; Performance; Physical activity; Play; Process; Production; Research; Respiration; Rest; Role; Running; STAT3 gene; Signal Pathway; Signal Transduction; Skeletal Muscle; Societies; Testing; Tissues; Training; cytokine; endurance exercise; exercise training; fitness; glucose metabolism; mimetics; new therapeutic target; novel; paracrine; preference; response; symptomatic improvement; treadmill

Obesity and related metabolic disorders, as a result of over-nutrition and reduced physical activity, are common health issues in modern societies. Exercise, notably endurance training has been shown to increase metabolic fitness and improve symptoms of the metabolic syndrome. Endurance exercise is an energy-demanding process, which triggers a systemic metabolic response to provide energy supply to support exercise physiology. This includes a transition from glycolytic to oxidative metabolism in prolonged exercise. This metabolic reprogramming is met with specialized muscle fibers exhibiting distinct energy substrate preferences and performances. Although exercise-associated metabolic benefits have been well documented in humans and animal models, the underlying mechanisms remain unclear. Several factors have been suggested to mediate certain exercise-induced metabolic effects within muscle and between muscle and other metabolically active tissues. IL-6 is one of the “myokines” whose production is rapidly increased after exercise but its level at the resting state declines with endurance training. We have found that the Th2 cytokine IL-13 and type 2 innate lymphoid (ILC2) cells that produce IL-13 are induced in muscle of mice trained on a treadmill. Circulating IL-13 levels are also increased in humans with endurance exercise training. Preliminary data indicate IL-13 acts directly on muscle cells to control mitochondrial respiration. The current proposal will test the hypothesis that IL-13 signaling regulates muscle metabolic adaptation in endurance exercise by promoting mitochondrial oxidative metabolism through a novel IL-13-IL-13Rα1-STAT3 regulatory mechanism. We believe the potential scientific impact and human health relevance of the current study is high, as results derived from the research plan will help our understanding of mechanisms mediating metabolic benefits of endurance exercise.

由于营养过剩和体力活动减少而导致的肥胖和相关代谢紊乱是现代社会常见的健康问题。运动，尤其是耐力训练已被证明可以增强代谢健康并改善代谢综合征的症状。耐力运动是一个需要能量的过程，它会触发全身代谢反应，为运动生理提供能量供应。这包括长时间运动时从糖酵解代谢到氧化代谢的转变。这种代谢重编程是通过表现出独特的能量底物偏好和性能的特殊肌肉纤维来满足的。尽管运动相关的代谢益处已在人类和动物模型中得到充分记录，但其潜在机制仍不清楚。已经提出了几种因素来介导肌肉内以及肌肉与其他代谢活跃组织之间的某些运动引起的代谢效应。 IL-6 是一种“肌因子”，其产生量在运动后迅速增加，但在静息状态下的水平会随着耐力训练而下降。我们发现，在跑步机上训练的小鼠肌肉中会诱导产生 Th2 细胞因子 IL-13 和产生 IL-13 的 2 型先天淋巴 (ILC2) 细胞。在进行耐力运动训练的人中，循环中的 IL-13 水平也会增加。初步数据表明 IL-13 直接作用于肌肉细胞以控制线粒体呼吸。目前的提案将测试这样的假设：IL-13 信号传导通过一种新型的 IL-13-IL-13Rα1-STAT3 调节机制促进线粒体氧化代谢，从而调节耐力运动中的肌肉代谢适应。我们相信当前研究的潜在科学影响和人类健康相关性很高，因为研究计划得出的结果将有助于我们了解介导耐力运动代谢益处的机制。