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.

肥胖和相关的代谢障碍，由于过度营养和体育锻炼减少，是现代社会中常见的健康问题。运动表明耐力训练已被证明可以增加代谢健康并改善代谢综合征的症状。耐力运动是一个能量的过程，它触发了系统的代谢反应，以提供支持运动生理的能量供应。这包括长时间运动中从糖酵解向氧化代谢的过渡。这种代谢重编程符合专门的肌肉纤维，进行不同的能量底物偏好和性能。尽管在人类和动物模型中已经充分证明了与运动相关的代谢益处，但潜在的机制尚不清楚。已经提出了几个因素来介导肌肉内以及肌肉和其他代谢活性组织之间的某些运动诱导的代谢作用。 IL-6是运动后的产量迅速增加，但由于耐力训练的水平下降。我们发现，产生IL-13的Th2细胞因子IL-13和2型先天淋巴样（ILC2）细胞是在训练有跑步机的肌肉中诱导的。通过耐力运动训练，人类循环IL-13水平也增加。表明IL-13的初步数据直接作用于肌肉细胞，以控制线粒体呼吸。当前的建议将检验以下假设：IL-13信号传导通过新型的IL-13-IL-13R-13Rα1-STAT3调节机制来促进线粒体氧化代谢，从而在耐力运动中调节肌肉代谢适应。我们认为，当前研究的潜在科学影响和人类健康相关性很高，因为从研究计划中得出的结果将有助于我们理解介导耐力运动的代谢益处的机制。