Cellular signaling in muscle metabolic adaptation and energy metabolism

由于营养过剩和体力活动减少而导致的肥胖和相关的代谢紊乱，是现代社会常见的健康问题。运动，特别是耐力训练，已被证明可以提高新陈代谢健康，改善代谢综合征的症状。耐力运动是一个需要能量的过程，它触发全身代谢反应，为运动生理学提供能量供应。这包括在长时间的运动中从糖酵解到氧化代谢的转变。这种代谢重新编程满足了特殊的肌肉纤维，表现出不同的能量底物偏好和性能。尽管运动相关的代谢益处已经在人类和动物模型中得到了很好的证明，但其潜在的机制仍然不清楚。有几个因素被认为在肌肉内以及肌肉和其他代谢活跃的组织之间介导了运动诱导的某些代谢效应。IL-6是一种运动后迅速增加，但静息状态下的水平随着耐力训练而下降的“肌动蛋白”。我们发现，Th2细胞因子IL-13和产生IL-13的2型先天淋巴样细胞(ILC2)是在跑步机上训练的小鼠肌肉中诱导出来的。在进行耐力运动训练的人中，循环IL-13水平也会增加。初步数据显示，IL-13直接作用于肌肉细胞，控制线粒体呼吸。本研究将通过一种新的IL-13-IL-13Rα1-STAT3调节机制来验证IL-13信号通过促进线粒体氧化代谢来调节耐力运动中肌肉代谢适应的假设。我们相信，当前研究的潜在科学影响和与人类健康的相关性很高，因为研究计划得出的结果将有助于我们理解耐力运动对代谢有益的调节机制。

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.