Cellular signaling in muscle metabolic adaptation and energy metabolism

由于营养过剩和体力活动减少，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增加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，它触发全身代谢反应，提供能量供应，支持运动生理。这包括在长时间运动中从糖酵解到氧化代谢的转变。这种代谢重编程是由特殊的肌肉纤维来满足的，这些肌肉纤维表现出不同的能量基质偏好和性能。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充分的证明，但其潜在的机制仍不清楚。已经提出了几个因素介导某些运动诱导的肌肉内和肌肉与其他代谢活跃组织之间的代谢作用。IL-6是一种“肌因子”，其在运动后迅速增加，但在静息状态下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，Th2细胞因子IL-13和产生IL-13的2型先天淋巴细胞（ILC2）被诱导。在耐力运动训练的人群中，循环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，控制线粒体呼吸。目前的提案将验证IL-13信号通过一种新的IL-13- il - 13r α1- stat3调节机制促进线粒体氧化代谢，从而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人类健康相关性很高，因为研究计划的结果将有助于我们理解耐力运动代谢益处的机制。

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.