Histamine as a Molecular Transducer of Adaptation to Exercise

项目总结/摘要 运动是促进和维持健康的心血管、肌肉骨骼和 代谢功能然而，解释这些效应的信号和机制并不清楚， 明白NIH的主任通过建立共同的 基金项目“人类身体活动的分子传感器”，以确定新的机制， 运动对健康的益处这项建议的长期目标是更详细地审查各种因素， 调节运动对健康和功能的影响，重点是肥大细胞释放的组胺， 骨骼肌运动刺激骨骼肌肥大细胞释放组胺， 组胺受体，并可能在刺激积极适应中发挥作用。支持证据是， 在运动中阻断组胺受体会影响25%以上的运动反应基因， 骨骼肌。运动转录组上的组胺足迹跨越许多细胞功能， 包括血管功能、代谢、细胞维持和炎症。然而，不知道是什么 在运动过程中引发骨骼肌组胺的释放，组胺介导的反应如何 对健康和功能的影响，或者组胺受体的激活是否是 对有氧运动训练的积极适应。这些未知数将在以下目标中得到解决： 1)确定引起骨骼肌组胺释放的运动相关信号，2）确定 组胺在长期适应运动训练中的更广泛作用。这些目标得到了我们的支持。 先前的工作，并将在人类中使用最先进的方法来解决。这些研究的信息将 在三个方面都很有价值。首先，这些研究将确定有助于健康的关键途径， 通过调节适应的关键信号， 知识第二，这些研究将确定机制（组胺释放的信号）， 通过未来的干预措施，模仿或增强运动的一些有益效果。这可能会使 具有公共卫生影响的转化研究阶段。最后，这些研究可能证明组胺， 通常与病理生理反应相关，是运动的重要分子转换器 影响心血管、肌肉骨骼和代谢健康的反应，增强我们广泛的 对人类状况的理解。总之，这些研究将增加对组胺的了解 及其受体在治疗和预防与身体活动不足相关的疾病中的作用， 针对高危人群的新干预措施。

PROJECT SUMMARY/ABSTRACT Exercise is an important strategy to promote and maintain healthy cardiovascular, musculoskeletal, and metabolic function. However, the signals and mechanisms which transduce these effects are poorly understood. NIH’s Director has highlighted this as a critical gap in knowledge by establishing the Common Fund program on “Molecular Transducers of Physical Activity in Humans” to identify novel mechanisms for exercise-induced health benefits. The long-term goal of this proposal is to examine in greater detail the factors that regulate exercise effects on health and function, with a focus on histamine released from mast cells in skeletal muscle. Exercise stimulates the release of histamine from mast cells in skeletal muscle, which binds to histamine receptors and may play a role in stimulating positive adaptations. Supporting evidence is that blocking histamine receptors during exercise influences more than 25% of exercise-responsive genes in skeletal muscle. The histamine footprint on the exercise transcriptome crosses many cellular functions, including vascular function, metabolism, cellular maintenance, and inflammation. However, it is not known what triggers release of histamine from skeletal muscle during exercise, how the histamine-mediated responses impact on health and function, or whether activation of histamine receptors is a necessary step on the path to the positive adaptations to aerobic exercise training. These unknowns will be addressed in the following aims: 1) Identify the exercise-related signals that cause release of histamine in skeletal muscle, and 2) Determine the broader role of histamine in longer-term adaptations to exercise training. These aims are supported by our prior work and will be addressed using state-of-the-art methods in humans. Information from these studies will prove valuable on three fronts. First, these studies will identify a key pathway that contributes to the health benefits of lifetime physical activity by modulating critical signals for adaptation, filling a critical gap in knowledge. Second, these studies will identify mechanisms (the signals for histamine release) that can be exploited by future interventions, to mimic or enhance some of the beneficial effects of exercise. This may set the stage for translational research with public health impact. Last, these studies may prove that histamine, generally associated with pathophysiological responses, is an important molecular transducer of exercise responses impacting cardiovascular, musculoskeletal, and metabolic health, enhancing our broad understanding of the human condition. In summary, these studies will add to the understanding of histamine and its receptors in treatment and prevention of disease associated with physical inactivity and set the stage for new interventions targeting at-risk populations.