Histamine as a Molecular Transducer of Adaptation to Exercise

项目摘要/摘要 锻炼是促进和保持健康心血管、肌肉骨骼和 新陈代谢功能。然而，传递这些效应的信号和机制很差。 明白了。美国国立卫生研究院院长强调，这是知识的一个关键差距，他建立了共同的 “人类体力活动的分子传感器”基金项目，以确定 运动带来的健康益处。这项建议的长期目标是更详细地审查这些因素 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，组胺与 组胺受体，并可能在刺激积极适应方面发挥作用。支持的证据是 在运动中阻断组胺受体会影响超过25%的运动反应基因 骨骼肌。运动转录组上的组胺足迹跨越了许多细胞功能， 包括血管功能、新陈代谢、细胞维持和炎症。然而，目前还不知道是什么 在运动中触发骨骼肌释放组胺，组胺如何介导反应 对健康和功能的影响，或者组胺受体的激活是否是通往 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)确定导致骨骼肌中组胺释放的运动相关信号，以及2)确定 组胺在运动训练的长期适应中发挥更广泛的作用。这些目标是由我们的 之前的工作，并将在人类中使用最先进的方法解决。来自这些研究的信息将 在三个方面证明是有价值的。首先，这些研究将确定有助于健康的关键途径 通过调节关键信号进行适应的终生体力活动的好处，填补了 知识。其次，这些研究将确定机制(组胺释放的信号)可以 被未来的干预措施所利用，以模仿或增强锻炼的一些有益效果。这可能会设置 具有公共卫生影响的转化性研究的舞台。最后，这些研究可能会证明组胺， 通常与病理生理反应有关，是运动的重要分子转导 影响心血管、肌肉骨骼和新陈代谢健康的反应，增强我们的 对人类状况的理解。总而言之，这些研究将增加对组胺的理解 及其受体在治疗和预防运动缺乏相关疾病中的作用 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.