Mechanisms for Impaired Adaptation to Aerobic Exercise with Metabolic Disease

项目摘要/摘要 运动能力，也被称为心肺健康，已经成为最好的预测因素之一。 健康长寿。低运动量是心血管疾病发展的强烈危险因素 疾病和总死亡率。有氧运动训练是增加运动量的唯一有效方法 提高运动能力，减少与低运动能力相关的健康风险。然而，即使当 体力活动相匹配，患有T型等代谢性疾病的人运动能力仍然较低 与没有代谢性疾病的人相比，1型和2型糖尿病患者的表现型为“低反应” 去训练“。这项调查的目标是确定导致低反应的机制 训练代谢性疾病，并制定治疗策略，以提高对运动的反应。临床 研究和我们的动物模型数据表明，慢性高血糖水平(即 高血糖)可能是训练反应低的一个原因，因为它削弱了正常情况下有益的适应 在骨骼肌等组织中，随着运动而发生。我们假设高血糖会导致糖化和 细胞外基质(ECM)在肌肉中的积累，反过来，这些由葡萄糖引起的ECM改变 可以通过3种不同的方式通过运动来防止组织重塑：1)通过 新发现的JNK/SMAD机械信号轴；2)肌祖细胞功能受损和 3)降低循环ECM重塑蛋白水平。一个具体的目标是 确定降血糖治疗是否可以改善运动能力和肌肉重塑 代谢性疾病动物模型对运动的反应。第二个目标是确定细胞和 肌肉中导致高血糖条件下低运动反应的分子机制。 最后，我们将使用先进的蛋白质组筛选结合体外方法学来鉴定循环。 受试者对训练反应较低的中介物。高血糖症正变得越来越普遍，因为 代谢性疾病的发病率在全球范围内上升。这可能会导致一个日益抵制改良的人口 运动能力与训练，以及相关的健康风险的降低。尽管有重要的临床证据 将慢性高血糖与“训练低反应”表型联系起来，对其分子机制知之甚少 这些关联背后的机制。这个项目将极大地促进我们对 导致代谢性疾病患者对训练反应低的机制，并确定治疗方法 提高运动能力，健康跨度，长寿。

PROJECT SUMMARY/ABSTRACT Exercise capacity, also known as cardiorespiratory fitness, has emerged as one of the single best predictors of health and longevity. Low exercise capacity is a strong risk factor for the development of cardiovascular disease and overall mortality. Aerobic exercise training is the only effective treatment to increase exercise capacity and reduce the health risks associated with low exercise capacity. However, even when levels of physical activity are matched, exercise capacity remains lower in people with metabolic diseases such as Type 1 and Type 2 diabetes compared to those without metabolic disease, suggesting a phenotype of “low response to training”. The goal of this investigation is to determine the mechanisms that contribute to low response to training in metabolic disease, and develop treatment strategies to improve the response to exercise. Clinical investigations and our data from animal models suggest that chronically high blood glucose levels (i.e. hyperglycemia) may be a cause for low response to training by blunting beneficial adaptations that normally occur with exercise in tissues like skeletal muscle. We hypothesize that hyperglycemia causes glycation and accumulation of the extracellular matrix (ECM) in muscle, and in turn, these glucose-induced ECM alterations can prevent tissue remodeling with exercise in 3 distinct ways: 1) Altering muscle signal transduction via a newly discovered JNK/SMAD mechanical signaling axis; 2) Impairing the function of muscle progenitor and endothelial cells; and 3) Reducing levels of circulating ECM remodeling proteins. One specific aim is to determine whether blood glucose lowering treatments can improve exercise capacity and muscle remodeling in response to exercise in animal models of metabolic disease. A second aim is to determine the cellular and molecular mechanisms in muscle that contribute to low exercise response under conditions of hyperglycemia. Finally, we will use advanced proteomic screening combined with in vitro methodology to identify circulating mediators of low response to training in humans subjects. Hyperglycemia is becoming more common as rates of metabolic disease rise globally. This may lead to a population that is increasingly resistant to improved exercise capacity with training, and the associated reduction in health risk. Despite significant clinical evidence linking chronic hyperglycemia to the “low-response to training” phenotype, little is known about the molecular mechanisms underlying these associations. This project will significantly advance our understanding of the mechanisms that cause low response to training in people with metabolic disease, and identify treatments to improve exercise capacity, health span, and longevity.