Mechanisms for Impaired Adaptation to Aerobic Exercise with Metabolic Disease

项目总结/摘要 运动能力，也被称为心肺适能，已经成为一个最好的预测， 健康和长寿。低运动能力是心血管疾病发展的一个强危险因素 疾病和总死亡率。有氧运动训练是唯一有效的增加运动量的治疗方法 降低运动能力低带来的健康风险。然而，即使水平 身体活动相匹配，运动能力仍然较低的人与代谢疾病，如型 1型和2型糖尿病相比，没有代谢疾病，表明表型的“低反应” 训练”。本研究的目的是确定导致低反应的机制， 训练代谢疾病，并制定治疗策略，以改善对运动的反应。临床 研究和我们来自动物模型的数据表明，慢性高血糖水平（即， 高血糖症）可能是对训练反应低下的原因，因为它钝化了有益的适应， 骨骼肌等组织在运动时发生。我们假设高血糖引起糖基化， 细胞外基质（ECM）在肌肉中的积累，反过来，这些葡萄糖诱导的ECM改变 可以通过3种不同的方式防止运动引起的组织重塑：1）通过 新发现的JNK/SMAD机械信号轴; 2）损害肌肉祖细胞的功能， 内皮细胞;和3）降低循环ECM重塑蛋白的水平。一个具体目标是 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 在高血糖条件下导致低运动反应的肌肉中的分子机制。 最后，我们将使用先进的蛋白质组学筛选结合体外方法学来鉴定循环中的 对人类受试者的训练反应低的介质。高血压正变得越来越普遍， 代谢性疾病的发病率在全球范围内上升。这可能会导致一个人口越来越抗拒改善 通过训练提高运动能力，并降低相关的健康风险。尽管有显著的临床证据 将慢性高血糖症与“训练低反应”表型联系起来， 这些关联背后的机制。该项目将大大促进我们对 导致代谢疾病患者对训练反应低下的机制，并确定治疗方法， 提高运动能力、健康寿命和长寿。

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.