Mechanisms for Impaired Adaptation to Aerobic Exercise with Metabolic Disease

代谢性疾病对有氧运动的适应受损的机制

• 批准号: 10681230
• 负责人: Sarah Lessard
• 金额: $ 52.87万
• 依托单位: JOSLIN DIABETES CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-15 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10681230
• 关键词: Aerobic; Aerobic Exercise; Animal Model; Biological Markers; Blood Glucose; Breeding; Cardiovascular Diseases; Chronic; Chronic Disease; Clinical; Cultured Cells; Data; Development; Diabetes Mellitus; Endothelial Cells; Event; Exercise; Extracellular Matrix; Glucose; Goals; Health; Human; Hyperglycemia; Impairment; In Vitro; Individual; Investigation; Knockout Mice; Link; Longevity; MAPK8 gene; Measures; Mediator; Metabolic; Metabolic Diseases; Metabolic syndrome; Methodology; Modeling; Modification; Molecular; Muscle; Muscle Fibers; Muscle function; Muscle satellite cell; Non-Insulin-Dependent Diabetes Mellitus; Oxygen Consumption; Persons; Phenotype; Physical activity; Physiological; Population; Prevention; Process; Proteins; Proteomics; Rattus; Research; Resistance; Risk; Risk Factors; Risk Marker; Risk Reduction; Serum; Signal Transduction; Skeletal Muscle; Testing; Tissues; Training; angiogenesis; animal data; cardiorespiratory fitness; circulating biomarkers; clinical investigation; dietary; effective therapy; endothelial stem cell; exercise capacity; exercise training; genetic selection; glucose metabolism; glucose tolerance; glycation; healthspan; human subject; impaired glucose tolerance; improved; mechanical signal; metabolic rate; mortality; mouse model; novel; prevent; response; screening; tissue culture; translational approach; treatment strategy; type I and type II diabetes; virtual

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.

项目概要/摘要 运动能力，也称为心肺健康，已成为最佳的单一预测因素之一 健康长寿。运动能力低是心血管疾病发生的重要危险因素 疾病和总体死亡率。有氧运动训练是增加运动量唯一有效的治疗方法 能力并降低与低运动能力相关的健康风险。然而，即使当水平 体力活动相匹配，患有代谢性疾病的人的运动能力仍然较低，例如 1 型和 2 型糖尿病与无代谢疾病的患者相比，表明“低反应”表型 这项调查的目的是确定导致低反应的机制 代谢疾病培训，并制定治疗策略以改善对运动的反应。临床 调查和我们从动物模型中获得的数据表明，长期高血糖水平（即 高血糖）可能会削弱通常情况下有益的适应，从而导致对训练反应低下 骨骼肌等组织运动时会发生。我们假设高血糖会导致糖化， 肌肉中细胞外基质 (ECM) 的积累，以及这些葡萄糖诱导的 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和 内皮细胞； 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运动反应低的分子机制。 最后，我们将使用先进的蛋白质组筛选结合体外方法来识别循环 对人类受试者训练反应低的中介因素。高血糖症正变得越来越普遍 全球代谢疾病发病率上升。这可能会导致人们越来越抵制改良的 通过训练提高运动能力，以及相关的健康风险降低。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，但人们对分子机制知之甚少 这些关联背后的机制。该项目将极大地增进我们对 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、健康寿命和寿命。