Aging and Microvascular Dysfunction in Human Skeletal Muscle

描述（由申请人提供）：预计在未来几十年，不断扩大的老年人口将造成巨大的公共卫生负担。老年人在运动中也表现出运动能力下降和肌肉血流量减少的现象。本研究计划的总体目标是研究年龄引起的微血管结构、功能和蛋白质表达的变化对老年人肌肉血流量受损的影响。本研究旨在直接测试年轻人和老年人（60岁）四头肌骨骼肌阻力动脉（RAs）的血管控制。一般的假设是内皮依赖性扩张（EDD）通过一氧化氮（NO）生物利用度的降低和从环氧化酶（COX）衍生的血管舒张剂前列腺素（pg）向血管收缩剂pg的增加转变而受损。这种转变部分是由于氧化应激的增加。这些观察是在静止的前臂中进行的，因此尚不清楚老年人的腿部是否发生血管功能障碍。为实现这些目标所采用的方法包括肌肉活检，以研究控制年轻和老年健康人抵抗动脉的机制。我们有几个令人兴奋的初步发现支持我们的假设，并为1-2年内完整的R01应用奠定了基础。这些研究的发现将为老年人的肌肉血流调节和血管控制提供新的见解，也可以提供治疗干预措施，以改善患有内皮功能障碍的患病人群（如糖尿病患者或高血压患者）的肌肉血流和运动不耐受。公共卫生相关性：老年人表现出较差的运动能力，从而降低生活质量并增加心血管风险。本应用程序的研究旨在了解血管功能受损对血流限制的潜在贡献，从而了解老年人运动不耐受。关于衰老如何改变血管功能和蛋白质表达的发现将为如何预防或改善功能提供思路，以努力恢复老年人的生活质量。这些研究的发现将为老年人的肌肉血流量调节和血管控制提供新的见解，也可以提供治疗干预措施，以改善血管功能不佳的患病人群（如糖尿病或高血压）的肌肉血流量和运动不耐受。

DESCRIPTION (provided by applicant): The expanding population of aging adults is predicted to create a large public health burden in the next few decades. Older humans also exhibit reduced exercise capacity and lower muscle blood flow during exercise. The overall goal of this research program is to investigate the age-induced changes in microvascular structure, function and protein expression contributing to impaired muscle blood flow in older adults. This proposal seeks to directly test vascular control in human skeletal muscle resistance arteries (RAs) from quadriceps of young and older (e60 years) adults. The general hypothesis is that endothelium dependent dilation (EDD) is impaired via reductions in nitric oxide (NO) bioavailability and a shift away from cyclooxygenase (COX)-derived vasodilator prostaglandins (PGs) to increased vasoconstrictor PGs. This shift is due in part to increases in oxidative stress. These observations were made in resting forearms, so it remains unknown whether vascular dysfunction is occurring in the leg of older adults. The methods employed to address these aims involve muscle biopsies to investigate mechanisms that control of resistance arteries from young and older healthy humans. We have several exciting preliminary findings that support our hypotheses, and lay the groundwork for a complete R01 application in 1-2 years. The findings from these studies will provide novel insight into the regulation of muscle blood flow and vascular control in aging humans, and also could provide treatment interventions to improve muscle blood flow and exercise intolerance in diseased populations that also demonstrate endothelial dysfunction (e.g., diabetics or hypertensives). PUBLIC HEALTH RELEVANCE: Aging adults exhibit poor exercise capacity which reduces quality of life and increases cardiovascular risk. The studies in this application are designed to understand the potential contribution of impaired blood vessel function to limitations in blood flow and therefore exercise intolerance in older adults. The findings of how aging changes blood vessel function and protein expression will provide ideas on how to prevent or improve function, in an effort to restore the quality of life of older adults. The findings from these studies will provide novel insight into the regulation of muscle blood flow and vascular control in aging humans, and also could provide treatment interventions to improve muscle blood flow and exercise intolerance in diseased populations that also demonstrate poor blood vessel function (e.g., diabetes or high blood pressure).