Impact of Aging on Skeletal Muscle Blood Flow Kinetics During Exercise

项目摘要/摘要 在动态运动中，骨骼肌血流量迅速而显著地增加(运动 充血)以满足收缩组织的新陈代谢需求。衰老与衰弱的 动态运动中的充血反应。导致动脉血流量增加的机制 年轻人开始锻炼并随着时间的推移保持锻炼涉及一个复杂的相互作用 机械因素、交感神经系统和局部代谢及内皮衍生物质 会影响血管紧张度。运动血流量减少的机制 在老年人中的作用尚不完全清楚。 申请人提出了两个主要目标：1)确定导致血管扩张剂改变的机制 老年人对单一肌肉收缩和动态运动的反应，以及2)检查其影响 增龄对运动中骨骼肌血流/血管扩张动力学的影响。在K99/指导期间 在赠款阶段，申请者将检查血管的机械、内皮和神经变化。 并确定这些变化与减弱的快速血管扩张剂之间的关系 单次肌肉收缩后的反应。在授权的R00/独立阶段的第一部分中， 申请者将在有节奏的运动中检查血管扩张的动力学(静息到稳定状态的转变)。 并量化老化对这些反应的影响。在R00阶段的第二部分，申请人 评估血管扩张剂对单个肌肉收缩和运动减慢的反应是否减弱 在有节奏的运动中，老年人的上肢和下肢的血管扩张是相似的。最后，在 R00阶段的第三部分，申请人将确定以下流量是否发生变化 老年人的收缩和/或血管扩张动力学是生理性衰老的结果或与 培训状态。总而言之，本提案中概述的实验侧重于机械、 随着年龄的增长，骨骼肌血管系统中发生的内皮和神经变化及其原因 这些变化会影响运动肌肉中的血液流动。确定血液流向的机制 随着年龄的增长，收缩肌肉的变化将有助于理解这些变化是否是由于 生理年龄生理年龄本身或不活动的结果 在该奖项的K99/指导阶段，申请者将1)继续获得基础知识 有意识的人类的综合生理学研究，以及2)继续学习药理学和生化 从力学角度研究肌肉血流量控制的方法。此外， 应聘者将获得与先进的尖端超声技术相关的新的研究技能和知识 和动脉特性的测量(具体地说，剪切波色散超声测振仪；SDUV) 詹姆斯·格林利夫博士(共同导师)的指导。在成熟和高效的实验室进行培训，如 迈克尔·乔伊纳博士和梅奥诊所的詹姆斯·格林利夫博士的帮助将提供 实现上述目标所需的机会。重要的是，这项培训将促进 实现申请人的长期目标，发展享誉国际的独立 心血管生理学研究计划。

PROJECT SUMMARY/ABSTRACT During dynamic exercise skeletal muscle blood flow increases rapidly and dramatically (exercise hyperemia) to meet the metabolic needs of the contracting tissue. Aging is associated with an attenuated hyperemic response during dynamic exercise. The mechanisms responsible for increasing blood flow at the onset of exercise as well as maintaining it over time in young adults involves a complex interaction between mechanical factors, the sympathetic nervous system and local metabolic and endothelial derived substances that influence vascular tone. The mechanisms responsible for the observed reductions in exercise blood flow in older humans are not completely clear. The applicant proposes two main goals: 1) to identify mechanisms contributing to the altered vasodilator responses to single muscle contractions and dynamic exercise in aging humans, and 2) to examine the effect of aging on the kinetics of skeletal muscle blood flow/vasodilation during exercise. During the K99/Mentored phase of the grant, the applicant will examine the mechanical, endothelial, and neural alterations in vascular function that occur with aging and determine how these changes relate to the attenuated rapid vasodilator response following a single muscle contraction. In the first portion of the R00/Independent phase of the grant, the applicant will examine the kinetics (rest to steady state transition) of vasodilation during rhythmic exercise and quantify the effects of aging on these responses. In the second portion of the R00 phase, the applicant evaluate whether the attenuated vasodilator response to single muscle contractions and slower kinetics of vasodilation during rhythmic exercise are similar in the upper and lower limbs of older subjects. Lastly, in the third portion of the R00 phase, the applicant will determine whether the changes in flow following single contractions and/or the kinetics of vasodilation in older humans is a result of physiological aging or related to training status. Collectively, the experiments outlined in this proposal focus on the mechanical, endothelial, and neural alterations that occur in the skeletal muscle vasculature with aging and how these changes impact blood flow in exercising muscle. Identifying the mechanisms by which blood flow to contracting muscles is altered with advancing age will help in understanding whether these changes are due to physiological age per se or a result of inactivity. During the K99/Mentored phase of the award the applicant will 1) continue to gain expertise in basic integrative physiology studies in conscious humans, and 2) continue to learn pharmacological and biochemical approaches to study the control of muscle blood flow from a mechanistic standpoint. Additionally, the candidate will gain new research skills and knowledge related to advanced cutting-edge ultrasound techniques and measures of arterial properties (specifically, Shearwave Dispersion Ultrasound Vibrometry; SDUV) under the mentorship of Dr. James Greenleaf (co-mentor). Training in an established and productive laboratory such as that of Dr. Michael Joyner along with the help of Dr. James Greenleaf at the Mayo Clinic will provide opportunities needed to achieve the goals listed above. Importantly, this training will facilitate the achievement of the applicant's long-term goal to develop an internationally-renowned independent research program in cardiovascular physiology.