Impact of Aging on Skeletal Muscle Blood Flow Kinetics During Exercise

描述(申请人提供)：在动态运动中，骨骼肌血流量迅速和急剧增加(运动性充血)，以满足收缩组织的新陈代谢需求。衰老与动态运动中的充血反应减弱有关。年轻人在运动开始时增加血流量并在一段时间内保持血流量的机制涉及机械因素、交感神经系统和影响血管张力的局部代谢和内皮衍生物质之间的复杂相互作用。在老年人中观察到的运动血流量减少的机制尚不完全清楚。申请人提出了两个主要目标：1)确定导致老年人对单个肌肉收缩和动态运动的血管扩张剂反应改变的机制，以及2)检查衰老对运动期间骨骼肌血流/血管扩张动力学的影响。在K99/导师资助阶段，申请者将检查随年龄增长而发生的血管功能的机械、内皮和神经变化，并确定这些变化与单一肌肉收缩后减弱的快速血管扩张剂反应之间的关系。在R00/独立资助阶段的第一部分，申请者将检查在有节奏的运动中血管扩张的动力学(静止到稳定状态的转变)，并量化老化对这些反应的影响。在R00阶段的第二部分，申请人评估在有节奏的运动中，血管扩张剂对单一肌肉收缩的减弱反应和血管扩张动力学减慢在老年受试者的上肢和下肢是否相似。最后，在R00阶段的第三部分，申请人将确定老年人单次收缩后的血流变化和/或血管扩张动力学是生理衰老的结果还是与训练状态有关。总的来说，本提案中概述的实验侧重于骨骼肌血管系统中随年龄增长而发生的机械、内皮和神经变化，以及这些变化如何影响锻炼肌肉的血液流动。识别血液流向收缩肌肉的机制随着年龄的增长而改变，这将有助于理解这些变化是由于生理年龄本身还是不活动的结果。在该奖项的K99/指导阶段，申请者将1)继续获得意识人类基础综合生理学研究方面的专业知识，2)继续学习药理学和生化方法，从机械学的角度研究肌肉血液流动的控制。此外，候选人将在詹姆斯·格林利夫博士(共同导师)的指导下获得与先进的尖端超声技术和动脉特性测量(特别是横波频散超声测振仪；SDUV)相关的新研究技能和知识。在迈克尔·乔伊纳博士等成熟和富有成效的实验室接受培训，并在梅奥诊所詹姆斯·格林利夫博士的帮助下进行培训，将提供实现上述目标所需的机会。重要的是，这项培训将有助于实现申请者的长期目标，即开发一个享誉国际的心血管生理学独立研究项目。

DESCRIPTION (provided by applicant): 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.