Impact of Aging on Skeletal Muscle Blood Flow Kinetics During Exercise

描述（由申请人提供）：在动态运动中，骨骼肌血流量急剧增加（运动充血），以满足收缩组织的代谢需要。衰老与动态运动时充血反应的减弱有关。在年轻人中，运动开始时增加血流量并长期维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复杂的相互作用。老年人运动时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)确定导致衰老人类单肌肉收缩和动态运动改变血管舒张剂反应的机制，以及2)检查衰老对运动期间骨骼肌血流/血管舒张动力学的影响。在K99/指导阶段，申请人将检查随年龄增长而发生的血管功能的机械、内皮和神经改变，并确定这些变化与单次肌肉收缩后血管快速扩张剂反应减弱的关系。在R00/独立资助阶段的第一部分，申请人将研究节律性运动期间血管舒张的动力学（从静止状态到稳态过渡），并量化衰老对这些反应的影响。在R00期的第二部分，申请人评估老年受试者的上肢和下肢血管舒张剂对单个肌肉收缩的减弱反应和节律性运动时血管舒张动力学的减慢是否相似。最后，在R00阶段的第三部分，申请人将确定老年人单次收缩和/或血管舒张动力学后的血流变化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随着年龄的增长而发生的机械、内皮和神经改变，以及这些变化如何影响运动肌肉的血液流动。确定血液流向收缩肌肉的机制随着年龄的增长而改变，将有助于理解这些变化是由于生理年龄本身还是由于缺乏运动。在K99/指导阶段，申请人将1)继续在有意识的人类的基础综合生理学研究中获得专业知识，2)继续学习药理学和生化方法，从机制的角度研究肌肉血流的控制。此外，候选人将在James Greenleaf博士（共同导师）的指导下获得与先进尖端超声技术和动脉特性测量（特别是Shearwave Dispersion ultrasound Vibrometry； SDUV）相关的新研究技能和知识。在梅奥诊所（Mayo Clinic）的詹姆斯·格林利夫（James Greenleaf）博士的帮助下，在迈克尔·乔伊纳（Michael Joyner）博士等成熟而富有成效的实验室进行培训，将为实现上述目标提供必要的机会。重要的是，此次培训将有助于实现申请人在心血管生理学方面发展国际知名的独立研究项目的长期目标。

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.