REGULATION OF MUSCLE BLOOD FLOW IN OLDER WOMEN AND MEN

描述(申请人提供)：这项研究的长期目标是确定人类衰老对运动骨骼肌血流调节的影响及其对功能能力的影响。我们之前的研究得出了新的结果，表明在健康的老年女性和男性中，大肌肉运动(腿部自行车)中活跃的肌肉血流量的调节随着年龄的变化而改变。具体地说，老年女性表现出在次极量运动中腿部血管扩张受到显著限制的证据；而在老年男性中，有证据表明腿部血管收缩反应增强。这些特定性别的改变可能会削弱老年人满足日常功能和新陈代谢需求的能力。这一修订后的竞争更新的目标是调查导致这些年龄和性别特定变化的中央和地方机制。具体目标1将确定在非耐力训练的老年女性和男性的次极量运动中，中枢机制(心输出量)限制腿部血流的程度。在中枢(腿部自行车)或外周(单膝伸展运动或腿部自行车+通过生理盐水输注增加心脏预负荷)腿部血液供应有限的情况下，我们假设老年女性将表现出腿部血管扩张的局限性，而老年男性将分别相对于年轻男性表现出心输出量和腿部血管扩张之间的平衡改变。具体目标2将确定导致随着年龄增长而进行腿部血流动力学锻炼的性别差异的局部机制。这一系列研究将考察腿部动脉血管的结构和机械特性(假说2)、减弱(假说3)和增强(假说4A：缺血握手，IHG)对腿部充血的交感神经调节、运动中内皮介导的血管扩张(假说4B；联合使用NO/PG拮抗剂)，以及这些机制在调节腿部运动充血中的相互作用(假说4C；NO/PG拮抗剂+IHG)。根据初步结果，我们预测，与男性相比，女性在腿部内皮介导的血管扩张和血管顺应性方面将有更大的年龄相关性下降。我们将通过测量年轻(20-30岁)和老年(60-75岁)男性和女性在腿部锻炼中的全身和腿部血流量(多普勒超声)、动脉压(股导管或臂袖)和局部氧合(NIRS)来研究这些目标，并适当考虑腿部肌肉质量(DXA)、股四头肌力量和腿部动脉结构(小腿峰值电导和动态动脉顺应性)的年龄和性别差异。这些研究的结果将扩展前一个奖项的发现，确定在运动过程中腿部血流调节的年龄和性别差异背后的中央和局部机制，从而为未来旨在优化老年女性和男性肌肉血液供应和功能能力的干预性研究奠定基础。

DESCRIPTION (provided by applicant): The long-range goal of this research is to determine the effects of human aging on the regulation of blood flow to exercising skeletal muscles and its consequent impact on functional capacity. Our previous studies yielded novel results suggesting that the regulation of active muscle blood flow during large muscle exercise (leg cycling) is altered with age in healthy older women and men. Specifically, older women exhibit evidence of a significant limitation to vasodilation in the legs during submaximal exercise; whereas in older men there is evidence for augmented leg vasoconstrictor responsiveness. These sex-specific alterations could impair the ability of older adults to meet daily functional and metabolic demands. The goals of this revised competitive renewal are to investigate the central and local mechanisms responsible for these age and sex-specific alterations. Specific Aim 1 will determine the extent to which central mechanisms (cardiac output) limit leg perfusion during submaximal exercise in non-endurance trained older women and men. During conditions in which blood supply to the leg is limited centrally (leg cycling) or peripherally (single knee extensor exercise or leg cycling+augmented cardiac preload via saline infusion), we hypothesize that older women will exhibit a limit to leg vasodilation, whereas older men will demonstrate an altered balance between cardiac output and leg vasodilation, relative to their younger counterparts, respectively. Specific Aim 2 will define the local mechanisms responsible for sex differences in exercising leg hemodynamics with aging. This series of studies will examine structural and mechanical properties of the leg arterial vasculature (hypothesis 2), the effects of diminished (hypothesis 3) and enhanced (hypothesis 4A: ischemic handgrip, IHG) sympathetic modulation of leg hyperemia, endothelium-mediated vasodilation during exercise (hypothesis 4B; combined NO/PG blockade), and the interaction of these mechanisms in regulating leg exercise hyperemia (hypothesis 4C; NO/PG blockade + IHG). Based on preliminary results, we predict that women will have greater age-associated reductions in endothelium-mediated vasodilation and vascular compliance in the legs compared to men. We will investigate these aims by measuring systemic and leg blood flow (Doppler ultrasound), arterial pressure (femoral catheter or brachial cuff) and local oxygenation (NIRS) in younger (20-30 yr) and older (60-75 yr) men and women during leg exercise, with appropriate consideration for age and sex differences in leg muscle mass (DXA), quadriceps strength, and leg arterial structure (peak calf conductance, dynamic arterial compliance). The results of these studies will extend the findings from the previous award by defining the central and local mechanisms underlying age- and sex-differences in leg blood flow regulation during exercise, thereby setting the stage for future interventional studies aimed at optimizing muscle blood supply and functional capacity in older women and men.