Microcirculation in Aging Skeletal Muscle

衰老骨骼肌的微循环

基本信息

批准号：
7262728
负责人：
STEVEN S SEGAL
金额：
$ 50.42万
依托单位：
UNIVERSITY OF MISSOURI-COLUMBIA
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-01 至 2012-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7262728
关键词：
Adverse effects Affect Age Aging Attenuated Autacoids Biological Models Blood flow C57BL/6 Mouse Caliber Cell Communication Cells Connexins Coupling Diabetes Mellitus Disruption Electric Stimulation Endothelial Cells Endothelium Excision Exercise Exercise Tolerance Female Gap Junctions Gender Goals Hip region structure Human Hyperemia Hypertension Intervention Life Style Light Locomotion Maintenance Microcirculation Microelectrodes Modeling Monitor Mus Muscle Muscle Contraction Muscle Fibers Muscle Tonus Muscle function Nerve Neural Inhibition Numbers Nutrient Oxygen Pathway interactions Performance Perfusion Pharmacology Physical activity Polymerase Chain Reaction Potassium Potassium Channel Production Protocols documentation Quality of life Recovery Research Research Personnel Sex Characteristics Signal Pathway Signal Transduction Skeletal Muscle Smooth Muscle Techniques Testing Time Vasodilation Vasomotor Work age effect arteriole base cardiovascular risk factor in vivo insight male obesity risk patch clamp programs research study response sedentary transmission process

项目摘要

DESCRIPTION (provided by applicant): Physical performance declines with aging, promoting a sedentary lifestyle and increasing the risk of obesity, hypertension and diabetes. The capacity of skeletal muscle to sustain activity requires oxygen delivery and metabolite removal. We hypothesize that aging impairs the ability of the microcirculation to supply blood flow to active skeletal muscle fibers by adversely affecting underlying signaling pathways. We have developed the gluteus maximus muscle (a hip extensor essential to locomotion) of the mouse as a model to study how aging affects the control of skeletal muscle blood flow in arteriolar networks. A rapid increase in blood flow in response to contractile activity promotes exercise tolerance by delivering oxygen and removing metabolites, as does the maintenance of hyperemia during exercise and into recovery. With aging, the time course and magnitude of arteriolar dilation and perfusion are severely blunted however the mechanisms underlying these adverse effects on muscle function are unknown. Aim 1 of this research is to determine how cell-to-cell communication is affected by aging. We will selectively disrupt signaling along arteriolar endothelium and smooth muscle, record the electrical activity of respective cells in vivo, and determine connexin (gap unction) expression with immunolabeling and Real-Time PCR to reveal these mechanisms. Whereas potassium (K+) channels in both smooth muscle and endothelium are integral to vasodilation, the effect of aging on K+ channels in arterioles is unknown. Aim 2 is to determine how aging effects the functional expression of K+ channels that govern vasodilation using patch clamp recording (and preceding techniques) from freshly-dissociated arteriolar smooth muscle and endothelial cells. Sympathetic nerve activity (SNA) increases with aging and can restrict blood flow to active skeletal muscle, particularly in males. Aim 3 will determine how aging affects the interaction between SNA and muscle fiber contraction in controlling arteriolar diameter and will do so in light of gender differences. Our long term goal is to define how key signaling pathways that underlie the interaction between muscle fiber contraction and arteriolar dilation are affected by aging. Findings from these studies will provide new and mechanistic insight for developing strategies to ameliorate decrements in muscle blood flow and thereby enhance the quality of life through promoting the ability to engage in physical activity and reduce cardiovascular risks.

描述（由申请人提供）：身体机能随着年龄的增长而下降，促进久坐的生活方式并增加肥胖、高血压和糖尿病的风险。骨骼肌维持活动的能力需要氧气输送和代谢物清除。我们假设衰老通过对潜在的信号通路产生不利影响，损害微循环向活跃骨骼肌纤维供应血流的能力。我们开发了小鼠的臀大肌（运动所必需的髋部伸肌）作为模型来研究衰老如何影响小动脉网络中骨骼肌血流的控制。响应收缩活动的血流量迅速增加，通过输送氧气和去除代谢物来促进运动耐量，就像运动期间和恢复期间充血的维持一样。随着年龄的增长，小动脉扩张和灌注的时间进程和幅度严重减弱，但这些对肌肉功能产生不利影响的机制尚不清楚。这项研究的目标 1 是确定衰老如何影响细胞间的通讯。我们将选择性地破坏沿小动脉内皮和平滑肌的信号传导，记录体内各个细胞的电活动，并通过免疫标记和实时 PCR 确定连接蛋白（间隙功能）的表达，以揭示这些机制。尽管平滑肌和内皮细胞中的钾 (K+) 通道对于血管舒张至关重要，但衰老对小动脉中 K+ 通道的影响尚不清楚。目标 2 是使用膜片钳记录（和之前的技术）从新鲜分离的小动脉平滑肌和内皮细胞确定衰老如何影响控制血管舒张的 K+ 通道的功能表达。交感神经活动 (SNA) 随着年龄的增长而增加，并会限制血液流向活跃的骨骼肌，尤其是男性。目标 3 将确定衰老如何影响 SNA 和肌纤维收缩之间的相互作用以控制小动脉直径，并将根据性别差异进行此研究。我们的长期目标是确定衰老如何影响肌纤维收缩和小动脉扩张之间相互作用的关键信号通路。这些研究的结果将为制定改善肌肉血流量减少的策略提供新的机制见解，从而通过促进身体活动的能力和降低心血管风险来提高生活质量。