Microcirculation in Aging Skeletal Muscle

衰老骨骼肌的微循环

• 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
• 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

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）：随着衰老的衰老，久坐的生活方式以及增加肥胖，高血压和糖尿病的风险，身体表现会下降。骨骼肌维持活动的能力需要递送氧气和去除代谢物。我们假设衰老会损害微循环通过不利影响潜在信号通路来提供血液流向活性骨骼肌纤维的能力。我们已经开发了小鼠的臀大肌（髋关节伸肌至关重要），以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迅速增加，通过输送氧和去除代谢物，促进运动的耐受性，运动过程中充血的维持和恢复。随着衰老，小动脉扩张和灌注的时间和幅度严重钝化，但是这些对肌肉功能的不良影响的机制尚不清楚。这项研究的目的1是确定细胞间通信如何受老化的影响。我们将有选择地破坏沿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，并用免疫标记和实时PCR确定连接蛋白（GAP UNICTION）表达表达以揭示这些机制。尽管平滑肌和内皮中的钾（K+）通道都是血管舒张不可或缺的，但衰老对小动脉K+通道的影响尚不清楚。 AIM 2是确定衰老如何使用新鲜分离的小动脉平滑肌和内皮细胞的贴片夹记录（以及先前的技术）来影响血管舒张的K+通道的功能表达。交感神经活动（SNA）随着衰老而增加，并且可以限制血液流向活跃的骨骼肌，尤其是在男性中。 AIM 3将决定衰老如何影响SNA和肌肉纤维收缩在控制小动脉直径时的相互作用，并根据性别差异来影响SNA和肌肉纤维收缩。我们的长期目标是定义肌肉纤维收缩与小动脉扩张之间相互作用的关键信号通路如何受老化影响。这些研究的发现将为制定策略提供新的和机械的见解，以减轻肌肉血流的减少，从而通过促进从事体育锻炼和降低心血管风险的能力来增强生活质量。