Cardiovascular and intramuscular interactions in the control of skeletal muscle O2 consumption kinetics

心血管和肌肉内相互作用在控制骨骼肌耗氧动力学中的作用

• 批准号: BB/F019521/1
• 负责人: Harry Rossiter
• 金额: $ 50.02万
• 依托单位: University of Leeds
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2009
• 资助国家: 英国
• 起止时间: 2009 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FF019521%2F1
• 关键词: Cardiovascular; intramuscular; interactions; control; skeletal

The ability to sustain muscular exercise is a key determinant of health, quality of life, and mortality. Poor exercise tolerance contributes to a downward spiral of inactivity, which is debilitating in the healthy elderly and is described by The Centers of Disease Control, USA, as an 'actual cause' of many chronic diseases. Therefore, a better understanding of the mechanisms that allow exercise to be sustained is central to our ability to help maintain health, quality of life and promote the longevity. Sustaining muscular exercise depends in large part upon the provision of energy through 'oxidative' pathways. These are pathways that synthesise energy in the muscles through the consumption of oxygen. Therefore, the function of the body's systems that transport oxygen from the atmosphere to where it is utilised in the mitochondria of the active muscles, and the ability of the mitochondria to use the oxygen that they receive, is crucial to the ability to sustain high work rates. It is also significant that most conditions of physical activity are 'non-steady state'; that is, the demands for muscular oxygen consumption are not constant, but are continually changing as activity levels are altered. As such, it is the kinetics with which the oxygen transport and utilisation systems can respond that determine whether the body is able meet the energy demands through oxidative means. Rapid response kinetics, therefore, are a characteristic of the effective integration of these physiological systems: Highly trained endurance athletes have fast response kinetics. It is of considerable concern, however, that the response kinetics of oxygen consumption in the elderly are very slow - about twice as slow as young people, and four times slower than in endurance-trained subjects. The mechanisms that determine these response kinetics, however, in health, training, or the elderly are currently unresolved. The studies in this proposal aim to elucidate the interactions between oxygen delivery to, and utilisation in, the active muscles during the transition from rest to exercise. A better understanding of how these processes work will improve our ability to address the slow oxygen consumption kinetics in the elderly, which contribute to the reduced exercise tolerance in this group. It is not possible to control (experimentally) all the physiological systems that contribute to determining oxygen consumption kinetics in human volunteers. I have, therefore, designed and validated a new experimental technique to achieve this in a rat model of exercise. Rats are an ideal model in this regard: their muscles are similar to those of large human locomotor muscles (such as the muscles of legs); and they manifest similar adaptations to those seen in humans during endurance training and ageing. They also represent an important refinement of the current state-of-the-art, because this type of study is typically made in dogs. Using this new model then, oxygen delivery to skeletal muscles can be controlled via a pump, and key 'oxidative' chemical reactions in the muscles can be controlled (either activated or inhibited) by delivery of drugs. The information provided from this project will benefit the health and quality of life of society by improving our understanding of how the cardiovascular and skeletal muscular systems integrate to allow exercise to be sustained. These novel findings will establish the mechanisms that control oxygen consumption kinetics in healthy animals, and determine how endurance exercise training alters these to bring about improvements in oxygen consumption kinetics. They will also determine how ageing affects the control of oxygen consumption kinetics. These studies will therefore underpin the development of new strategies (either pharmacological or exercise based) for ameliorating the mechanisms limiting exercise tolerance in humans.

维持肌肉锻炼的能力是健康、生活质量和死亡率的关键决定因素。运动耐量差导致不活动的螺旋式下降，这在健康的老年人中是衰弱的，并且被美国疾病控制中心描述为许多慢性疾病的“实际原因”。因此，更好地了解允许运动持续的机制对于我们帮助保持健康，生活质量和促进长寿的能力至关重要。持续的肌肉锻炼在很大程度上取决于通过“氧化”途径提供能量。这些是通过消耗氧气在肌肉中合成能量的途径。因此，将氧气从大气中运输到活动肌肉的线粒体中的身体系统的功能，以及线粒体使用它们接收的氧气的能力，对于维持高工作率的能力至关重要。同样重要的是，大多数身体活动的条件是“非稳态”;也就是说，肌肉耗氧量的需求不是恒定的，而是随着活动水平的改变而不断变化的。因此，氧运输和利用系统可以响应的动力学决定了身体是否能够通过氧化方式满足能量需求。因此，快速反应动力学是这些生理系统有效整合的特征：训练有素的耐力运动员具有快速反应动力学。然而，值得关注的是，老年人的耗氧量反应动力学非常慢--大约是年轻人的两倍，比接受过耐力训练的受试者慢四倍。然而，在健康、训练或老年人中，确定这些反应动力学的机制目前尚未解决。这项研究的目的是阐明从休息到运动的过渡过程中，氧气输送到活动肌肉和利用活动肌肉之间的相互作用。更好地了解这些过程如何工作将提高我们解决老年人缓慢耗氧动力学的能力，这有助于降低这一群体的运动耐量。不可能控制（实验）所有有助于确定人类志愿者耗氧动力学的生理系统。因此，我设计并验证了一种新的实验技术，以在大鼠运动模型中实现这一目标。在这方面，大鼠是一个理想的模型：它们的肌肉与人类大型运动肌肉（如腿部肌肉）相似;它们在耐力训练和衰老过程中表现出与人类相似的适应性。它们也代表了当前最先进技术的重要改进，因为这种类型的研究通常是在犬中进行的。然后，使用这种新模型，可以通过泵控制骨骼肌的氧气输送，并且可以通过药物输送控制（激活或抑制）肌肉中的关键“氧化”化学反应。该项目提供的信息将通过提高我们对心血管和骨骼肌肉系统如何整合以使运动得以持续的理解，有益于社会的健康和生活质量。这些新的发现将建立控制健康动物耗氧动力学的机制，并确定耐力运动训练如何改变这些机制，以改善耗氧动力学。他们还将确定老化如何影响耗氧动力学的控制。因此，这些研究将支持开发新的策略（药理学或运动为基础），以改善机制，限制人类的运动耐量。

项目成果

Effects of superoxide, nitric oxide and peroxynitrite on skeletal muscle mitochondrial function

超氧化物、一氧化氮和过氧亚硝酸盐对骨骼肌线粒体功能的影响

• 发表时间: 2012
• 期刊: Medicine and Science in Sport and Exercise
• 作者: Lancaster CJ

Oxygen consumption kinetics are related to mitochondrial content but not fiber type in single Xenopus skeletal muscle fibers

耗氧动力学与线粒体含量有关，但与单个爪蟾骨骼肌纤维中的纤维类型无关

• DOI: 10.1096/fasebj.25.1_supplement.1058.1
• 发表时间: 2011
• 期刊: The FASEB Journal
• 作者: Wust R

Slowed muscle VO2 kinetics with raised metabolism: not dependent on blood flow or recruitment dynamics

减缓肌肉摄氧量动力学并提高新陈代谢：不依赖于血流或募集动态

• 发表时间: 2012
• 期刊: Medicine and Science in Sport and Exercise
• 作者: Wust RC

Differential regulation of perineuronal nets in the brain and spinal cord with exercise training.

运动训练对大脑和脊髓神经周围网的差异调节。

• DOI: 10.1016/j.brainresbull.2014.12.005
• 发表时间: 2015
• 期刊: Brain research bulletin
• 影响因子: 3.8
• 作者: Smith CC

An (un)paralleled process?

一个（非）并行的过程？

• DOI: 10.1113/expphysiol.2012.071217
• 发表时间: 2013
• 期刊: Experimental physiology
• 影响因子: 2.7
• 作者: Rossiter HB