Nutritional modulation to minimize resistance exercise induced metabolic deregulations and improve training responsiveness in Chronic Obstructive Pulmonary Disease

营养调节可最大程度地减少阻力运动引起的代谢失调并提高慢性阻塞性肺疾病的训练反应能力

• 批准号: 10009819
• 负责人: Nicolaas E Deutz
• 金额: $ 75.66万
• 依托单位: TEXAS A&M UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-15 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10009819
• 关键词: Acids; Acute; Aerobic; Amino Acids; Autophagocytosis; Behavioral; Biopsy; Branched-Chain Amino Acids; Caring; Catabolism; Chronic Obstructive Airway Disease; Clinical; Clinical Trials; Comorbidity; Complement; Controlled Clinical Trials; Data; Development; Diet; Dietary Intervention; Disease; Double-Blind Method; Effectiveness; Essential Amino Acids; Essential amino acids supplementation; Evaluation; Exercise; FRAP1 gene; Fatigue; Formulation; Functional disorder; Future; Goals; Hospital Mortality; Hospitalization; Hour; Hydroxy Acids; Hypoxemia; Hypoxia; Impairment; Intake; Keto Acids; Limb structure; Mediating; Metabolic; Metabolism; Molecular; Muscle; Muscle Fibers; Muscle Proteins; Muscle Weakness; Muscle function; Muscular Atrophy; Nutritional; Oral; Outcome; Pathway interactions; Patient-Focused Outcomes; Patients; Performance; Peripheral; Personal Satisfaction; Pharmaceutical Preparations; Physical Performance; Physical activity; Physiologic pulse; Pilot Projects; Placebos; Production; Property; Protein Biosynthesis; Proteins; Quality of life; Randomized; Reporting; Research; Resistance; Risk; Role; Safety; Severity of illness; Signal Transduction; Skeletal Muscle; Supplementation; Testing; Therapeutic Intervention; Time; Tissues; Tracer; Training; Translations; active lifestyle; base; clinical application; cost effective; design; effective therapy; exercise intensity; exercise training; expectation; high risk; hypoxia inducible factor 1; improved; improved outcome; innovation; insight; metabolic profile; mortality; muscle form; muscle strength; negative affect; novel; nutritional supplementation; physical inactivity; primary endpoint; proteostasis; regenerative; resistance exercise; resistance mechanism; response; standard of care; therapeutic target

A physically active lifestyle is an essential component of care in Chronic Obstructive Pulmonary Disease (COPD) to restore limb muscle function. However, patients with limited improvement after exercise (EXEC) training remain at increased risk for hospital admission and mortality. The potential of nutritional supplementation and anabolic drugs to enhance efficacy of EXEC training are inconclusive and/or have safety concerns. We recently observed that muscle dysfunction in COPD is associated with severe disturbances in the metabolism of the branched-chain amino acids, their keto acids, and β-hydroxy β-methylbutyric acid (HMB) and enhanced net protein loss 24 hours after high-intensity resistance EXEC (rEXEC), known to induce acute muscle hypoxia, in stable moderate to severe COPD (GOLD II-III) patients. As rEXEC is a key component of training in COPD, there is a critical need to identify the mechanisms of rEXEC induced metabolic deregulations, and the role of hypoxia via the HIF1α-mTOR pathway so that safe, clinically- and cost-effective therapies can be developed. Our overall objective is to identify the metabolic deregulations and molecular mechanisms underlying protein loss induced by rEXEC in COPD, and to evaluate the effectiveness of targeted nutritional supplementation alongside EXEC training. Our central hypothesis is that improving the metabolic and molecular responses to rEXEC via targeted essential amino acid modulation enriched with HMB (EAA+HMB) will increase muscle function in COPD patients more than EAA alone because of the anti-catabolic and prolonged anabolic properties of HMB. Also, recent data showed favorable effects of HMB on muscle contractility, aerobic capacity and EXEC regenerative capacity. In aim 1, we will identify the metabolic and molecular mechanisms by which rEXEC induces protein catabolism in well characterized COPD patients (GOLD II-III), known of their elevated risk for tissue hypoxia, muscle atrophy, and metabolic disturbances, versus healthy matched control subjects. We will use an innovative 15 stable tracer iv pulse approach to analyze metabolism of multiple amino acids including HMB in depth (metabolic profile), muscle protein synthesis/ breakdown, and the molecular mechanisms how rEXEC impairs skeletal muscle protein homeostasis. In aim 2, a randomized, double blind, placebo controlled, clinical trial will evaluate the efficacy of dietary EAA+HMB versus EAA supplementation versus placebo (reflecting standard of care) alongside 8 weeks of EXEC training to improve muscle strength (primary endpoint) and endurance, physical activity, well-being, and disease related- and global clinical outcomes in COPD (GOLD I-III). GOLD I is included as muscle dysfunction is already present and therefore timely therapeutic interventions are needed to achieve realistic behavioral changes. These results are expected to have an important positive impact because proof of principle demonstration of the effectiveness of a targeted nutritional formulation to be used alongside EXEC in COPD will provide strong justification for its continued development and future clinical trials to improve patient outcomes and to optimize current strategies to restore muscle function.

体育活跃的生活方式是慢性阻塞性肺部疾病（COPD）的重要组成部分，以恢复肢体肌肉功能。但是，运动后（EXEC）培训后有限改善的患者仍处于住院和死亡率的风险增加。营养补充和合成代谢药物提高EXEC培训效率的潜力是不确定的和/或有安全问题。我们最近观察到，COPD中的肌肉功能障碍与分支链氨基酸的代谢严重疾病有关，其酮酸和β-羟基β-羟基β-甲基丁酸（HMB）（HMB）和净蛋白质损失增强了24小时的净蛋白质损失，以使高高的强度抑制（Rexec）高高地构成敏锐的脉冲（Rexec），以促进敏锐的敏感性，以促进敏锐的脉冲（Rexec），以促进敏锐的脉冲（Rexec）敏锐的刺激性（Rexecte）。 II-III）患者。由于REXEC是COPD训练的关键组成部分，因此至关重要的是确定REXEC诱导的代谢失调的机制，并且缺氧通过HIF1α-MTOR途径的作用，以便可以开发出安全，临床和成本效益的疗法。我们的总体目标是确定REXEC在COPD中诱导的蛋白质损失的代谢不足和分子机制，并评估靶向营养补充在EXEC培训的有效性。我们的中心假设是，通过富含HMB（EAA+HMB）的靶向必需氨基酸调节来改善对REXEC的代谢和分子反应，由于抗代谢和延长HMB的替代性归类性特性，因此COPD患者的肌肉功能比EAA的肌肉功能更大。此外，最近的数据显示了HMB对肌肉收缩力，有氧能力和EXEN再生能力的有利影响。在AIM 1中，我们将确定REXEC诱导良好特征性COPD患者（金II-III）的蛋白质分解代谢的代谢和分子机制，这些蛋白质分解代谢（Gold II-III）已知其升高组织缺氧，肌肉萎缩和代谢灾害的风险升高，而新陈代谢的灾难与健康匹配的对照组相对于健康匹配的对照组。我们将使用创新的15个稳定的示踪剂IV脉冲方法来分析多种氨基酸的代谢，包括深度HMB（代谢谱），肌肉蛋白质合成/分解以及分子机制如何损害骨骼肌蛋白质稳态。在AIM 2中，一项随机，双盲，安慰剂控制的临床试验将评估饮食中的EAA+HMB与EAA补充与安慰剂（反映护理标准）的有效性，以及8周的EXEC培训，以改善肌肉力量（主要终点）和耐力，体育锻炼，体育活动，福祉，以及与疾病相关的和疾病相关的和全球临床临床和全球临床临床（copd copd（GOLD）（GODD）。金I被包括在内，因为已经存在肌肉功能障碍，因此需要及时进行治疗干预以实现现实的行为改变。预计这些结果将产生重要的积极影响，因为原理证明将与COPD中的Exec一起使用有针对性的营养公式的有效性将为其持续发展和未来的临床试验提供强有力的理由，以改善患者的结果，并优化当前的策略以恢复肌肉功能。