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.

积极运动的生活方式是慢性阻塞性肺疾病（COPD）治疗中恢复肢体肌肉功能的重要组成部分。然而，运动（EXEC）训练后改善有限的患者入院和死亡的风险仍然增加。营养补充和合成代谢药物提高EXEC训练效力的潜力尚无定论和/或存在安全问题。我们最近观察到，COPD患者的肌肉功能障碍与支链氨基酸、酮酸和β-羟基β-甲基丁酸（HMB）代谢的严重紊乱有关，并且在稳定的中度至重度COPD （GOLD II-III）患者中，高强度耐药EXEC （rEXEC）后24小时净蛋白损失增加，已知会诱导急性肌肉缺氧。由于rEXEC是COPD训练的关键组成部分，因此迫切需要确定rEXEC诱导代谢失调的机制，以及缺氧通过HIF1α-mTOR途径的作用，以便开发安全，临床有效且具有成本效益的治疗方法。我们的总体目标是确定慢性阻塞性肺疾病中rEXEC诱导的代谢失调和蛋白质损失的分子机制，并评估在EXEC训练的同时进行有针对性的营养补充的有效性。我们的中心假设是，通过靶向必需氨基酸调节富集HMB （EAA+HMB）改善对rEXEC的代谢和分子反应，将比单独EAA更能提高COPD患者的肌肉功能，因为HMB具有抗分解代谢和延长合成代谢的特性。此外，最近的数据显示，HMB对肌肉收缩力、有氧能力和EXEC再生能力有良好的影响。在目的1中，我们将确定rEXEC在特征明确的COPD患者（GOLD II-III）中诱导蛋白质分解代谢的代谢和分子机制，已知其组织缺氧，肌肉萎缩和代谢紊乱的风险高于健康匹配的对照受试者。我们将使用创新的15稳定示踪剂iv脉冲方法来深入分析包括HMB在内的多种氨基酸的代谢（代谢谱），肌肉蛋白质合成/分解，以及rEXEC如何损害骨骼肌蛋白质稳态的分子机制。在目标2中，一项随机、双盲、安慰剂对照的临床试验将评估膳食EAA+HMB与EAA补充剂与安慰剂（反映标准护理）的疗效，同时进行8周的EXEC训练，以改善COPD的肌肉力量（主要终点）和耐力、身体活动、幸福感以及疾病相关和全球临床结果（GOLD I-III）。由于肌肉功能障碍已经存在，因此需要及时的治疗干预来实现现实的行为改变，因此包括GOLD I。这些结果预计将产生重要的积极影响，因为与EXEC一起用于COPD的靶向营养配方的有效性的原理证明将为其继续开发和未来的临床试验提供强有力的理由，以改善患者预后并优化当前恢复肌肉功能的策略。