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

积极的体育生活方式是慢性阻塞性肺疾病(COPD)患者恢复四肢肌肉功能护理的重要组成部分。然而，运动(EXEC)训练后改善有限的患者仍然面临入院和死亡的更高风险。营养补充剂和合成代谢药物提高执行训练效果的可能性尚不确定和/或存在安全问题。我们最近观察到，慢性阻塞性肺疾病患者的肌肉功能障碍与支链氨基酸及其酮酸和β-羟基β-甲基丁酸(HMB)代谢的严重紊乱以及高强度抵抗运动后24小时蛋白质净损失增加有关，高强度阻力运动可导致急性肌肉缺氧，在稳定的中到重度COPD(GOLD II-III)患者中。由于rEXEC是慢性阻塞性肺疾病训练的关键组成部分，迫切需要确定rEXEC诱导代谢紊乱的机制，以及缺氧通过HIF1α-mTOR途径所起的作用，以便开发安全、临床和经济有效的治疗方法。我们的总体目标是确定rEXEC导致COPD患者蛋白质丢失的代谢紊乱和分子机制，并评估在进行EXEC训练的同时进行靶向营养补充的有效性。我们的中心假设是，通过富含HMB的靶向必需氨基酸调节(EAA+HMB)来改善对rEXEC的代谢和分子反应将比单独使用EAA更能提高COPD患者的肌肉功能，因为HMB具有抗分解代谢和持久的合成代谢特性。此外，最近的数据显示，HMB在肌肉收缩能力、有氧能力和执行再生能力方面具有良好的效果。在目标1中，我们将确定rEXEC诱导COPD患者(GOLD II-III)蛋白质分解代谢的代谢和分子机制，与健康对照组受试者相比，这些患者组织缺氧、肌肉萎缩和代谢紊乱的风险增加。我们将使用一种创新的15稳定示踪剂IV脉冲方法来分析多种氨基酸的代谢，包括HMB深度(代谢谱)、肌肉蛋白质合成/分解，以及rEXEC如何破坏骨骼肌蛋白质动态平衡的分子机制。在目标2中，一项随机、双盲、安慰剂对照的临床试验将评估饮食EAA+HMB与EAA补充剂与安慰剂(反映护理标准)以及8周执行训练的疗效，以改善COPD患者的肌肉力量(主要终点)和耐力、体力活动、幸福感、疾病相关和全球临床结果(GOLD I-III)。GOLD I被包括在内，因为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。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的靶向营养配方有效性的原则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，以改善患者的预后，并优化当前恢复肌肉功能的策略。

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.