NAD+ precursor supplementation with exercise training to improve aerobic capacity in Friedreich's Ataxia

通过运动训练补充 NAD 前体以提高弗里德赖希共济失调患者的有氧能力

基本信息

批准号：
10329962
负责人：
SHANA ERIN MCCORMACK
金额：
$ 79.14万
依托单位：
CHILDREN'S HOSP OF PHILADELPHIA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-01-01 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10329962
关键词：
Activities of Daily Living Adult Aerobic Affect Age Animals Attenuated Cardiomyopathies Caring Cessation of life Child Combined Modality Therapy Complement Defect Diabetes Mellitus Disease Progression Engineering Enrollment Ergometry Exercise Exercise Test Friedreich Ataxia Future Genes Heart failure Home Impairment Individual Insulin Iron Knowledge Measures Mediating Mitochondria Mus Muscle Muscle Mitochondria Muscular Atrophy Mutation Myocardium Natural History Neurodegenerative Disorders Nicotinamide adenine dinucleotide OGTT Outcome Oxidative Phosphorylation Oxygen Participant Pediatric Hospitals Philadelphia Premature Mortality Production Randomized Randomized Controlled Trials Rare Diseases Regimen Registries Resistance Respiration Respiratory Chain Skeletal Muscle Stimulus Supplementation Symptoms Testing VO2max Wasting Syndrome advocacy organizations arm clinical outcome measures cofactor cohort design diabetes risk exercise training frataxin functional decline functional status glucose metabolism glucose tolerance heart function high risk improved in vivo imaging innovation insight insulin sensitivity knockout animal mimetics muscle form muscle metabolism nicotinamide-beta-riboside novel strategies premature preservation primary outcome recruit reduced muscle mass safety and feasibility sedentary skeletal abnormality skeletal muscle metabolism stable isotope translational potential uptake young adult

项目摘要

ABSTRACT Friedreich’s Ataxia (FA) is a progressive neurodegenerative disease affecting 1 in 50,000 in the U.S. FA- related heart failure is the predominant cause of premature mortality. There is no approved treatment. At the Children’s Hospital of Philadelphia (CHOP) Center for Excellence (COE) in FA, we provide care for >400 children and adults with FA. We have found that decreased aerobic capacity, specifically low maximal oxygen uptake (VO2max) with exercise, is common, and reflects disease progression. Low VO2max is likely related to decreased insulin sensitivity (Si) that often progresses to diabetes. VO2max also predicts capacity to perform activities of daily living. We propose that in the absence of FA-related heart failure, deficits in skeletal muscle metabolism contribute most to decreased VO2max in FA. FA is caused by mutations in the gene encoding frataxin (FXN), which impacts mitochondrial oxidative phosphorylation (OXPHOS) capacity. We have found a 52% deficit in muscle OXPHOS in FA that is related to reduced insulin sensitivity. Low muscle OXPHOS has been identified as a potentially reversible contributor to decreased functional status in individuals with heart failure from causes other than FA. Therefore, we posit that improving muscle OXPHOS and aerobic capacity may also attenuate symptoms in FA. There is a critical knowledge gap regarding the best ways to improve VO2max in FA prior to the onset of heart failure. Exercise is the most potent known stimulus to increase muscle mass, OXPHOS, and glucose tolerance. One adaptation to exercise is an increase in muscle nicotinamide adenine dinucleotide (NAD+), a cofactor required for ATP production. NAD+ precursors are called “exercise mimetics”, because they increase muscle OXPHOS, endurance, and glucose tolerance even in sedentary animals. In cardiac- and skeletal muscle FXN knock-out animals, NAD+ precursors rescued cardiac function to near-normal. Nicotinamide riboside (NR) is a currently available NAD+ precursor that is safe and well-tolerated. We propose a randomized controlled trial with a 2x2 factorial design testing 12 wks of exercise and NR in FA. Individuals with FA (N=72, ages 10y-40y, without heart failure or DM requiring insulin) will be recruited from our cohort and from an FA registry. They will be randomized to 1 of 4 arms: exercise+NR, exercise alone, NR alone, or control. We will quantify changes in muscle mass, NAD+, and FXN, and use a novel strategy that will complement ex vivo measures of mitochondrial respiration with direct in vivo imaging of skeletal muscle OXPHOS. We will assess changes in aerobic capacity (VO2max) and glucose metabolism (Si). For both outcomes, we expect that exercise+NR will produce larger changes than exercise alone, and that changes will be mediated by increases in muscle NAD+ and OXPHOS. With insights from this initial study of skeletal muscle metabolism and aerobic capacity in individuals without heart failure, we will next pursue trials to improve functional status in individuals with FA both with and without heart failure. These pathobiological mechanisms may also be relevant for increasing functional status in heart failure from other causes.

抽象的弗里德里希（Friedreich）的共济失调（FA）是一种进行性神经退行性疾病相关心力衰竭是过早死亡的主要原因。没有批准的治疗方法。在费城儿童医院（CHOP）卓越中心（COE）在FA，我们提供> 400的护理儿童和成人有足总。我们发现有氧运动能力降低，特别是低最大氧气用运动吸收（Vo2max）是常见的，并且反映了疾病的进展。低Vo2max可能与胰岛素敏感性（SI）降低，通常会发展为糖尿病。 Vo2max还预测执行能力日常生活的活动。我们建议在没有FA相关的心力衰竭的情况下定义骨骼肌肉代谢在FA中的VO2MAX降低最大。 FA是由编码基因突变引起的 Frataxin（FXN），影响线粒体氧化磷酸化（OXPHOS）的能力。我们发现了一个与胰岛素敏感性降低有关的FA肌肉Oxphos的缺陷为52％。低肌肉oxphos具有被确定为具有心脏个体功能状态下降的潜在可逆贡献者 FA以外的其他原因失败。因此，我们肯定会提高肌肉的肌肉和有氧运动能力也可能减轻FA的症状。关于最佳方法有关键的知识差距在心力衰竭发作之前，改善FA中的Vo2max。运动是最潜在的已知刺激增加肌肉质量，Oxphos和葡萄糖耐受性。一种适应运动的是肌肉增加烟酰胺腺嘌呤二核苷酸（NAD+），ATP生产所需的辅助因子。 NAD+前体称为 “运动模仿者”，因为它们甚至在久坐的动物。在心脏和骨骼肌肉FXN敲除动物中，NAD+前体检索了心脏功能至近正常。烟酰胺核苷（NR）是当前可用的NAD+前体，是安全且耐受性良好。我们提出了一项随机对照试验，并使用2x2阶乘设计测试12周运动和NR在FA中。具有FA的个体（n = 72，年龄为10Y-40Y，无心力衰竭或需要胰岛素的DM）它们将从我们的同伙和足总注册表中招募。他们将被随机分为4个武器中的1个：锻炼+NR，独自运动，单独进行或控制。我们将量化肌肉质量，NAD+和FXN的变化，并使用新型策略将与直接在体内成像的线粒体呼吸进行体内测量骨骼肌的肌肉。我们将评估有氧能力（VO2MAX）和葡萄糖代谢（SI）的变化。对于这两个结果，我们都希望锻炼+NR会产生比单独锻炼更大的变化，并且变化将通过肌肉NAD+和OXPHOS的增加来介导。从这项最初研究的见解没有心力衰竭的个体的骨骼肌肉代谢和有氧能力，我们将接下来进行试验改善有或没有心力衰竭的FA个体的功能状态。这些病理生物学机制也可能与增加其他原因的心力衰竭功能状态有关。