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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：
10543547
负责人：
SHANA ERIN MCCORMACK
金额：
$ 79.04万
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/10543547
关键词：
Activities of Daily Living Adult Aerobic Affect Age Animals Ataxia 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 Immobilization 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 Safety 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 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.

抽象的弗里德赖希共济失调 (FA) 是一种进行性神经退行性疾病，在美国影响五万分之一的人相关的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) 位于 FA，我们为超过 400 名患者提供护理患有 FA 的儿童和成人。我们发现有氧能力下降，特别是最大摄氧量低运动时的摄取量（最大摄氧量）很常见，反映了疾病的进展。低 VO2max 可能与胰岛素敏感性 (Si) 降低，通常会进展为糖尿病。 VO2max 还可以预测执行能力日常生活活动。我们建议，在没有 FA 相关心力衰竭的情况下，骨骼肌缺陷新陈代谢对 FA 中最大摄氧量 (VO2max) 降低的影响最大。 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) 能力。我们找到了一个 FA 中肌肉 OXPHOS 缺失 52%，这与胰岛素敏感性降低有关。低肌肉 OXPHOS 有被确定为心脏病患者功能状态下降的潜在可逆因素 FA 以外的原因造成的故障。因此，我们认为提高肌肉 OXPHOS 和有氧能力也可能减轻 FA 的症状。关于最佳方法存在严重的知识差距在心力衰竭发作前提高 FA 中的 VO2max。运动是已知最有效的刺激增加肌肉质量、氧化磷和葡萄糖耐量。对运动的一种适应是肌肉的增加烟酰胺腺嘌呤二核苷酸 (NAD+)，ATP 生成所需的辅助因子。 NAD+前体被称为 “运动模拟物”，因为它们可以增加肌肉氧化磷酸、耐力和葡萄糖耐量，即使在久坐的动物。在心脏和骨骼肌 FXN 敲除动物中，NAD+ 前体挽救了心脏功能接近正常。烟酰胺核苷 (NR) 是目前可用的 NAD+ 前体，安全且有效耐受性良好。我们提出了一项随机对照试验，采用 2x2 析因设计测试 12 周 FA 中的运动和 NR。患有 FA 的个体（N=72，年龄 10 岁至 40 岁，无心力衰竭或需要胰岛素的 DM）将从我们的队列和 FA 注册表中招募。他们将被随机分配到 4 个组中的一个：运动+NR，单独运动、单独 NR 或控制。我们将量化肌肉质量、NAD+ 和 FXN 的变化，并使用新策略将通过直接体内成像补充线粒体呼吸的离体测量骨骼肌 OXPHOS。我们将评估有氧能力 (VO2max) 和葡萄糖代谢 (Si) 的变化。对于这两种结果，我们预计运动+NR 会比单独运动产生更大的变化，并且变化将通过肌肉 NAD+ 和 OXPHOS 的增加来介导。根据这项初步研究的见解无心力衰竭个体的骨骼肌代谢和有氧能力，我们下一步将进行试验改善患有或不患有心力衰竭的 FA 患者的功能状态。这些病理生物学机制也可能与其他原因导致的心力衰竭的功能状态增加有关。