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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：
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.

摘要弗里德里希共济失调(FA)是一种进行性神经退行性疾病，在美国FA中每50,000人中就有1例发病。相关性心力衰竭是导致过早死亡的主要原因。目前还没有批准的治疗方法。在费城儿童医院(CHOP)卓越中心(COE)在FA，我们为&GT；400提供护理患有FA的儿童和成人。我们发现有氧能力降低，特别是最大氧气量降低运动摄取(最大摄氧量)是很常见的，反映了疾病的进展。低VO2max可能与胰岛素敏感度(Si)降低，通常会发展为糖尿病。VO2max还预测要执行的容量日常生活活动。我们认为，在没有FA相关的心力衰竭的情况下，骨骼肌的缺陷代谢是FA中VO2max降低的主要原因。FA是由编码基因突变引起的 Frataxin(FXN)，它影响线粒体氧化磷酸化(OXPHOS)能力。我们发现了一个 FA中肌肉OXPHOS缺乏52%与胰岛素敏感性降低有关。下肌肉OXPHOS有已被确定为心脏病患者功能状态下降的潜在可逆因素由FA以外的原因造成的故障。因此，我们假设，提高肌肉的氧合能力和有氧能力也可以减轻FA的症状。在最佳方法方面存在严重的知识差距在心力衰竭发作前改善FA的最大摄氧量。运动是已知的最有效的刺激增加肌肉质量、氧磷酸盐和葡萄糖耐量。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+)，一种产生ATP所需的辅因子。NAD+前体被称为 “模拟运动”，因为它们提高了肌肉的氧合能力、耐力和葡萄糖耐量，即使在久坐的动物。在心肌和骨骼肌FXN基因敲除动物中，NAD+前体拯救了心脏功能恢复到接近正常状态。烟酰胺核苷(NR)是一种目前可用的NAD+前体，安全且耐受性很好。我们提出了一项随机对照试验，采用2x2析因设计，测试12周足总运动和硝酸甘油。FA患者(N=72，年龄10岁-40岁，无心力衰竭或需要胰岛素的糖尿病) 将从我们的队列和FA注册中招募。他们将被随机分成4组中的1组：锻炼+NR，单独锻炼，单独锻炼，或对照。我们将量化肌肉质量、NAD+和FXN的变化，并使用一种新的策略，将补充线粒体呼吸的体外测量与体内直接成像骨骼肌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将比单独运动产生更大的变化，而且变化将通过肌肉NAD+和OXPHOS的增加来调节。从这项初步研究中获得的见解无心衰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伴有和不伴有心力衰竭的FA患者的功能状态。这些病原体机制也可能与其他原因引起的心力衰竭患者功能状态增加有关。