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

摘要 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1/50，000。 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）在FA，我们提供护理>400 儿童和成人FA。我们发现有氧能力下降，特别是最大氧含量低 运动时的最大摄氧量（VO 2 max）是常见的，反映了疾病的进展。最大摄氧量低可能与 胰岛素敏感性（Si）降低，通常进展为糖尿病。VO 2 max还可预测执行能力 日常生活活动。我们认为，在没有FA相关心力衰竭的情况下， FA代谢对降低VO 2 max贡献最大。FA是由基因编码突变引起的， frataxin（FXN），其影响线粒体氧化磷酸化（OXPHOS）能力。我们找到了一个 FA中52%的肌肉OXPHOS缺陷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 除FA之外的其他原因导致的故障。因此，我们认为，提高肌肉OXPHOS和有氧能力， 也可以减轻FA的症状。在最佳方法方面存在着严重的知识差距， 改善心力衰竭发作前FA中的VO 2 max。运动是已知的最强有力的刺激， 增加肌肉质量、OXPHOS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产生所需的辅因子。NAD+前体被称为 “运动模拟”，因为他们增加肌肉OXPHOS，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，其是安全的且 宽容。我们提出了一项随机对照试验，采用2x2析因设计测试12周的 FA中的运动和NR。FA患者（N=72，年龄10 - 40岁，无心力衰竭或需要胰岛素的DM） 将从我们的队列和FA注册中招募。他们将被随机分配到4个组中的1个：运动+NR， 单独运动、单独NR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，将补充离体测量线粒体呼吸与直接在体内成像， 骨骼肌OXPHOS我们将评估有氧能力（VO 2 max）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， 变化将通过肌肉NAD+和OXPHOS的增加来介导。从这个最初的研究中， 在没有心力衰竭的个体中，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。这些病理生物学 机制也可能与其他原因引起的心力衰竭中功能状态的增加有关。

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.