Intensive tailored exercise training with NAD+ precursor supplementation to improve muscle mass and fitness in adolescent and young adult survivors of hematopoietic stem cell transplantation

补充 NAD 前体的强化定制运动训练可改善造血干细胞移植的青少年和年轻成年幸存者的肌肉质量和体能

• 批准号: 10477388
• 负责人: SHANA ERIN MCCORMACK
• 金额: $ 67.78万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10477388
• 关键词: Address; Adolescent and Young Adult; Adult; Adverse effects; Aerobic; Age; Aging; Animal Model; Area; Biometry; Cancer Survivorship; Cardiology; Cardiopulmonary; Cardiovascular Diseases; Cardiovascular system; Child; Chronic; Combined Modality Therapy; Development; Dual-Energy X-Ray Absorptiometry; Elderly; Endocrinology; Excess Mortality; Exercise; Exercise Test; Future; Glucocorticoids; Hematopoietic Stem Cell Transplantation; High-Risk Cancer; Home; Human; Hypogonadism; Imaging Techniques; Immunosuppression; Individual; Inflammation; Intervention; Leg; Long-Term Survivors; Lung; Magnetic Resonance Imaging; Malnutrition; Measures; Mediating; Metabolism; Mitochondria; Morbidity - disease rate; Muscle; Muscle Mitochondria; Muscle function; Muscular Atrophy; Musculoskeletal System; Myopathy; National Heart, Lung, and Blood Institute; Nicotinamide adenine dinucleotide; Oral; Outcome; Oxidative Phosphorylation; Oxygen; Physical activity; Physiological; Population; Production; Randomized; Randomized Controlled Trials; Research; Research Priority; Risk; Risk Factors; Skeletal Muscle; Supervision; Supplementation; Survivors; Testing; Thinness; Toxic effect; Transplantation Conditioning; Treatment-Related Cancer; VO2max; Vascular System; acylcarnitine; arm; base; clinically relevant; cofactor; comorbidity; design; exercise capacity; exercise training; fitness; graft vs host disease; growth hormone deficiency; hematopoietic cell transplantation; high risk; improved; indexing; innovation; intervention effect; metabolome; metabolomics; mimetics; mitochondrial metabolism; mortality; multidisciplinary; muscle form; muscle metabolism; muscle strength; nicotinamide riboside supplementation; nicotinamide-beta-riboside; non-invasive imaging; novel; organic acid; physical inactivity; premature; prevent; primary outcome; recruit; reduced muscle mass; response; sarcopenia; secondary outcome; sedentary; skeletal muscle wasting; strength training; therapy design; transplant survivor; uptake

ABSTRACT Advances in hematopoietic cell transplantation (HCT) have led to improvements in survival. Adolescents and young adults (AYAs) who undergo HCT are at an especially high risk of developing sarcopenia (loss of skeletal muscle mass) due to the impact of HCT-related exposures on the immature musculoskeletal system. We have shown that sarcopenia occurs earlier in HCT survivors than would be expected from advancing age alone. HCT survivors who are sarcopenic have a two-fold risk of non-relapse mortality excess rates of premature cardiovascular disease. Therefore, to improve the lives of AYA HCT survivors, it is of critical importance to develop interventions to increase skeletal muscle mass, metabolism, strength, and function. Skeletal muscle is highly reliant on mitochondrial energy production, as measured by oxidative phosphorylation (OXPHOS) capacity. Thus, one strategy to improve skeletal muscle function is to increase muscle OXPHOS in these survivors. Home-based exercise (aerobic and resistance) training is a well-established intervention to increase skeletal muscle mitochondrial OXPHOS, as well as mass, strength, and function. Another approach is to use an “exercise mimetic”, an intervention designed to recapitulate the physiologic benefits of exercise. Precursors of nicotinamide adenine dinucleotide (NAD+), a cofactor required for ATP production, are exercise mimetics. In humans, short-term oral nicotinamide riboside (NR) supplementation has been found to increase the NAD+ muscle metabolome and reduce chronic inflammation associated with aging. Exercise combined with NAD+ precursor supplementation may yield additional benefits compared to either alone, but this approach has not been tested in AYA HCT survivors. We propose a randomized controlled trial with a 2x2 factorial design testing 16 weeks of exercise and NR in AYA survivors of HCT, with a primary outcome of muscle strength. We will also examine the effects of these interventions on exercise capacity, use an innovative non-invasive imaging technique to measure muscle mitochondrial function, and metabolomics to test circulating correlates of increased ATP production, including NAD+, acylcarnitines, and organic acids. Individuals (N=80, ages 15-30y) will be recruited 6-24 mos post-HCT and randomized to 1 of 4 arms: exercise+NR, exercise alone, NR alone, or control. We will use DXA to measure lower leg lean muscle mass, non-invasive MRI to measure OXPHOS, dynamometry to test strength (primary outcome) and cardiopulmonary exercise testing to measure maximal oxygen uptake (VO2max; secondary outcome), at baseline and 16 wks. We expect exercise+NR will produce larger changes than exercise alone in key outcomes, and that changes will be mediated by increases in muscle OXPHOS. This study will address a shared NCI and NHLBI research priority, namely how best to prevent the late development of complications following HCT, and thereby reduce the burden of HCT-related morbidity and mortality. Our findings will inform strategies to prevent or mitigate the myriad downstream adverse effects of low muscle mass in AYA HCT survivors, an important area of focus for the NCI and NHLBI.

抽象的 造血细胞移植（HCT）的进步提高了青少年和儿童的生存率。 接受 HCT 的年轻人 (AYA) 患肌肉减少症（骨骼丧失）的风险特别高 肌肉质量），这是由于 HCT 相关暴露对不成熟的肌肉骨骼系统的影响。 研究表明，HCT 幸存者中肌肉减少症的发生时间比仅因年龄增长而预期的发生时间要早。 肌肉减少症的 HCT 幸存者的非复发死亡率超额风险是早产儿死亡率的两倍 因此，为了改善 AYA HCT 幸存者的生活，至关重要的是 制定干预措施以增加骨骼肌质量、新陈代谢、力量和功能。 高度依赖线粒体能量产生，通过氧化磷酸化 (OXPHOS) 测量 因此，改善骨骼肌功能的一种策略是增加肌肉中的 OXPHOS。 家庭运动（有氧运动和阻力）训练是一种行之有效的干预措施，可以提高幸存者的能力。 骨骼肌线粒体 OXPHOS，以及质量、强度和功能的另一种方法是使用。 一种“运动模拟”，旨在概括运动的生理益处的干预措施。 烟酰胺腺嘌呤二核苷酸 (NAD+) 是 ATP 生成所需的辅助因子，是运动模拟物。 人类短期口服烟酰胺核苷 (NR) 补充剂已被发现可增加 NAD+ 肌肉代谢组和减少与衰老相关的慢性炎症结合运动与 NAD+。 与单独使用任何一种方法相比，补充前体可能会产生额外的好处，但这种方法并没有 我们提出了一项采用 2x2 析因设计的随机对照试验。 对 HCT 的 AYA 幸存者进行 16 周的运动和 NR 测试，主要结果是肌肉力量。 我们还将检查这些干预措施对运动能力的影响，使用创新的非侵入性方法 成像技术测量肌肉线粒体功能，代谢组学测试循环相关性 ATP 产量增加，包括 NAD+、酰基肉碱和有机酸 个体（N=80，年龄 15-30 岁）。 将在 HCT 后 6-24 个月内招募并随机分配至 4 个组中的 1 个：运动 + NR、仅运动、仅 NR， 我们将使用 DXA 测量小腿肌肉瘦质量，使用非侵入性 MRI 测量 OXPHOS， 用于测试力量（主要结果）的测功机和用于测量最大运动量的心肺运动测试 我们预计运动+NR 会产生基线和 16 周的摄氧量（最大摄氧量；次要结果）。 在关键结果上，比单独锻炼带来的变化更大，并且这种变化将通过增加 这项研究将解决 NCI 和 NHLBI 共同的研究重点，即如何最好地 预防HCT后并发症的后期发展，从而减轻HCT相关的负担 我们的研究结果将为预防或减轻无数下游疾病的策略提供信息。 低肌肉质量对 AYA HCT 幸存者的不利影响是 NCI 和 NHLBI 关注的重要领域。