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

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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.