Short term nicotinamide riboside treatment improves muscle quality and function in mice as well as increases cellular energetics and differentiating capacity of myogenic progenitors

Abstract Nicotinamide adenine dinucleotide (NAD+), an essential co-factor for mitochondrial function, declines with aging, which may lead to impaired physical performance. Nicotinamide riboside (NR), a NAD+ precursor, restores cellular NAD+ levels. Here we examined the impacts of short term NR supplementation on physical performance in middle-aged mice and impacts on mouse and human muscle stem cells. We treated fifteen-month-old male C57BL/6J mice with NR at 300 mg/kg/day (NR3), 600 mg/kg/day (NR6), or placebo (PLB), n=8 per group, and assessed changes in physical performance, muscle histology, and NAD+ content after 4 weeks of treatment. We found that NR increased total NAD+ in muscle tissue (NR3 p=0.01; NR6 p=0.004, both versus PLB), enhanced treadmill endurance and open field activity, and prevented decline in grip strength. Histologic analysis revealed NR treated mice exhibited enlarged slow twitch fibers (NR6 versus PLB p=0.014; NR3 p=0.16) and a trend towards more slow fibers (NR3 p=0.14; NR6 p=0.22). We next carried out experiments to characterize NR impacts on mitochondrial activity and cellular energetics in vitro. We observed that NR boosted basal and maximal cellular aerobic and anaerobic respiration in both mouse and human myoblasts and human myotubes. Additionally, NR treatment improved the differentiating capacity of myoblasts and increased myotube size and fusion index upon stimulation of these progenitors to form multinucleated myotubes. These findings support a role for NR in improving cellular energetics and functional capacity in mice, which support the translation of this work into clinical settings as a strategy for improving and/or maintaining healthspan during aging.