NAD+ and Exercise in FA

Exercise is the most potent known stimulus for increasing muscle mass and mitochondrial oxidative phosphorylation (OXPHOS) capacity, increasing VO2 max, and increasing insulin sensitivity (SI), however, it had not been studied in people with FA. One adaptation seen in exercised muscles is an increase in muscle nicotinamide adenine dinucleotide (NAD+), a cofactor required for glycolytic and mitochondrial adenosine triphosphate (ATP) production. 

In skeletal- and cardiac muscle-specific frataxin (FXN) knock-out animals, NAD+ precursors rescued cardiac function to near-normal.  

2026-May, Results Published: 

This phase 2 randomized controlled trial enrolled 66 individuals aged 10–40 years (50% children; 50% adults) across four groups for 12 weeks: placebo only, nicotinamide riboside (NR) only, exercise only, or NR plus exercise. The home-based exercise program consisted of three aerobic sessions and two resistance sessions per week, supervised by telephone check-ins. Weight-based dosing of nicotinamide riboside or placebo was 300 mg (1 capsule) for weights of 24 kg up to 48 kg, 600 mg (2 capsules) for weight 48 kg up to 72 kg, and 900 mg (3 capsules) for weights of over 72 kg. All participants completed the study, with 97% pill adherence and 94% exercise session adherence.

“The combination of nicotinamide riboside plus exercise for 12 weeks was safe and increased cardiopulmonary fitness in children and adults with Friedreich’s ataxia. Longer studies are needed to establish whether adding nicotinamide riboside to exercise could be considered as part of a long-term, comprehensive treatment approach.”

The combination group reached statistical significance versus control for the primary outcome, peak aerobic capacity (VO₂): +0.16 L/min (+13.2%; p=0.030). Exercise alone trended positive (+0.11 L/min; +9.5%) and NR alone showed a smaller trend (+0.06 L/min; +5.0%), but neither reached statistical significance after correction for multiple comparisons. The control group declined (−0.05 L/min; −3.9%). There were no serious adverse events, and fall rates were similar across exercising and non-exercising groups.

Secondary and exploratory findings included improved oxygen pulse (a surrogate for cardiac output) in both exercise-containing groups, and increased self-reported leisure physical activity in the NR plus exercise group. Fatigue, grip strength, and neurological ratings (mFARS) did not change significantly in any group. Circulating frataxin levels were also unchanged, suggesting fitness gains occurred independently of frataxin restoration. Glucose homeostasis outcomes (aim 2 of the trial) will be reported in a separate publication.

FARA does not endorse or recommend any particular study or supplement. Nicotinamide riboside is available as a dietary supplement but is not an FDA-approved treatment for FA.

Study Plan: There is a critical knowledge gap regarding the best ways to intervene to increase aerobic capacity (VO2 max on exercise testing) in FA. Exercise is the most potent known stimulus for increasing muscle mass and mitochondrial oxidative phosphorylation (OXPHOS) capacity, increasing VO2 max, and increasing insulin sensitivity (SI), however, it has not been studied in FA. One adaptation seen in exercised muscles is an increase in muscle nicotinamide adenine dinucleotide (NAD+), a cofactor required for glycolytic and mitochondrial adenosine triphosphate (ATP) production. In skeletal- and cardiac muscle-specific frataxin (FXN) knock-out animals, NAD+ precursors rescued cardiac function to near-normal, additionally highlighting its translational potential in FA. Nicotinamide riboside (NR) is a NAD+ precursor currently available as a dietary supplement (Tru Niagen ®, ChromaDex, Irvine CA) that is expected to be safe and well-tolerated in adults and children. The central hypothesis is that exercise + NR will increase skeletal muscle mitochondrial OXPHOS and increase muscle mass to increase VO2max in FA. The investigators expect that exercise + NR will also increase SI in this cohort. Randomized, placebo-controlled trial with a 2×2 factorial design testing the effects of an NAD+ precursor (NR) and exercise on VO2 max and SI in Friedreich’s Ataxia (FA).

The primary objective of this research is to measure the effect of combination administration (NR + exercise) on aerobic capacity (VO2 max) in FA. A key secondary objective is to measure the effect of combination administration (NR + exercise) on glucose homeostasis (SI) in FA.