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. NMN influences several aspects of mitochondrial metabolism.  

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

Dr. Shana McCormack, Children’s Hospital of Philadelphia, received approval to initiate the clinical trial, supported by a grant from the National Institutes of Health (NIH).

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.