NAD+ precursor supplementation with exercise training to improve aerobic capacity in Friedreich's Ataxia

摘要

ABSTRACT Friedreich’s Ataxia (FA) is a progressive neurodegenerative disease affecting 1 in 50,000 in the U.S. FA- related heart failure is the predominant cause of premature mortality. There is no approved treatment. At the Children’s Hospital of Philadelphia (CHOP) Center for Excellence (COE) in FA, we provide care for >400 children and adults with FA. We have found that decreased aerobic capacity, specifically low maximal oxygen uptake (VO2max) with exercise, is common, and reflects disease progression. Low VO2max is likely related to decreased insulin sensitivity (Si) that often progresses to diabetes. VO2max also predicts capacity to perform activities of daily living. We propose that in the absence of FA-related heart failure, deficits in skeletal muscle metabolism contribute most to decreased VO2max in FA. FA is caused by mutations in the gene encoding frataxin (FXN), which impacts mitochondrial oxidative phosphorylation (OXPHOS) capacity. We have found a 52% deficit in muscle OXPHOS in FA that is related to reduced insulin sensitivity. Low muscle OXPHOS has been identified as a potentially reversible contributor to decreased functional status in individuals with heart failure from causes other than FA. Therefore, we posit that improving muscle OXPHOS and aerobic capacity may also attenuate symptoms in FA. There is a critical knowledge gap regarding the best ways to improve VO2max in FA prior to the onset of heart failure. Exercise is the most potent known stimulus to increase muscle mass, OXPHOS, and glucose tolerance. One adaptation to exercise is an increase in muscle nicotinamide adenine dinucleotide (NAD+), a cofactor required for ATP production. NAD+ precursors are called “exercise mimetics”, because they increase muscle OXPHOS, endurance, and glucose tolerance even in sedentary animals. In cardiac- and skeletal muscle FXN knock-out animals, NAD+ precursors rescued cardiac function to near-normal. Nicotinamide riboside (NR) is a currently available NAD+ precursor that is safe and well-tolerated. We propose a randomized controlled trial with a 2x2 factorial design testing 12 wks of exercise and NR in FA. Individuals with FA (N=72, ages 10y-40y, without heart failure or DM requiring insulin) will be recruited from our cohort and from an FA registry. They will be randomized to 1 of 4 arms: exercise+NR, exercise alone, NR alone, or control. We will quantify changes in muscle mass, NAD+, and FXN, and use a novel strategy that will complement ex vivo measures of mitochondrial respiration with direct in vivo imaging of skeletal muscle OXPHOS. We will assess changes in aerobic capacity (VO2max) and glucose metabolism (Si). For both outcomes, we expect that exercise+NR will produce larger changes than exercise alone, and that changes will be mediated by increases in muscle NAD+ and OXPHOS. With insights from this initial study of skeletal muscle metabolism and aerobic capacity in individuals without heart failure, we will next pursue trials to improve functional status in individuals with FA both with and without heart failure. These pathobiological mechanisms may also be relevant for increasing functional status in heart failure from other causes.