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

> **NIH NIH R01** · CHILDREN'S HOSP OF PHILADELPHIA · 2021 · $790,590

## Abstract

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
t...

## Key facts

- **NIH application ID:** 10077354
- **Project number:** 5R01HL149722-02
- **Recipient organization:** CHILDREN'S HOSP OF PHILADELPHIA
- **Principal Investigator:** SHANA ERIN MCCORMACK
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $790,590
- **Award type:** 5
- **Project period:** 2020-01-01 → 2024-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10077354

## Citation

> US National Institutes of Health, RePORTER application 10077354, NAD+ precursor supplementation with exercise training to improve aerobic capacity in Friedreich's Ataxia (5R01HL149722-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10077354. Licensed CC0.

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