Detection and enhancement of tissue NAD+ levels in Friedreich’s Ataxia

Nicotinamide adenine dinucleotide (NAD+) is a critical co-factor for cellular metabolism and signaling. It is especially important for energy generation by mitochondria, the “powerhouse of the cell.” Recently, it has been shown that NAD+ is lower in failing hearts and that boosting NAD+ improves heart function in animal models. In mice with heart-specific loss of frataxin, supplementing NAD+ with nicotinamide mononucleotide (NMN) improved heart function. Dr Baur and his group were able to enhance mitochondrial function with NAD+ supplementation in mice that have reduced frataxin levels in their whole bodies, which is thought to reflect the human disease better. In collaboration with Dr McCormack and other scientists at the University of Pennsylvania and the Children’s Hospital of Philadelphia, he plans to extend these findings in mice and evaluate tissue NAD+ levels in human subjects with FA. Mice with low levels of frataxin will be treated with nicotinamide riboside (NR) or NMN to increase NAD+ levels. Heart function will be evaluated by echocardiography, and mitochondria will be tested to determine their capacity to generate energy. In addition, they will measure the levels of metabolites in the brain, heart tissue, and mitochondria under each condition. In human subjects, these investigators will take advantage of a recently developed method for the detection of NAD+ in living tissue by proton magnetic resonance spectroscopy (MRS). This method will be used to measure NAD+ in both the brain and skeletal muscle of subjects with FA and healthy controls. Together, these studies have the potential to uncover novel biomarkers and will guide decisions concerning the suitability and therapeutic potential of NAD+ precursors in individuals with FA.