Complementary NAD+ Replacement Strategies Fail to Functionally Protect Dystrophin-Deficient Muscle [post]

David Frederick, Alan V. McDougal, Melisa Semenas, Johanna Vappiani, Andrea Nuzzo, John C. Ulrich, Eugene L. Stewart, Daniel C. Sévin, H. Fritz Kramer
2020 unpublished
Background Duchenne muscular dystrophy (DMD) is a progressive muscle wasting disorder stemming from a loss of functional dystrophin. Current therapeutic options for DMD are limited, as small molecule modalities remain largely unable to lessen the incidence or mitigate the consequences of repetitive mechanical insults to the muscle during eccentric contractions (ECCs). Methods Using a metabolomics approach, we observed distinct and transient molecular phenotypes in muscles of
more » ... MDX mice subjected to ECCs. Among the most depleted metabolites was nicotinamide adenine dinucleotide (NAD), an essential metabolic cofactor suggested to protect muscle from structural and metabolic degeneration over time. We tested whether the MDX muscle NAD pool can be expanded for therapeutic benefit by providing a biosynthetic precursor, nicotinamide riboside, or specifically inhibiting the NAD-degrading activity of the ADP-ribosyl cyclase, CD38. Results Administering a novel, potent, and orally available CD38 antagonist to MDX mice successfully reverted a majority of the muscle metabolome toward the wildtype state, while supplementing nicotinamide riboside did not significantly affect the molecular phenotype of the muscle. However, neither strategy effectively lessened muscle damage markers or improved hindlimb strength following repeated rounds of eccentric challenge and recovery. Conclusions Intramuscular NAD depletion occurs rapidly after eccentic injury, with broad pleitropic effects on the molecular phenotype of the tissue. Currently available means of protecting or replenishing the muscle NAD pool via orally administered small molecules are insufficient to functionally restore dystrophin-deficient muscle.
doi:10.21203/ fatcat:johhm2tzrvg5da6cnm7amwvqz4