Work

NAD+ dyshomeostasis in RYR1-related myopathies

Year: 2025

Type: article

Abstract: Background Pathogenic variants in RYR1 cause a spectrum of rare congenital myopathies associated with intracellular calcium dysregulation. Glutathione redox imbalance has been reported in several Ryr1 disease model systems and clinical studies. NAD+ and NADP are essential cofactors in cellular metabolism and redox homeostasis. NAD+ deficiency has been associated with skeletal muscle bioenergetic deficits in mitochondrial myopathy and sarcopenia. Methods Using a new colorimetric assay and large control dataset (n = 299), we assessed redox balance (glutathione, NAD+, and NADP) in whole blood from 28 RYR1-RM affected individuals (NCT02362425). Analyses were expanded to human skeletal muscle (n = 4), primary myotube cultures (n = 5), and whole blood and skeletal muscle specimens from Ryr1 Y524S mice. The in vitro effects of nicotinamide riboside (NR) on cellular NAD+ content and mitochondrial respirometry were also tested. Results At baseline, a majority of affected individuals exhibited systemic NAD+ deficiency (19/28 [68%] < 21 µM) and increased NADPH concentrations (22/26 [85%] > 1.6 µM). When compared to controls, decreased NAD+/NADH and NADP/NADPH ratios were observed in 9/28 and 23/26 individuals, respectively. In patient-derived myotube cultures (n = 5), NR appeared to increase cellular NAD+ concentrations in a dose and time-dependent manner at 72-h only and favorably modified maximal respiration and ATP production. Average whole blood GSH/GSSG ratio was comparable between groups, and redox imbalance was not observed in Ryr1 Y524S specimens. Conclusions NAD+ and NADP dyshomeostasis was identified in a subset of RYR1-RM affected individuals. Further experiments are warranted to confirm if NAD+ repletion could be an attractive therapeutic approach given the favorable outcomes reported in other neuromuscular disorders. Graphical Abstract

Source: Skeletal Muscle

DOI: 10.1186/s13395-025-00390-6