Summary by Josine de Winter

Publication

Targeting NAD+-deficiency to improve bioenergetics in RYR1-related myopathies.

Tokunbor A Lawal 1 2 , Willa Riekhof 1 , Linda Groom 3 , Pooja Varma 1 , Irene C Chrismer 1 2 , Angela Kokkinis 4 , Christopher Grunseich 4 , Jessica W Witherspoon 1 , Muslima S Razaqyar 1 , Ninet Sinaii 5 , Katherine G Meilleur 1 , Lichen Xiang 1 , Jana Buzkova 6 , Liliya Euro 6 , Payam Mohassel 7 8 , Robert T Dirksen 3 , Joshua J Todd 9 10

Skeletal Muscle  2025 Aug 22;15(1):22.

doi: 10.1186/s13395-025-00390-6.

https://pubmed.ncbi.nlm.nih.gov/40846977/

• PMID: 40846977
• PMCID: PMC12374369
• DOI: 10.1186/s13395-025-00390-6

Summary

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.

Lawal et al., assessed redox balance (glutathione, NAD+, and NADP) in whole blood from RYR1-RM affected individuals and large control dataset using a new colourimetric assay. Analyses were expanded to human skeletal muscle biopsies and primary myotube cultures. At baseline, the majority of affected individuals exhibited systemic NAD+ deficiency and increased NADPH concentrations. As nicotinamide riboside (NR) is a well-established precursor to improve NAD+ levels in muscle, the in vitro effects of (NR) on cellular NAD+ content and mitochondrial respirometry were in patient-derived myotube cultures: NR appeared to increase cellular NAD+ concentrations in a dose and time-dependent manner and favorably modified maximal respiration and ATP production.

As mentioned above, NR is currently used in multiple pre-clinical and clinical studies and is reported to be well-tollerated and safe. But, despite the promising results of NAD+ precursors in other pre-clinical studies, the clinical efficacy in humans is not well established. However, why the study of Lawal et al drew my attention, is the following: in a recent review by Vinten et al., (Nature Metabolism, 2025 https://pubmed.ncbi.nlm.nih.gov/41083806/) the main message is that lower basal NAD+ levels might be crucial for observing functional effects of NAD+ precursor in humans. This is supported by a previous study in patients with mitochondrial myopathy with lower basal NAD+ levels where 10-months treatment with a NAD+ precursor, improved muscle strength and induced mitochondrial biogenesis. Hence the results of Lawal et al. provide proof-of-concept to repurpose NR for RYR1 myopathy, a very exciting prospect.

I anticipate that this study will be of great interest to the WMS community as the use of NR may also be beneficial for other neuromuscular disorders associated with mitochondrial dysfunction and decreased NAD+ levels.

About the author

Tokunbor Lawal is a Research Scientist at the National Institutes of Health (NIH) Clinical Center (Bethesda, MD). His research aims to functionally characterise genetic variants associated with skeletal muscle excitation-contraction coupling disorders, specifically RYR1-related myopathies, using relevant, reliable, and cost-effective nonclinical models. These nonclinical models allow his lab to screen promising therapeutic compounds and elucidate the patho-mechanisms that can be targeted for therapeutic interventions in clinical trials.