Differentially Disrupted Spinal Cord and Muscle Energy Metabolism in Spinal and Bulbar Muscular Atrophy

Authors

Danielle DeBartolo, Thomas Jefferson UniversityFollow
Frederick Arnold, Thomas Jefferson UniversityFollow
Y Liu, Thomas Jefferson UniversityFollow
Elana Molotsky, Thomas Jefferson UniversityFollow
Hsin-Yao Tang
Diane Merry, Thomas Jefferson UniversityFollow

Document Type

Article

Publication Date

3-5-2024

Comments

This article is the author's final published version in JCI Insight, Volume 9, Issue 7, 2024, Article number e178048.

The published version is available at https://doi.org/10.1172/jci.insight.178048.

Copyright © 2024, DeBartolo et al.

Abstract

Prior studies showed that polyglutamine-expanded androgen receptor (AR) is aberrantly acetylated and that deacetylation of the mutant AR by overexpression of nicotinamide adenine dinucleotide-dependent (NAD+-dependent) sirtuin 1 is protective in cell models of spinal and bulbar muscular atrophy (SBMA). Based on these observations and reduced NAD+ in muscles of SBMA mouse models, we tested the therapeutic potential of NAD+ restoration in vivo by treating postsymptomatic transgenic SBMA mice with the NAD+ precursor nicotinamide riboside (NR). NR supplementation failed to alter disease progression and had no effect on increasing NAD+ or ATP content in muscle, despite producing a modest increase of NAD+ in the spinal cords of SBMA mice. Metabolomic and proteomic profiles of SBMA quadriceps muscles indicated alterations in several important energy-related pathways that use NAD+, in addition to the NAD+ salvage pathway, which is critical for NAD+ regeneration for use in cellular energy production. We also observed decreased mRNA levels of nicotinamide riboside kinase 2 (Nmrk2), which encodes a key kinase responsible for NR phosphorylation, allowing its use by the NAD+ salvage pathway. Together, these data suggest a model in which NAD+ levels are significantly decreased in muscles of an SBMA mouse model and intransigent to NR supplementation because of decreased levels of Nmrk2.

Recommended Citation

DeBartolo, Danielle; Arnold, Frederick; Liu, Y; Molotsky, Elana; Tang, Hsin-Yao; and Merry, Diane, "Differentially Disrupted Spinal Cord and Muscle Energy Metabolism in Spinal and Bulbar Muscular Atrophy" (2024). Department of Biochemistry and Molecular Biology Faculty Papers. Paper 256.
https://jdc.jefferson.edu/bmpfp/256

Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 License.

PubMed ID

38452174

Language

English