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

Overview

Journal JCI Insight

Specialties Biomedical Engineering
General Medicine

Date 2024 Mar 7

PMID 38452174

Authors

Danielle DeBartolo

Frederick J Arnold

Yuhong Liu

Elana Molotsky

Hsin-Yao Tang

Diane E Merry

Affiliations

Soon will be listed here.

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.

Citing Articles

Altered Metabolic Signaling and Potential Therapies in Polyglutamine Diseases.

Vohra A, Keefe P, Puthanveetil P Metabolites. 2024; 14(6).

PMID: 38921455 PMC: 11205831. DOI: 10.3390/metabo14060320.

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