Differentially disrupted spinal cord and muscle energy metabolism in spinal and bulbar muscular atrophy
Danielle DeBartolo, Frederick J. Arnold, Yuhong Liu, Elana Molotsky, Hsin-Yao Tang, Diane E. Merry
Danielle DeBartolo, Frederick J. Arnold, Yuhong Liu, Elana Molotsky, Hsin-Yao Tang, Diane E. Merry
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Research Article Genetics Neuroscience

Differentially disrupted spinal cord and muscle energy metabolism in spinal and bulbar muscular atrophy

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.

Authors

Danielle DeBartolo, Frederick J. Arnold, Yuhong Liu, Elana Molotsky, Hsin-Yao Tang, Diane E. Merry

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Figure 7

The NAD+ salvage pathway is altered in AR112Q quadriceps muscle.

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The NAD+ salvage pathway is altered in AR112Q quadriceps muscle. (A) Joi...
(A) Joint pathway analysis determined from combined metabolomic and proteomic alterations identifies significantly altered metabolic pathways that include nicotinamide metabolism and several other pathways that rely on nicotinamide metabolism, including pentose phosphate pathway, glutathione metabolism, and amino acid metabolism. Dot sizes increase with the increasing pathway impact; color intensifies according to the y axis. (B) Pathway diagram of NAD+ salvage pathway. Metabolic intermediates and proteins depicted in red were found to be increased and blue were found to be decreased in our metabolomics and proteomic analysis of quadriceps muscles from AR112Q versus nontransgenic mice at 36 weeks of age. Black, proteins and metabolites undetected in quadriceps muscle. Gray, unchanged. NR, nicotinamide riboside; NMN, nicotinamide mononucleotide; NAM, nicotinamide; NRK2, nicotinamide riboside kinase 2; NAMPT, nicotinamide phosphoribosyl transferase; NMNAT1-3, nicotinamide nucleotide adenylyltransferases; PRPP, phosphoribosyl pyrophosphate; SIRT, sirtuins; PARPs, poly (ADP-ribose) polymerases; SARM1, sterile alpha and TIR motif containing 1. (C) Real-time qPCR analysis of quadriceps muscle for Nmrk2, the enzyme responsible for conversion of NR to NMN, with transcript levels normalized to Cpsf2. Statistical significance was determined by Student’s t test. Data represent mean ± SEM. *P ≤ 0.05, n = 3 per group.