Increased SIRT3 Combined With Parp Inhibition Rescues Motor Function of Sbma Mice

Authors

David R Garcia Castro
Joseph R Mazuk
Erin M Heine
Daniel Simpson
R Seth Pinches
Caroline Lozzi
Kathryn Hoffman
Phillip Morrin
Dylan Mathis
Maria V Lebedev
Elyse Nissley
Kang Hoo Han
Tyler Farmer
Diane E Merry
Qiang Tong
Maria Pennuto
Heather L Montie

Publication Date

8-18-2023

Journal

iScience

DOI

10.1016/j.isci.2023.107375

PMID

37599829

PMCID

PMC10433013

PubMedCentral® Posted Date

7-22-2023

PubMedCentral® Full Text Version

Post-Print

Published Open-Access

yes

Keywords

Biological sciences, Biochemistry, Molecular biology, Cell biology

Abstract

Spinal and bulbar muscular atrophy (SBMA) is a neuromuscular disease with substantial mitochondrial and metabolic dysfunctions. SBMA is caused by polyglutamine (polyQ) expansion in the androgen receptor (AR). Activating or increasing the NAD+-dependent deacetylase, SIRT3, reduced oxidative stress and death of cells modeling SBMA. However, increasing diminished SIRT3 in AR100Q mice failed to reduce acetylation of the SIRT3 target/antioxidant, SOD2, and had no effect on increased total acetylated peptides in quadriceps. Yet, overexpressing SIRT3 resulted in a trend of motor recovery, and corrected TCA cycle activity by decreasing acetylation of SIRT3 target proteins. We sought to boost blunted SIRT3 activity by replenishing diminished NAD+ with PARP inhibition. Although NAD+ was not affected, overexpressing SIRT3 with PARP inhibition fully restored hexokinase activity, correcting the glycolytic pathway in AR100Q quadriceps, and rescued motor endurance of SBMA mice. These data demonstrate that targeting metabolic anomalies can restore motor function downstream of polyQ-expanded AR.

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