Increased SIRT3 combined with PARP inhibition rescues motor function of SBMA mice

Authors: GARCIA CASTRO, DAVID - Philadelphia College Of Osteopathic Medicine; MAZUK, JOSEPH - Philadelphia College Of Osteopathic Medicine; HEINE, ERIN - Philadelphia College Of Osteopathic Medicine; SIMPSON, DANIEL - Philadelphia College Of Osteopathic Medicine; PINCHES, R. SETH - Philadelphia College Of Osteopathic Medicine; LOZZI, CAROLINE - Philadelphia College Of Osteopathic Medicine; HOFFMAN, KATHRYN - Philadelphia College Of Osteopathic Medicine; MORRIN, PHILLIP - Philadelphia College Of Osteopathic Medicine; MATHIS, DYLAN - Philadelphia College Of Osteopathic Medicine; LEBEDEV, MARIA - Philadelphia College Of Osteopathic Medicine; NISSLEY, ELYSE - Philadelphia College Of Osteopathic Medicine; HOO HAN, KAN - Philadelphia College Of Osteopathic Medicine; FARMER, TYLER - Philadelphia College Of Osteopathic Medicine; MERRY, DIANE - Children'S Nutrition Research Center (CNRC); TONG, QIANG - Children'S Nutrition Research Center (CNRC); PENNUTO, MARIA - University Of Padua; MONTIE, HEATHER - Philadelphia College Of Osteopathic Medicine

Submitted to: iScience
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 7/8/2023
Publication Date: 7/22/2023
Citation: Garcia Castro, D.R., Mazuk, J.R., Heine, E.M., Simpson, D., Pinches, R., Lozzi, C., Hoffman, K., Morrin, P., Mathis, D., Lebedev, M.V., Nissley, E., Hoo Han, K., Farmer, T., Merry, D.E., Tong, Q., Pennuto, M., Montie, H.L. 2023. Increased SIRT3 combined with PARP inhibition rescues motor function of SBMA mice. iScience. 26(3):Article 107375. https://doi.org/10.1016/j.isci.2023.107375.
DOI: https://doi.org/10.1016/j.isci.2023.107375

Interpretive Summary: Spinal and bulbar muscular atrophy (SBMA) is a neuromuscular disease with substantial metabolic dysfunctions. SBMA is caused by genetic mutations in the androgen receptor (AR) gene. Activating or increasing the amount of the SIRT3 gene reduced free radical damage and cell death of SBMA cells. However, increasing SIRT3 expression in a mouse model of SBMA failed to activate the antioxidant enzyme SOD2. Yet, overexpressing SIRT3 resulted in a trend of motor recovery, and corrected metabolic activity by improving the modification of SIRT3 target proteins. We sought to boost SIRT3 activity by replenishing diminished vitamin NAD using a PARP inhibitor, as SIRT3 is a NAD-dependent protein modification enzyme. Although the NAD level was not changed, overexpressing SIRT3 with PARP inhibition fully restored the activity of the metabolic enzyme hexokinase, correcting the carbohydrate metabolic pathway in SBMA mice muscles, and rescuing the motor endurance of SBMA mice. These data demonstrate that targeting metabolic defects by activating SIRT3 can restore motor function and offer a novel therapeutic approach to treat SBMA.

Technical 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.