Increased SIRT3 combined with PARP inhibition rescues motor function of SBMA mice
Summary: 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...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2023-08-01
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| Series: | iScience |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2589004223014529 |
| _version_ | 1797749080648056832 |
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| author | 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 |
| author_facet | 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 |
| author_sort | David R. Garcia Castro |
| collection | DOAJ |
| description | Summary: 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. |
| first_indexed | 2024-03-12T16:15:06Z |
| format | Article |
| id | doaj.art-0ad1fa7b373a453e989aeb3538dcebdf |
| institution | Directory Open Access Journal |
| issn | 2589-0042 |
| language | English |
| last_indexed | 2024-03-12T16:15:06Z |
| publishDate | 2023-08-01 |
| publisher | Elsevier |
| record_format | Article |
| series | iScience |
| spelling | doaj.art-0ad1fa7b373a453e989aeb3538dcebdf2023-08-09T04:33:31ZengElsevieriScience2589-00422023-08-01268107375Increased SIRT3 combined with PARP inhibition rescues motor function of SBMA miceDavid R. Garcia Castro0Joseph R. Mazuk1Erin M. Heine2Daniel Simpson3R. Seth Pinches4Caroline Lozzi5Kathryn Hoffman6Phillip Morrin7Dylan Mathis8Maria V. Lebedev9Elyse Nissley10Kang Hoo Han11Tyler Farmer12Diane E. Merry13Qiang Tong14Maria Pennuto15Heather L. Montie16Department of Bio-Medical Sciences, Philadelphia College of Osteopathic Medicine, Philadelphia, PA 19131, USADepartment of Bio-Medical Sciences, Philadelphia College of Osteopathic Medicine, Philadelphia, PA 19131, USADepartment of Bio-Medical Sciences, Philadelphia College of Osteopathic Medicine, Philadelphia, PA 19131, USADepartment of Bio-Medical Sciences, Philadelphia College of Osteopathic Medicine, Philadelphia, PA 19131, USADepartment of Bio-Medical Sciences, Philadelphia College of Osteopathic Medicine, Philadelphia, PA 19131, USADepartment of Bio-Medical Sciences, Philadelphia College of Osteopathic Medicine, Philadelphia, PA 19131, USADepartment of Bio-Medical Sciences, Philadelphia College of Osteopathic Medicine, Philadelphia, PA 19131, USADepartment of Bio-Medical Sciences, Philadelphia College of Osteopathic Medicine, Philadelphia, PA 19131, USADepartment of Bio-Medical Sciences, Philadelphia College of Osteopathic Medicine, Philadelphia, PA 19131, USADepartment of Bio-Medical Sciences, Philadelphia College of Osteopathic Medicine, Philadelphia, PA 19131, USADepartment of Bio-Medical Sciences, Philadelphia College of Osteopathic Medicine, Philadelphia, PA 19131, USADepartment of Bio-Medical Sciences, Philadelphia College of Osteopathic Medicine, Philadelphia, PA 19131, USADepartment of Bio-Medical Sciences, Philadelphia College of Osteopathic Medicine, Philadelphia, PA 19131, USADepartment of Biochemistry and Molecular Biology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA 19107, USAUSDA/ARS Children’s Nutrition Research Center, Departments of Pediatrics, Medicine, Molecular Physiology & Biophysics, Baylor College of Medicine, Houston, TX 77030, USADepartment of Biomedical Sciences, University of Padova, 35131 Padova, Italy; Veneto Institute of Molecular Medicine (VIMM), 35131 Padova, ItalyDepartment of Bio-Medical Sciences, Philadelphia College of Osteopathic Medicine, Philadelphia, PA 19131, USA; Corresponding authorSummary: 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.http://www.sciencedirect.com/science/article/pii/S2589004223014529Biological sciencesBiochemistryMolecular biologyCell biology |
| spellingShingle | 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 Increased SIRT3 combined with PARP inhibition rescues motor function of SBMA mice iScience Biological sciences Biochemistry Molecular biology Cell biology |
| title | Increased SIRT3 combined with PARP inhibition rescues motor function of SBMA mice |
| title_full | Increased SIRT3 combined with PARP inhibition rescues motor function of SBMA mice |
| title_fullStr | Increased SIRT3 combined with PARP inhibition rescues motor function of SBMA mice |
| title_full_unstemmed | Increased SIRT3 combined with PARP inhibition rescues motor function of SBMA mice |
| title_short | Increased SIRT3 combined with PARP inhibition rescues motor function of SBMA mice |
| title_sort | increased sirt3 combined with parp inhibition rescues motor function of sbma mice |
| topic | Biological sciences Biochemistry Molecular biology Cell biology |
| url | http://www.sciencedirect.com/science/article/pii/S2589004223014529 |
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