Chivet, Mathilde and Marchioretti, Caterina and Pirazzini, Marco and Piol, Diana and Scaramuzzino, Chiara and Polanco, Maria Josè and Romanello, Vanina and Zuccaro, Emanuela and Parodi, Sara and D’Antonio, Maurizio and Rinaldi, Carlo and Sambataro, Fabio and Pegoraro, Elena and Soraru, Gianni and Pandey, Udai Bhan and Sandri, Marco and Basso, Manuela and Pennuto, Maria
(2020)
Polyglutamine-Expanded Androgen Receptor Alteration of Skeletal Muscle Homeostasis and Myonuclear Aggregation Are Affected by Sex, Age and Muscle Metabolism.
Cells, 9 (2).
p. 325.
ISSN 2073-4409
Abstract
Polyglutamine (polyQ) expansions in the androgen receptor (AR) gene cause spinal and bulbar muscular atrophy (SBMA), a neuromuscular disease characterized by lower motor neuron (MN) loss and skeletal muscle atrophy, with an unknown mechanism. We generated new mouse models of SBMA for constitutive and inducible expression of mutant AR and performed biochemical, histological and functional analyses of phenotype. We show that polyQ-expanded AR causes motor dysfunction, premature death, IIb-to-IIa/IIx fiber-type change, glycolytic-to-oxidative fiber-type switching, upregulation of atrogenes and autophagy genes and mitochondrial dysfunction in skeletal muscle, together with signs of muscle denervation at late stage of disease. PolyQ expansions in the AR resulted in nuclear enrichment. Within the nucleus, mutant AR formed 2% sodium dodecyl sulfate (SDS)-resistant aggregates and inclusion bodies in myofibers, but not spinal cord and brainstem, in a process exacerbated by age and sex. Finally, we found that two-week induction of expression of polyQ-expanded AR in adult mice was sufficient to cause premature death, body weight loss and muscle atrophy, but not aggregation, metabolic alterations, motor coordination and fiber-type switch, indicating that expression of the disease protein in the adulthood is sufficient to recapitulate several, but not all SBMA manifestations in mice. These results imply that chronic expression of polyQ-expanded AR, i.e. during development and prepuberty, is key to induce the full SBMA muscle pathology observed in patients. Our data support a model whereby chronic expression of polyQ-expanded AR triggers muscle atrophy through toxic (neomorphic) gain of function mechanisms distinct from normal (hypermorphic) gain of function mechanisms.
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| Item Type: |
Article
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| Status: |
Published |
| Creators/Authors: |
| Creators | Email | Pitt Username | ORCID  |
|---|
| Chivet, Mathilde | | | | | Marchioretti, Caterina | | | | | Pirazzini, Marco | | | | | Piol, Diana | | | | | Scaramuzzino, Chiara | | | | | Polanco, Maria Josè | | | | | Romanello, Vanina | | | | | Zuccaro, Emanuela | | | | | Parodi, Sara | | | | | D’Antonio, Maurizio | | | | | Rinaldi, Carlo | | | | | Sambataro, Fabio | | | | | Pegoraro, Elena | | | | | Soraru, Gianni | | | | | Pandey, Udai Bhan | udai@pitt.edu | udai | | | Sandri, Marco | | | | | Basso, Manuela | | | | | Pennuto, Maria | | | |
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| Date: |
30 January 2020 |
| Date Type: |
Publication |
| Journal or Publication Title: |
Cells |
| Volume: |
9 |
| Number: |
2 |
| Publisher: |
MDPI AG |
| Page Range: |
p. 325 |
| DOI or Unique Handle: |
10.3390/cells9020325 |
| Schools and Programs: |
School of Public Health > Public Health Genetics |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
polyglutamine diseases, androgen receptor, skeletal muscle, 2% sds-resistant aggregates, inclusion bodies, muscle metabolism |
| ISSN: |
2073-4409 |
| Official URL: |
http://dx.doi.org/10.3390/cells9020325 |
| Funders: |
Telethon-Italy and Provincia Autonoma di Trento, Association Française contre les Myopathies, CNCCS Scarl Pomezia, National Institute of Health, Muscular Dystrophy Association, PRIN-MIUR, Fondazione Veronesi, Arimura Foundation, Kennedy’s Disease Association Research Grants, Marie Curie International Outgoing Fellowships |
| Article Type: |
Research Article |
| Date Deposited: |
29 Jun 2021 18:39 |
| Last Modified: |
29 Jun 2021 18:39 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/41308 |
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