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Open AccessArticle

Polyglutamine-Expanded Androgen Receptor Alteration of Skeletal Muscle Homeostasis and Myonuclear Aggregation Are Affected by Sex, Age and Muscle Metabolism

1
Dulbecco Telethon Institute, Centre for Integrative Biology (CIBIO), University of Trento, 38123 Trento, Italy
2
Department of Biomedical Sciences (DBS), University of Padova, 35131 Padova, Italy
3
Veneto Institute of Molecular Medicine (VIMM), 35129 Padova, Italy
4
Myology Center (Cir-Myo), University of Padova, 35129 Padova, Italy
5
Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia (IIT), 16163 Genova, Italy
6
Division of Genetics and Cell Biology, San Raffaele Scientific Institute, 20132 Milan, Italy
7
Department of Paediatrics, University of Oxford, OX1 3QX Oxford, UK
8
Department of Neuroscience (DNS), University of Padova, 35128 Padova, Italy
9
Padova Neuroscience Center (PNC), 35100 Padova, Italy
10
Department of Human Genetics, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA 15261, USA
11
Division of Child Neurology, Department of Pediatrics, Children’s Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, PA 15224, USA
12
Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
13
Centre for Integrative Biology (CIBIO), University of Trento, 38123 Trento, Italy
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Cells 2020, 9(2), 325; https://doi.org/10.3390/cells9020325
Received: 12 December 2019 / Revised: 23 January 2020 / Accepted: 24 January 2020 / Published: 30 January 2020
(This article belongs to the Special Issue Key Signalling Molecules in Aging and Neurodegeneration)
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. View Full-Text
Keywords: polyglutamine diseases; androgen receptor; skeletal muscle; 2% SDS-resistant aggregates; inclusion bodies; muscle metabolism polyglutamine diseases; androgen receptor; skeletal muscle; 2% SDS-resistant aggregates; inclusion bodies; muscle metabolism
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MDPI and ACS Style

Chivet, M.; Marchioretti, C.; Pirazzini, M.; Piol, D.; Scaramuzzino, C.; Polanco, M.J.; Romanello, V.; Zuccaro, E.; Parodi, S.; D’Antonio, M.; Rinaldi, C.; Sambataro, F.; Pegoraro, E.; Soraru, G.; Pandey, U.B.; Sandri, M.; Basso, M.; Pennuto, M. Polyglutamine-Expanded Androgen Receptor Alteration of Skeletal Muscle Homeostasis and Myonuclear Aggregation Are Affected by Sex, Age and Muscle Metabolism. Cells 2020, 9, 325. https://doi.org/10.3390/cells9020325

AMA Style

Chivet M, Marchioretti C, Pirazzini M, Piol D, Scaramuzzino C, Polanco MJ, Romanello V, Zuccaro E, Parodi S, D’Antonio M, Rinaldi C, Sambataro F, Pegoraro E, Soraru G, Pandey UB, Sandri M, Basso M, Pennuto M. Polyglutamine-Expanded Androgen Receptor Alteration of Skeletal Muscle Homeostasis and Myonuclear Aggregation Are Affected by Sex, Age and Muscle Metabolism. Cells. 2020; 9(2):325. https://doi.org/10.3390/cells9020325

Chicago/Turabian Style

Chivet, Mathilde; Marchioretti, Caterina; Pirazzini, Marco; Piol, Diana; Scaramuzzino, Chiara; Polanco, Maria J.; Romanello, Vanina; Zuccaro, Emanuela; Parodi, Sara; D’Antonio, Maurizio; Rinaldi, Carlo; Sambataro, Fabio; Pegoraro, Elena; Soraru, Gianni; Pandey, Udai B.; Sandri, Marco; Basso, Manuela; 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, no. 2: 325. https://doi.org/10.3390/cells9020325

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