Polyglutamine-Expanded Androgen Receptor Alteration of Skeletal Muscle Homeostasis and Myonuclear Aggregation Are Affected by Sex, Age and Muscle Metabolism
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 an...
Main Authors: | , , , , , , , , , , , , , , , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
MDPI AG
2020-01-01
|
Series: | Cells |
Subjects: | |
Online Access: | https://www.mdpi.com/2073-4409/9/2/325 |
id |
doaj-7511012dd5ea4998bf29bae7fce0d28c |
---|---|
record_format |
Article |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Mathilde Chivet Caterina Marchioretti Marco Pirazzini Diana Piol Chiara Scaramuzzino Maria Josè Polanco Vanina Romanello Emanuela Zuccaro Sara Parodi Maurizio D’Antonio Carlo Rinaldi Fabio Sambataro Elena Pegoraro Gianni Soraru Udai Bhan Pandey Marco Sandri Manuela Basso Maria Pennuto |
spellingShingle |
Mathilde Chivet Caterina Marchioretti Marco Pirazzini Diana Piol Chiara Scaramuzzino Maria Josè Polanco Vanina Romanello Emanuela Zuccaro Sara Parodi Maurizio D’Antonio Carlo Rinaldi Fabio Sambataro Elena Pegoraro Gianni Soraru Udai Bhan Pandey Marco Sandri Manuela Basso Maria Pennuto Polyglutamine-Expanded Androgen Receptor Alteration of Skeletal Muscle Homeostasis and Myonuclear Aggregation Are Affected by Sex, Age and Muscle Metabolism Cells polyglutamine diseases androgen receptor skeletal muscle 2% sds-resistant aggregates inclusion bodies muscle metabolism |
author_facet |
Mathilde Chivet Caterina Marchioretti Marco Pirazzini Diana Piol Chiara Scaramuzzino Maria Josè Polanco Vanina Romanello Emanuela Zuccaro Sara Parodi Maurizio D’Antonio Carlo Rinaldi Fabio Sambataro Elena Pegoraro Gianni Soraru Udai Bhan Pandey Marco Sandri Manuela Basso Maria Pennuto |
author_sort |
Mathilde Chivet |
title |
Polyglutamine-Expanded Androgen Receptor Alteration of Skeletal Muscle Homeostasis and Myonuclear Aggregation Are Affected by Sex, Age and Muscle Metabolism |
title_short |
Polyglutamine-Expanded Androgen Receptor Alteration of Skeletal Muscle Homeostasis and Myonuclear Aggregation Are Affected by Sex, Age and Muscle Metabolism |
title_full |
Polyglutamine-Expanded Androgen Receptor Alteration of Skeletal Muscle Homeostasis and Myonuclear Aggregation Are Affected by Sex, Age and Muscle Metabolism |
title_fullStr |
Polyglutamine-Expanded Androgen Receptor Alteration of Skeletal Muscle Homeostasis and Myonuclear Aggregation Are Affected by Sex, Age and Muscle Metabolism |
title_full_unstemmed |
Polyglutamine-Expanded Androgen Receptor Alteration of Skeletal Muscle Homeostasis and Myonuclear Aggregation Are Affected by Sex, Age and Muscle Metabolism |
title_sort |
polyglutamine-expanded androgen receptor alteration of skeletal muscle homeostasis and myonuclear aggregation are affected by sex, age and muscle metabolism |
publisher |
MDPI AG |
series |
Cells |
issn |
2073-4409 |
publishDate |
2020-01-01 |
description |
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. |
topic |
polyglutamine diseases androgen receptor skeletal muscle 2% sds-resistant aggregates inclusion bodies muscle metabolism |
url |
https://www.mdpi.com/2073-4409/9/2/325 |
work_keys_str_mv |
AT mathildechivet polyglutamineexpandedandrogenreceptoralterationofskeletalmusclehomeostasisandmyonuclearaggregationareaffectedbysexageandmusclemetabolism AT caterinamarchioretti polyglutamineexpandedandrogenreceptoralterationofskeletalmusclehomeostasisandmyonuclearaggregationareaffectedbysexageandmusclemetabolism AT marcopirazzini polyglutamineexpandedandrogenreceptoralterationofskeletalmusclehomeostasisandmyonuclearaggregationareaffectedbysexageandmusclemetabolism AT dianapiol polyglutamineexpandedandrogenreceptoralterationofskeletalmusclehomeostasisandmyonuclearaggregationareaffectedbysexageandmusclemetabolism AT chiarascaramuzzino polyglutamineexpandedandrogenreceptoralterationofskeletalmusclehomeostasisandmyonuclearaggregationareaffectedbysexageandmusclemetabolism AT mariajosepolanco polyglutamineexpandedandrogenreceptoralterationofskeletalmusclehomeostasisandmyonuclearaggregationareaffectedbysexageandmusclemetabolism AT vaninaromanello polyglutamineexpandedandrogenreceptoralterationofskeletalmusclehomeostasisandmyonuclearaggregationareaffectedbysexageandmusclemetabolism AT emanuelazuccaro polyglutamineexpandedandrogenreceptoralterationofskeletalmusclehomeostasisandmyonuclearaggregationareaffectedbysexageandmusclemetabolism AT saraparodi polyglutamineexpandedandrogenreceptoralterationofskeletalmusclehomeostasisandmyonuclearaggregationareaffectedbysexageandmusclemetabolism AT mauriziodantonio polyglutamineexpandedandrogenreceptoralterationofskeletalmusclehomeostasisandmyonuclearaggregationareaffectedbysexageandmusclemetabolism AT carlorinaldi polyglutamineexpandedandrogenreceptoralterationofskeletalmusclehomeostasisandmyonuclearaggregationareaffectedbysexageandmusclemetabolism AT fabiosambataro polyglutamineexpandedandrogenreceptoralterationofskeletalmusclehomeostasisandmyonuclearaggregationareaffectedbysexageandmusclemetabolism AT elenapegoraro polyglutamineexpandedandrogenreceptoralterationofskeletalmusclehomeostasisandmyonuclearaggregationareaffectedbysexageandmusclemetabolism AT giannisoraru polyglutamineexpandedandrogenreceptoralterationofskeletalmusclehomeostasisandmyonuclearaggregationareaffectedbysexageandmusclemetabolism AT udaibhanpandey polyglutamineexpandedandrogenreceptoralterationofskeletalmusclehomeostasisandmyonuclearaggregationareaffectedbysexageandmusclemetabolism AT marcosandri polyglutamineexpandedandrogenreceptoralterationofskeletalmusclehomeostasisandmyonuclearaggregationareaffectedbysexageandmusclemetabolism AT manuelabasso polyglutamineexpandedandrogenreceptoralterationofskeletalmusclehomeostasisandmyonuclearaggregationareaffectedbysexageandmusclemetabolism AT mariapennuto polyglutamineexpandedandrogenreceptoralterationofskeletalmusclehomeostasisandmyonuclearaggregationareaffectedbysexageandmusclemetabolism |
_version_ |
1724948474591444992 |
spelling |
doaj-7511012dd5ea4998bf29bae7fce0d28c2020-11-25T02:03:24ZengMDPI AGCells2073-44092020-01-019232510.3390/cells9020325cells9020325Polyglutamine-Expanded Androgen Receptor Alteration of Skeletal Muscle Homeostasis and Myonuclear Aggregation Are Affected by Sex, Age and Muscle MetabolismMathilde Chivet0Caterina Marchioretti1Marco Pirazzini2Diana Piol3Chiara Scaramuzzino4Maria Josè Polanco5Vanina Romanello6Emanuela Zuccaro7Sara Parodi8Maurizio D’Antonio9Carlo Rinaldi10Fabio Sambataro11Elena Pegoraro12Gianni Soraru13Udai Bhan Pandey14Marco Sandri15Manuela Basso16Maria Pennuto17Dulbecco Telethon Institute, Centre for Integrative Biology (CIBIO), University of Trento, 38123 Trento, ItalyDepartment of Biomedical Sciences (DBS), University of Padova, 35131 Padova, ItalyDepartment of Biomedical Sciences (DBS), University of Padova, 35131 Padova, ItalyDulbecco Telethon Institute, Centre for Integrative Biology (CIBIO), University of Trento, 38123 Trento, ItalyDepartment of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia (IIT), 16163 Genova, ItalyDulbecco Telethon Institute, Centre for Integrative Biology (CIBIO), University of Trento, 38123 Trento, ItalyDepartment of Biomedical Sciences (DBS), University of Padova, 35131 Padova, ItalyDepartment of Biomedical Sciences (DBS), University of Padova, 35131 Padova, ItalyDepartment of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia (IIT), 16163 Genova, ItalyDivision of Genetics and Cell Biology, San Raffaele Scientific Institute, 20132 Milan, ItalyDepartment of Paediatrics, University of Oxford, OX1 3QX Oxford, UKDepartment of Neuroscience (DNS), University of Padova, 35128 Padova, ItalyMyology Center (Cir-Myo), University of Padova, 35129 Padova, ItalyMyology Center (Cir-Myo), University of Padova, 35129 Padova, ItalyDepartment of Human Genetics, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA 15261, USADepartment of Biomedical Sciences (DBS), University of Padova, 35131 Padova, ItalyCentre for Integrative Biology (CIBIO), University of Trento, 38123 Trento, ItalyDulbecco Telethon Institute, Centre for Integrative Biology (CIBIO), University of Trento, 38123 Trento, ItalyPolyglutamine (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.https://www.mdpi.com/2073-4409/9/2/325polyglutamine diseasesandrogen receptorskeletal muscle2% sds-resistant aggregatesinclusion bodiesmuscle metabolism |