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Myostatin inhibition prevents skeletal muscle pathophysiology in Huntington's disease mice

Myostatin inhibition prevents skeletal muscle pathophysiology in Huntington's disease mice
Myostatin inhibition prevents skeletal muscle pathophysiology in Huntington's disease mice
Huntington's disease (HD) is an inherited neurodegenerative disorder of which skeletal muscle atrophy is a common feature, and multiple lines of evidence support a muscle-based pathophysiology in HD mouse models. Inhibition of myostatin signaling increases muscle mass, and therapeutic approaches based on this are in clinical development. We have used a soluble ActRIIB decoy receptor (ACVR2B/Fc) to test the effects of myostatin/activin A inhibition in the R6/2 mouse model of HD. Weekly administration from 5 to 11 weeks of age prevented body weight loss, skeletal muscle atrophy, muscle weakness, contractile abnormalities, the loss of functional motor units in EDL muscles and delayed end-stage disease. Inhibition of myostatin/activin A signaling activated transcriptional profiles to increase muscle mass in wild type and R6/2 mice but did little to modulate the extensive Huntington's disease-associated transcriptional dysregulation, consistent with treatment having little impact on HTT aggregation levels. Modalities that inhibit myostatin signaling are currently in clinical trials for a variety of indications, the outcomes of which will present the opportunity to assess the potential benefits of targeting this pathway in HD patients.
2045-2322
1-14
Bondulich, Marie
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Jolinon, Nelly
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Osborne, Georgina F
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Smith, Edward J
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Rattray, Ivan
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Neueder, Andreas
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Sathasivam, Kirupa
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Ahmed, Mhoriam
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Ali, Nadira
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Benjamin, Agnesska C
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Chang, Xiaoli
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Dick, James R T
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Ellis, Matthew
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Franklin, Sophie A
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Goodwin, Daniel
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Inuabasi, Linda
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Lazell, Hayley
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Lehar, Adam
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Richard-Loendt, Angela
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Rosinski, Jim
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Smith, Donna L
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Wood, Tobias
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Tabrizi, Sarah J
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Brandner, Sebastian
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Greensmith, Linda
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Howland, David
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Munoz-Sanjuan, Ignacio
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Lee, Se-Jin
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Bates, Gillian P
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Bondulich, Marie
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Jolinon, Nelly
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Osborne, Georgina F
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Smith, Edward J
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Rattray, Ivan
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Neueder, Andreas
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Sathasivam, Kirupa
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Ahmed, Mhoriam
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Ali, Nadira
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Benjamin, Agnesska C
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Chang, Xiaoli
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Dick, James R T
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Ellis, Matthew
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Franklin, Sophie A
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Goodwin, Daniel
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Inuabasi, Linda
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Lazell, Hayley
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Lehar, Adam
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Richard-Loendt, Angela
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Rosinski, Jim
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Smith, Donna L
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Wood, Tobias
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Tabrizi, Sarah J
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Brandner, Sebastian
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Greensmith, Linda
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Howland, David
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Munoz-Sanjuan, Ignacio
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Lee, Se-Jin
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Bates, Gillian P
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Bondulich, Marie, Jolinon, Nelly, Osborne, Georgina F, Smith, Edward J, Rattray, Ivan, Neueder, Andreas, Sathasivam, Kirupa, Ahmed, Mhoriam, Ali, Nadira, Benjamin, Agnesska C, Chang, Xiaoli, Dick, James R T, Ellis, Matthew, Franklin, Sophie A, Goodwin, Daniel, Inuabasi, Linda, Lazell, Hayley, Lehar, Adam, Richard-Loendt, Angela, Rosinski, Jim, Smith, Donna L, Wood, Tobias, Tabrizi, Sarah J, Brandner, Sebastian, Greensmith, Linda, Howland, David, Munoz-Sanjuan, Ignacio, Lee, Se-Jin and Bates, Gillian P (2017) Myostatin inhibition prevents skeletal muscle pathophysiology in Huntington's disease mice. Scientific Reports, 7 (1), 1-14. (doi:10.1038/s41598-017-14290-3).

Record type: Article

Abstract

Huntington's disease (HD) is an inherited neurodegenerative disorder of which skeletal muscle atrophy is a common feature, and multiple lines of evidence support a muscle-based pathophysiology in HD mouse models. Inhibition of myostatin signaling increases muscle mass, and therapeutic approaches based on this are in clinical development. We have used a soluble ActRIIB decoy receptor (ACVR2B/Fc) to test the effects of myostatin/activin A inhibition in the R6/2 mouse model of HD. Weekly administration from 5 to 11 weeks of age prevented body weight loss, skeletal muscle atrophy, muscle weakness, contractile abnormalities, the loss of functional motor units in EDL muscles and delayed end-stage disease. Inhibition of myostatin/activin A signaling activated transcriptional profiles to increase muscle mass in wild type and R6/2 mice but did little to modulate the extensive Huntington's disease-associated transcriptional dysregulation, consistent with treatment having little impact on HTT aggregation levels. Modalities that inhibit myostatin signaling are currently in clinical trials for a variety of indications, the outcomes of which will present the opportunity to assess the potential benefits of targeting this pathway in HD patients.

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abc_s41598-017-14290-3 - Version of Record
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Accepted/In Press date: 6 October 2017
Published date: 27 October 2017

Identifiers

Local EPrints ID: 427466
URI: https://eprints.soton.ac.uk/id/eprint/427466
ISSN: 2045-2322
PURE UUID: 804f0ade-f916-4578-bdaa-905b16e9c298

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Date deposited: 17 Jan 2019 17:30
Last modified: 13 Mar 2019 17:39

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Contributors

Author: Marie Bondulich
Author: Nelly Jolinon
Author: Georgina F Osborne
Author: Edward J Smith
Author: Ivan Rattray
Author: Andreas Neueder
Author: Kirupa Sathasivam
Author: Mhoriam Ahmed
Author: Nadira Ali
Author: Agnesska C Benjamin
Author: Xiaoli Chang
Author: James R T Dick
Author: Matthew Ellis
Author: Sophie A Franklin
Author: Daniel Goodwin
Author: Linda Inuabasi
Author: Hayley Lazell
Author: Adam Lehar
Author: Angela Richard-Loendt
Author: Jim Rosinski
Author: Donna L Smith
Author: Tobias Wood
Author: Sarah J Tabrizi
Author: Sebastian Brandner
Author: Linda Greensmith
Author: David Howland
Author: Ignacio Munoz-Sanjuan
Author: Se-Jin Lee
Author: Gillian P Bates

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