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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 bas...

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Autores principales: Bondulich, Marie K., 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-Londt, Angela, Rosinski, Jim, Smith, Donna L., Wood, Tobias, Tabrizi, Sarah J., Brandner, Sebastian, Greensmith, Linda, Howland, David, Munoz-Sanjuan, Ignacio, Lee, Se-Jin, Bates, Gillian P.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5660167/
https://www.ncbi.nlm.nih.gov/pubmed/29079832
http://dx.doi.org/10.1038/s41598-017-14290-3
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author Bondulich, Marie K.
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-Londt, Angela
Rosinski, Jim
Smith, Donna L.
Wood, Tobias
Tabrizi, Sarah J.
Brandner, Sebastian
Greensmith, Linda
Howland, David
Munoz-Sanjuan, Ignacio
Lee, Se-Jin
Bates, Gillian P.
author_facet Bondulich, Marie K.
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-Londt, Angela
Rosinski, Jim
Smith, Donna L.
Wood, Tobias
Tabrizi, Sarah J.
Brandner, Sebastian
Greensmith, Linda
Howland, David
Munoz-Sanjuan, Ignacio
Lee, Se-Jin
Bates, Gillian P.
author_sort Bondulich, Marie K.
collection PubMed
description 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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spelling pubmed-56601672017-11-01 Myostatin inhibition prevents skeletal muscle pathophysiology in Huntington’s disease mice Bondulich, Marie K. 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-Londt, Angela Rosinski, Jim Smith, Donna L. Wood, Tobias Tabrizi, Sarah J. Brandner, Sebastian Greensmith, Linda Howland, David Munoz-Sanjuan, Ignacio Lee, Se-Jin Bates, Gillian P. Sci Rep Article 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. Nature Publishing Group UK 2017-10-27 /pmc/articles/PMC5660167/ /pubmed/29079832 http://dx.doi.org/10.1038/s41598-017-14290-3 Text en © The Author(s) 2017 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Bondulich, Marie K.
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-Londt, Angela
Rosinski, Jim
Smith, Donna L.
Wood, Tobias
Tabrizi, Sarah J.
Brandner, Sebastian
Greensmith, Linda
Howland, David
Munoz-Sanjuan, Ignacio
Lee, Se-Jin
Bates, Gillian P.
Myostatin inhibition prevents skeletal muscle pathophysiology in Huntington’s disease mice
title Myostatin inhibition prevents skeletal muscle pathophysiology in Huntington’s disease mice
title_full Myostatin inhibition prevents skeletal muscle pathophysiology in Huntington’s disease mice
title_fullStr Myostatin inhibition prevents skeletal muscle pathophysiology in Huntington’s disease mice
title_full_unstemmed Myostatin inhibition prevents skeletal muscle pathophysiology in Huntington’s disease mice
title_short Myostatin inhibition prevents skeletal muscle pathophysiology in Huntington’s disease mice
title_sort myostatin inhibition prevents skeletal muscle pathophysiology in huntington’s disease mice
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5660167/
https://www.ncbi.nlm.nih.gov/pubmed/29079832
http://dx.doi.org/10.1038/s41598-017-14290-3
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