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

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

doi:10.1038/s41598-017-14290-3

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

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

^*Corresponding author for this work

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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.

Original language	English
Article number	14275
Journal	Scientific Reports
Volume	7
Issue number	1
Early online date	27 Oct 2017
DOIs	https://doi.org/10.1038/s41598-017-14290-3
Publication status	Published - 1 Dec 2017

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Myostatin inhibition BONDULICH Accepted 6Oct2017 Epub 27Oct2017 GOLD VoR CCBYFinal published version, 4.29 MBLicence: CC BY

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Bondulich, M. K., Jolinon, N., Osborne, G. F., Smith, E. J., Rattray, I., Neueder, A., Sathasivam, K., Ahmed, M., Ali, N., Benjamin, A. C., Chang, X., DIck, J. R. T., Ellis, M., Franklin, S. A., Goodwin, D., Inuabasi, L., Lazell, H., Lehar, A., Richard-Londt, A., ... Bates, G. P. (2017). Myostatin inhibition prevents skeletal muscle pathophysiology in Huntington's disease mice. Scientific Reports, 7(1), Article 14275. https://doi.org/10.1038/s41598-017-14290-3

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title = "Myostatin inhibition prevents skeletal muscle pathophysiology in Huntington's disease mice",

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.",

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

year = "2017",

month = dec,

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doi = "10.1038/s41598-017-14290-3",

language = "English",

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Bondulich, MK , Jolinon, N , Osborne, GF , Smith, EJ , Rattray, I , Neueder, A , Sathasivam, K, Ahmed, M, Ali, N , Benjamin, AC, Chang, X, DIck, JRT, Ellis, M, Franklin, SA , Goodwin, D , Inuabasi, L , Lazell, H, Lehar, A, Richard-Londt, A, Rosinski, J, Smith, DL, Wood, T, Tabrizi, SJ, Brandner, S, Greensmith, L, Howland, D, Munoz-Sanjuan, I, Lee, SJ & Bates, GP 2017, 'Myostatin inhibition prevents skeletal muscle pathophysiology in Huntington's disease mice', Scientific Reports, vol. 7, no. 1, 14275. https://doi.org/10.1038/s41598-017-14290-3

TY - JOUR

T1 - Myostatin inhibition prevents skeletal muscle pathophysiology in Huntington's disease mice

AU - Bondulich, Marie K.

AU - Jolinon, Nelly

AU - Osborne, Georgina F.

AU - Smith, Edward J.

AU - Rattray, Ivan

AU - Neueder, Andreas

AU - Sathasivam, Kirupa

AU - Ahmed, Mhoriam

AU - Ali, Nadira

AU - Benjamin, Agnesska C.

AU - Chang, Xiaoli

AU - DIck, James R.T.

AU - Ellis, Matthew

AU - Franklin, Sophie A.

AU - Goodwin, Daniel

AU - Inuabasi, Linda

AU - Lazell, Hayley

AU - Lehar, Adam

AU - Richard-Londt, Angela

AU - Rosinski, Jim

AU - Smith, Donna L.

AU - Wood, Tobias

AU - Tabrizi, Sarah J.

AU - Brandner, Sebastian

AU - Greensmith, Linda

AU - Howland, David

AU - Munoz-Sanjuan, Ignacio

AU - Lee, Se Jin

AU - Bates, Gillian P.

PY - 2017/12/1

Y1 - 2017/12/1

N2 - 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.

AB - 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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U2 - 10.1038/s41598-017-14290-3

DO - 10.1038/s41598-017-14290-3

M3 - Article

AN - SCOPUS:85032467505

SN - 2045-2322

VL - 7

JO - Scientific Reports

JF - Scientific Reports

IS - 1

M1 - 14275

ER -

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

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