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

Research output: Contribution to journalArticle

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 languageEnglish (US)
Article number14275
JournalScientific reports
Volume7
Issue number1
DOIs
StatePublished - Dec 1 2017

ASJC Scopus subject areas

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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), [14275]. https://doi.org/10.1038/s41598-017-14290-3