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.
N1 - Funding Information:
We wish to thank Rainer Kuhn, Andreas Weiss and Michal Mielcarek for helpful discussions and Michal Mielcarek for experimental work. This work was supported by the CHDI Foundation, the Medical Research Council (MR/L003627/1) to GPB and NIH to S.J.-L. (R01AR060636). LG is the Graham Watts Senior Research Fellow and LG and JRT Dick are supported by the Brain Research Trust. SB was supported by the Department of Health’s NIHR Biomedical Research Centre’s funding scheme.
Publisher Copyright:
© 2017 The Author(s).
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
C2 - 29079832
AN - SCOPUS:85032467505
SN - 2045-2322
VL - 7
JO - Scientific reports
JF - Scientific reports
IS - 1
M1 - 14275
ER -