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Sci Rep. 2017 Oct 27;7(1):14275. doi: 10.1038/s41598-017-14290-3.

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

Author information

1
Sobell Department of Motor Neuroscience and Movement Disorders, University College London Institute of Neurology, London, WC1N 3BG, UK.
2
Department Medical and Molecular Genetics, King's College London, London, SE1 9RT, UK.
3
Huntington's Disease Centre, UCL Institute of Neurology, London, WC1N 3BG, UK.
4
MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology, London, WC1N 3BG, UK.
5
Department Molecular Biology and Genetics, The Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
6
Division of Neuropathology, UCL Institute of Neurology, London, WC1N 3BG, UK.
7
Department of Neurodegenerative disease, UCL Institute of Neurology, London, WC1N 3BG, UK.
8
CHDI Management/CHDI Foundation Inc, New York, NY, 10001, USA.
9
Department of Neuroimaging, King's College London, Institute of Psychiatry, London, SE5 8AF, UK.
10
Sobell Department of Motor Neuroscience and Movement Disorders, University College London Institute of Neurology, London, WC1N 3BG, UK. gillian.bates@ucl.ac.uk.
11
Department Medical and Molecular Genetics, King's College London, London, SE1 9RT, UK. gillian.bates@ucl.ac.uk.
12
Huntington's Disease Centre, UCL Institute of Neurology, London, WC1N 3BG, UK. gillian.bates@ucl.ac.uk.

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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