Myostatin inhibition prevents skeletal muscle pathophysiology in Huntington\u2019s disease mice

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

doi:10.1038/s41598-017-14290-3

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.

Highlights

Huntington’s disease (HD) is an inherited progressive neurodegenerative disorder for which the age of onset is generally in midlife
The R6/2 mouse is transgenic for a genomic DNA fragment encoding exon 1 of human HTT and is a model of the incomplete splicing event that occurs in all HD knock-in mouse models, YAC128 and BACHD mice[17], and in HD patient tissues[18], resulting in an exon 1 – intron 1 mRNA that in all cases produces the highly pathogenic exon 1 HTT protein
We first set out to determine whether the inhibition of myostatin/activin A signaling might reduce the extent of muscle atrophy that occurs in the R6/2 mouse model of HD

Summary

Introduction

Huntington’s disease (HD) is an inherited progressive neurodegenerative disorder for which the age of onset is generally in midlife. The R6/2 mouse is transgenic for a genomic DNA fragment encoding exon 1 of human HTT and is a model of the incomplete splicing event that occurs in all HD knock-in mouse models, YAC128 and BACHD mice[17], and in HD patient tissues[18], resulting in an exon 1 – intron 1 mRNA that in all cases produces the highly pathogenic exon 1 HTT protein Both the R6/2 and HdhQ150 models develop a progressive failure to gain body weight, followed by weight loss[11] and a highly comparable skeletal muscle atrophy and underlying muscle pathophysiology[19]. Agents that block the myostatin signaling pathway have the potential to treat human disease associated with cachexia e.g. cancer, chronic kidney disease and chronic heart failure, as well as neuromuscular diseases[32]

Methods

Results

Conclusion