Myostatin inhibition prevents skeletal muscle pathophysiology in Huntington's disease mice. Issue 1 (December 2017)

• Record Type: Journal Article
• Authors: Bondulich, Marie; Jolinon, Nelly; Osborne, Georgina; Smith, Edward; Rattray, Ivan; Neueder, Andreas; Sathasivam, Kirupa; Ahmed, Mhoriam; Ali, Nadira; Benjamin, Agnesska; Chang, Xiaoli; Dick, James; Ellis, Matthew; Franklin, Sophie; Goodwin, Daniel; Inuabasi, Linda; Lazell, Hayley; Lehar, Adam; Richard-Londt, Angela; Rosinski, Jim; Smith, Donna; Wood, Tobias; Tabrizi, Sarah; Brandner, Sebastian; Greensmith, Linda; Howland, David; Munoz-Sanjuan, Ignacio; Lee, Se-Jin; Bates, Gillian
• Is Part Of: Scientific reports. Volume 7:Issue 1(2017)
• Page Start: 1
• Page End: 14
• Publication Date: 2017-12
• Subjects: Natural history -- Research -- Periodicals; Biology -- Research -- Periodicals; Physical sciences -- Research -- Periodicals; Earth sciences -- Research -- Periodicals; Environmental sciences -- Research -- Periodicals; 502.85
• DOI: 10.1038/s41598-017-14290-3
• Languages: English
• ISSNs: 2045-2322

Abstract

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.