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

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.

• Authors: 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 Rosinski, Donna L Smith, Tobias Wood, Sarah J Tabrizi, Sebastian Brandner, Linda Greensmith, David Howland, Ignacio Munoz-Sanjuan, Se-Jin Lee, Gillian P Bates
• Journal: Scientific reports (Sci Rep) Vol. 7 Issue 1 Pg. 14275 (10 27 2017) ISSN: 2045-2322 [Electronic] England
• PMID: 29079832 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Huntingtin Protein
• Myostatin
• Protein Aggregates
• Activin Receptors, Type II

Topics

• Activin Receptors, Type II (pharmacology)
• Animals
• Body Weight (drug effects)
• Hand Strength (physiology)
• Huntingtin Protein (chemistry)
• Huntington Disease (complications, pathology, physiopathology)
• Male
• Mice
• Muscle, Skeletal (drug effects, pathology, physiopathology)
• Muscular Atrophy (complications, prevention & control)
• Myostatin (antagonists & inhibitors)
• Protein Aggregates (drug effects)