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A19 Peripheral Pathologies in Mouse Models of HD and the Inhibtion of Myostatin Signalling as a Possible Therapeutic Target
  1. GP Bates
  1. King’s College London, Guy’s Hospital, Great Maze Pond, London SE1 9RT, UK


Progressive pathophysiological changes have been identified in multiple peripheral tissue and organs in a wide range of mouse models of Huntington’s disease (HD). Well studied examples include skeletal muscle, the pancreas, the heart, the hypothalamic-pituitary-adrenal (HPA) axis, the innate immune system and the GI tract. The evidence to indicate that these changes also occur in the peripheral organs of adult onset HD patients are often confined to studies involving small numbers of patients and in many cases, definitive studies remain to be performed.

Multiple epidemiological studies have shown that HD patients exhibit a high incidence of cardiovascular events leading to heart failure, and that this is the second highest cause of death. We have recently investigated cardiac dysfunction at a mechanistic level using the R6/2 and HdhQ150 knock-in mouse models of HD. Pre-symptomatic animals developed connexin-43 relocation and a significant deregulation of hypertrophic markers and Bdnf transcripts. In the symptomatic animals, pronounced functional changes were visualised by cardiac MRI revealing a contractile dysfunction, accompanied by the re-expression of foetal genes, apoptotic cardiomyocyte loss and a moderate degree of interstitial fibrosis. We were unable to identify mutant HTT aggregates in cardiac tissue and our data suggest that the cardiac dysfunction may be caused by altered central autonomic pathways.

R6/2 mice develop muscle atrophy which follows the appearance of huntingtin (HTT) aggregates in the nuclei of skeletal muscle fibres. Inhibition of the myostatin signalling pathway has been shown to increase muscle mass and therapeutic approaches are in clinical development for a number of indications. We have used an ActRIIB receptor decoy to test the effects of myostatin inhibition in R6/2 mice. We found that weekly administration from five weeks of age completely rescued the body weight loss, reduction in muscle mass, grip strength impairment and delayed end-stage disease by approximately 2 weeks. The treatment resulted in the considerable restoration of a range of neuromuscular functions. At the molecular level, the HTT aggregate load was decreased and the level of transcriptional dysregulation was less pronounced for a range of genes. Knowledge of the safety and tolerability of the various myostatin inhibition modalities that are in clinical trials will drive future preclinical work to evaluate this as a potential therapeutic target for HD.

This work was funded by the CHDI Foundation, Medical Research Council and Hereditary Disease Foundation.

  • peripheral pathology
  • HD mouse models
  • cardiac dysfunction
  • skeletal muscle pathology
  • myostatin inhibition

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