Inhibition of myostatin improves muscle atrophy in oculopharyngeal muscular dystrophy (OPMD)

Background: Oculopharyngeal muscular dystrophy (OPMD) is a late-onset muscle disease affecting 1 per 80,000 of the general population characterised by profound dysphagia and ptosis, and limb weakness at later stages. Affected muscles are characterised by increased fibrosis and atrophy. Myostatin is a negative regulator of muscle mass, and inhibition of myostatin has been demonstrated to ameliorate symptoms in dystrophic muscles. Methods: In this study, we performed a systemic delivery of a monoclonal antibody to immunologically block myostatin in the A17 mouse model of OPMD. The mice were administered a weekly dose of 10mg/kg RK35 intraperitonially for 10 weeks, following which histological analyses were performed on the samples. Results: This treatment significantly (p<0.01) improved body mass (11%) and muscle mass (for the TA and EDL by 19% and 41%) in the A17 mice treated with RK35 when compared to saline controls. Similarly, a significantly (p<0.01) increased muscle strength (18% increase in maximal tetanic force) and myofibre diameter (17% and 44% for the TA and EDL) and reduced expression of markers of muscle fibrosis (40% reduction in area of expression), was also observed. No change in the density of intranuclear inclusions (a hallmark of disease progression of OPMD) was however observed.Conclusions: Our study supports the clinical translation of such antibody-mediated inhibition of myostatin as a treatment of OPMD. This strategy has implications to be used as adjuvant therapies with gene therapy based approaches, or to stabilise the muscle prior to myoblast transplantation.