BackgroundOculopharyngeal muscular dystrophy (OPMD) is a late‐onset muscle disease affecting one per 80 000 of the general population characterized by profound dysphagia and ptosis, and limb weakness at later stages. Affected muscles are characterized 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.MethodsIn 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 10 mg/kg RK35 intraperitonially for 10 weeks, following which histological analyses were performed on the samples.ResultsThis treatment significantly (P < 0.01) improved body mass (11%) and muscle mass (for the tibialis anterior and extensor digitorum longus 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 tibialis anterior and extensor digitorum longus), 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.ConclusionsOur 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 stabilize the muscle prior to myoblast transplantation.

Aggregation tests were performed on platelet-rich plasma from healthy male volunteers to determine the minimum concentration of adenosine diphosphate (ADP), epinephrine, collagen, or thrombin required to induce secondary aggregation. Platelets were also analyzed for cholesterol and phospholipid, and in some cases their membrane fluidity was determined by fluorescence depolarization of the probe, diphenylhexatriene. Concentrations of the major lipoprotein fractions in the plasma were measured and related to the sensitivity of platelets to the four agonists. Low density lipoprotein (LDL) and total cholesterol concentrations, but not high density lipoproteins (HDL) or very low density lipoproteins (VLDL), were positively correlated with sensitivity to aggregation by epinephrine, but not by other agonists. By arrangement of the lipoprotein concentration into quintiles, the effect of LDL was most striking in the lower two quintiles, where the sensitivity to adrenaline and ADP were much diminished. The middle and upper two quintiles showed a similar sensitivity. Lower platelet cholesterol/phospholipid ratios were also associated with a reduced sensitivity to epinephrine or ADP, but only at the lower end of the range. Membrane microviscosity was correlated negatively with collagen sensitivity and with VLDL cholesterol concentrations, but positively with HDL cholesterol concentrations. Platelet behavior appears, therefore, to be influenced by lipoprotein concentrations within the range found in a healthy population.

Background: Oculopharyngeal muscular dystrophy (OPMD) is a late-onset muscle disease presented by ptosis, dysphagia, and limb weakness. Affected muscles display increased fibrosis and atrophy, with characteristic inclusion bodies in the nucleus. Myostatin is a negative regulator of muscle mass, and inhibition of myostatin has been demonstrated to improve symptoms in models of muscular dystrophy. Methods: We systemically administered a monoclonal antibody to block myostatin in the A17 mouse model of OPMD at 42 weeks of age. The mice were administered a weekly dose of 10 mg/kg RK35 intraperitonially for 10 weeks, following which serum and histological analyses were performed on muscle samples. Results: The administration of the antibody resulted in a significant decrease in serum myostatin and collagen deposition in muscles. However, minimal effects on body mass, muscle mass and myofiber diameter, or the density of intranuclear inclusions (INIs) (a hallmark of disease progression of OPMD) were observed. Conclusion: This study demonstrates that inhibition of myostatin does not revert muscle atrophy in a mouse model with established OPMD disease, but is effective at reducing observed histological markers of fibrosis in the treated muscles.

Aims Glioneuronal tumours (GNTs) are poorly distinguished by their histology and lack robust diagnostic indicators. Previously, we showed that common GNTs comprise two molecularly distinct groups, correlating poorly with histology. To refine diagnosis, we constructed a methylation‐based model for GNT classification, subsequently evaluating standards for molecular stratification by methylation, histology and radiology. Methods We comprehensively analysed methylation, radiology and histology for 83 GNT samples: a training cohort of 49, previously classified into molecularly defined groups by genomic profiles, plus a validation cohort of 34. We identified histological and radiological correlates to molecular classification and constructed a methylation‐based support vector machine (SVM) model for prediction. Subsequently, we contrasted methylation, radiological and histological classifications in validation GNTs. Results By methylation clustering, all training and 23/34 validation GNTs segregated into two groups, the remaining 11 clustering alongside control cortex. Histological review identified prominent astrocytic/oligodendrocyte‐like components, dysplastic neurons and a specific glioneuronal element as discriminators between groups. However, these were present in only a subset of tumours. Radiological review identified location, margin definition, enhancement and T2 FLAIR‐rim sign as discriminators. When validation GNTs were classified by SVM, 22/23 classified correctly, comparing favourably against histology and radiology that resolved 17/22 and 15/21, respectively, where data were available for comparison. Conclusions Diagnostic criteria inadequately reflect glioneuronal tumour biology, leaving a proportion unresolvable. In the largest cohort of molecularly defined glioneuronal tumours, we develop molecular, histological and radiological approaches for biologically meaningful classification and demonstrate almost all cases are resolvable, emphasising the importance of an integrated diagnostic approach.