P.15.2 Elucidating the mechanism of disease in BAG3 related myofibrillar myopathy

Abstract

Myofibrillar myopathies are a group of chronic muscle diseases characterised at the cellular level by failure of the muscle fibre at the Z-disk and accumulation of protein aggregates. The vast majority of these diseases are late onset dominant disorders with symptoms typically evident between 35 and 50 years of age. Patients suffer progressive muscle weakness over many years and have reduced life expectancy due to respiratory muscle failure and cardiac complications. Whilst structural failure of the muscle fibre is a feature of myofibrillar myopathies not all of the proteins associated with myofibrillar myopathy have a structural role. Recently mutations in BAG3, a co-chaperone with no direct role in muscle function, were identified as a cause of this disorder. This discovery opened a new area of investigation into the role of chaperones in myopathies and the mechanism of disease in myofibrillar myopathy. In order to investigate the role of BAG3 in muscle development and disease we examined zebrafish lacking BAG3 and those with ectopic expression of GFP-tagged forms of either wildtype BAG3 or the dominant myofibrillar myopathy mutant form Bag3P209L. Examination of these fish identified both the fibre failure and the formation of protein aggregates characteristic of myofibrillar myopathy. Utilising the advantage of the zebrafish model system to examine the onset and progression of the phenotype in vivo, combined with detailed characterisation by immunolabelling and confocal microscopy, we were able to develop a novel model that explains the mechanism of disease in BAG3 related myofibrillar myopathy. We will present this model and discuss its implications for other forms of myofibrillar myopathy.