P.80 - Identification of therapies for myofibrillar myopathy

Abstract

Myofibrillar myopathies exhibit progressive muscle weakness and are characterized by structural failure of the muscle at the Z-disk and the formation of cytoplasmic protein aggregates. Mutations in the co-chaperone, and autophagy regulator, BAG3 are known to cause myofibrillar myopathy, with the first identified and most frequent mutation being BAG3P209L. We have previously demonstrated that expression of BAG3P209L is sufficient to cause formation of the characteristic protein aggregates but it is the loss of BAG3 that results in fibre disintegration. To further investigate the biology underlying the disease and investigate potential therapies we have generated zebrafish models of BAG3P209L myofibrillar myopathy, which conditionally express fluorescently tagged, human wildtype BAG3, or BAG3P209L in the muscle and a BAG3 loss of function model through CRISPR/Cas9 genome editing. The transgenic BAG3P209L fish exhibit the protein aggregation and the BAG3-/- fish demonstrate exercise dependent fibre disintegration, reduced swimming activity, and have a significant reduction in autophagic activity. To identify drugs that may be effective in treating BAG3 myofibrillar myopathy we conducted a screen of 76 autophagy promoting compounds using an automated aggregate quantification system to identify compounds that significantly reduce the number of aggregates. We identified nine compounds effective at removing protein aggregates, including two that are currently FDA approved. Further evaluation of these compounds demonstrated that not only are they able to remove the protein aggregates but they are also able to rescue the swimming deficit observed in the BAG3-/- fish. Here we will describe the work examining pathology in the zebrafish disease models and demonstrating the action of the potential therapies for BAG3 myofibrillar myopathy.