Dominant de novo mutations in the co-chaperone BAG3 cause a severe form of myofibrillar myopathy, exhibiting progressive muscle weakness, muscle structural failure, and protein aggregation. To identify therapies we generated two zebrafish models, one conditionally expressing BAG3P209L and one with a nonsense mutation in bag3. Whilst transgenic BAG3P209L expressing fish display protein aggregation, modelling the early phase of the disease, bag3-/- fish demonstrate impaired autophagic activity, exercise dependent fibre disintegration, and reduced swimming activity, consistent with later stages. We confirmed the presence of impaired autophagy in patient samples and screened autophagy promoting compounds for their effectiveness at removing protein aggregates, identifying nine including Metformin. Further evaluation demonstrated Metformin is not only able to remove the protein aggregates in zebrafish and human myoblasts but is also able to rescue the fibre disintegration and swimming deficit observed in the bag3-/- fish. Therefore, repurposing Metformin provides a promising therapy for BAG3 myopathy.

Metformin rescues muscle function in BAG3 myofibrillar myopathy models