Metformin rescues muscle function in {BAG}3 myofibrillar myopathy models

Dominantde novomutations in the co-chaperone BAG3 cause a severe form of myofibrillar myopathy, exhibiting progressive muscle weakness, muscle structural failure, and protein aggregation. To elucidate the mechanism of disease in, and identify therapies for, BAG3 myofibrillar myopathy, we generated two zebrafish models, one conditionally expressing BAG3(P209L)and one with a nonsense mutation inbag3. While transgenic BAG3(P209L)-expressing fish display protein aggregation, modeling the early phase of the disease,bag3(-/-)fish exhibit exercise dependent fiber disintegration, and reduced swimming activity, consistent with later stages of the disease. Detailed characterization of thebag3(-/-)fish, revealed an impairment in macroautophagic/autophagic activity, a defect we confirmed inBAG3patient samples. Taken together, our data highlights that while BAG3(P209L)expression is sufficient to promote protein aggregation, it is the loss of BAG3 due to its sequestration within aggregates, which results in impaired autophagic activity, and subsequent muscle weakness. We therefore screened autophagy-promoting compounds for their effectiveness at removing protein aggregates, identifying nine including metformin. Further evaluation demonstrated metformin is not only able to bring about the removal of protein aggregates in zebrafish and human myoblasts but is also able to rescue the fiber disintegration and swimming deficit observed in thebag3(-/-)fish. Therefore, repurposing metformin provides a promising therapy for BAG3 myopathy.