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 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 in bag3. 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 the bag3-/fish, revealed an impairment in macroautophagic/autophagic activity, a defect we confirmed in BAG3 patient 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 the bag3 −/fish. Therefore, repurposing metformin provides a promising therapy for BAG3 myopathy.
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 BAG3 P209L and one with a nonsense mutation in bag3. Whilst transgenic BAG3 P209L 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.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.