biostudies-literatureUnknown17(9)Ruparelia AAFondazione RobyBellini FoundationDominant <i>de novo</i> 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 <i>bag3</i>. While transgenic BAG3^P209L-expressing fish display protein aggregation, modeling the early phase of the disease, <i>bag3</i>^-/- fish exhibit exercise dependent fiber disintegration, and reduced swimming activity, consistent with later stages of the disease. Detailed characterization of the <i>bag3</i>^-/- fish, revealed an impairment in Autophagy2494-2510https://www.ebi.ac.uk/biostudies/studies/S-EPMC8496720biostudies-literatureMetformin rescues muscle function in BAG3 myofibrillar myopathy models.PMC8496720Torrente YRamm GOorschot VMcKaige EASchulze KESerrano RJWilliams CBaxter ECStojkovic TBryson-Richardson RJMeregalli MLee CFuchs MRuparelia AALavoie JNMonro KLacene EfalseMetformin rescues muscle function in BAG3 myofibrillar myopathy models.Dominant <i>de novo</i> 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 <i>bag3</i>. While transgenic BAG3^P209L-expressing fish display protein aggregation, modeling the early phase of the disease, <i>bag3</i>^-/- fish exhibit exercise dependent fiber disintegration, and reduced swimming activity, consistent with later stages of the disease. Detailed characterization of the <i>bag3</i>^-/- fish, revealed an impairment in 2021-01-01T00:00:00Z2021 Sep2026-06-13T03:20:07.627Z2025-02-19T00:27:53.156ZS-EPMC84967203303039210.1080/15548627.2020.1833500