Metformin rescues muscle function in BAG3 myofibrillar myopathy models.

Metformin rescues muscle function in BAG3 myofibrillar myopathy models. Autophagy. 2020 Oct 08;: Authors: Ruparelia AA, McKaige EA, Williams C, Schulze KE, Fuchs M, Oorschot V, Lacene E, Meregalli M, Lee C, Serrano RJ, Baxter EC, Monro K, Torrente Y, Ramm G, Stojkovic T, Lavoie JN, Bryson-Richardson RJ Abstract 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 BAG3P209L and one with a nonsense mutation in bag3. While transgenic BAG3P209L-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 BAG3P209L 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 effectiv...
Source: Autophagy - Category: Cytology Authors: Tags: Autophagy Source Type: research