Metformin rescues muscle function in BAG3 myofibrillar myopathy models

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 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.

Pharmacological inhibition of BAG3‐HSP70 with the proposed cancer therapeutic JG‐98 is toxic for cardiomyocytes

“…Earlier work in zebrafish with BAG3 loss‐of‐function mutations found that protein aggregation was reduced with autophagy induction by rapamycin and with genetic haplo‐insufficiency of mTOR 17–19 . We, therefore, investigated whether cotreatment with rapamycin could mitigate the cardiotoxicity of JG‐98.…”

“…Thus, if one fails, its effects may be ameliorated by upregulating a different arm. Indeed, studies in zebrafish showed that the administration of autophagy‐inducing compounds, such as metformin and rapamycin, restores clearance of protein aggregates when BAG3‐mediated autophagy is compromised by pathogenic mutations or haplo‐insufficiency 17,18 . In this study, we investigated if cotreatment of NRVMs with JG‐98 and rapamycin could reduce the toxic effects of the compound and found that a 30 nM dose of rapamycin, chosen based on previous work in NRVMs, 38,39 reduced apoptosis and sarcomere disarray by 15% and 20%, respectively.…”

On the origin of BAG(3) and its consequences for an expansion of BAG3's role in protein homeostasis

“…Finally, we observed within the Actinopterygii strong conservation of a PolyQ‐, but not a PolyP‐domain. Thus, although studies investigated BAG3‐dependent pathologies in Danio rerio , and show the protein's importance for correct muscle function, drawing cross‐species deductions could turn into a slippery slope 39 . The high divergence of BAG3's structures between the Vertebrata classes would advise being wary of cross‐class conclusions in general.…”

The role of BAG3 in health and disease: A “Magic BAG of Tricks”

“…It should be noted that in the α MHC‐human BAG3 P209L transgenic mice, P209L BAG3 is overexpressed in the presence of wild type BAG3 but still leads to haploinsufficiency of wild‐type BAG3, 92 which is consistent with the findings of Ruparelia et al 91 Recently, Ruparelia and colleagues screened autophagy‐promoting compounds in P209L BAG3 mutant zebrafish and human myoblasts and identified nine, including metformin, that could reduce aggregates. Further evaluation of histology and behavior shows that metformin is also able to rescue the fiber disintegration and swimming deficit observed in the BAG3 −/− fish 93 . These studies suggest a mechanism that P209L BAG3 tends to aggregate with the available BAG3 pool leading to BAG3 insufficiency, which results in impaired autophagic activity.…”