Metformin rescues muscle function in BAG3 myofibrillar myopathy models

Area of Science:

• Molecular Biology
• Genetics
• Zebrafish Models

Background:

• Dominant de novo mutations in BAG3 (BAG cochaperone 3) lead to severe myofibrillar myopathy, characterized by muscle weakness, structural failure, and protein aggregation.
• Understanding the disease mechanism and identifying therapeutic strategies for BAG3 myofibrillar myopathy is crucial.

Purpose of the Study:

• To elucidate the disease mechanism of BAG3 myofibrillar myopathy.
• To identify potential therapeutic agents for BAG3 myofibrillar myopathy.

Main Methods:

• Generated two zebrafish models: one with conditional BAG3 P209L expression and one with a BAG3 knockout (bag3-/-).
• Characterized disease phenotypes including protein aggregation, fiber disintegration, and swimming activity.
• Assessed macroautophagic/autophagic activity in zebrafish models and patient samples.
• Screened autophagy-promoting compounds, including metformin, for efficacy in clearing protein aggregates and rescuing disease phenotypes.

Main Results:

• BAG3 P209L expression induced protein aggregation, modeling early disease stages.
• bag3-/- zebrafish exhibited fiber disintegration and reduced swimming, consistent with later disease stages, and impaired autophagic activity.
• Impaired autophagy was also confirmed in BAG3 patient samples.
• Metformin effectively cleared protein aggregates in zebrafish and human myoblasts, and rescued fiber disintegration and swimming deficits in bag3-/- zebrafish.

Conclusions:

• Loss of BAG3, due to sequestration in aggregates, impairs autophagic activity, leading to muscle weakness in BAG3 myofibrillar myopathy.
• Repurposing metformin shows promise as a therapeutic strategy for BAG3 myopathy by promoting aggregate clearance and restoring muscle function.