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Blockage of autophagy causes severe skeletal muscle disruption in a mouse model for myofibrillar myopathy 6.

Nature communications

Authors: Kerstin Filippi, Kathrin Graf-Riesen, Maithreyan Kuppusamy, Andreas Unger, Kenichi Kimura, Martin Matijass, Henrique Baeta, Magdalena Podlacha, Daniel Haertter, Alexei P Kudin, Martin Wiemann, Grzegorz Węgrzyn, Cornelia Kornblum, Jens Reimann, Wolfgang A Linke, Pitter F Huesgen, Wolfram S Kunz, Bernd K Fleischmann, Michael Hesse

Myofibrillar myopathy 6 is a rare, autosomal-dominant neuromuscular disorder caused by an amino acid exchange Pro209Leu in the co-chaperone BAG3, which disrupts muscle protein turnover and causes severe muscle weakness and shortened lifespan. We generated transgenic mice overexpressing the human mutant BAG3-GFP, which rapidly develop skeletal muscle weakness unlike controls expressing BAG3-GFP. Here we show that mutant mice exhibit sarcomere breakdown, inflammation, protein aggregates, centralized nuclei and mitochondrial defects in their skeletal muscles, thereby reducing contraction force by ~90%. Omics profiling uncovered impaired protein synthesis, blocked autophagy, impaired mitophagy and loss of sarcomere proteins. Pathway modulation in vitro and in vivo showed autophagy dysfunction as the primary driver for the pathology, while BAG3 knockdown gene therapy markedly restored muscle function in vivo. In summary, this model recapitulates core disease features, revealing how BAG3 aggregates and loss of BAG3 function impair autophagy to drive muscle degeneration.

© 2026. The Author(s).

PMID: 41965903

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