Abstract
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 BAG3P209L-GFP, which rapidly develop skeletal muscle weakness unlike controls expressing BAG3WT-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.
Data availability
The mass spectrometry proteomics raw data generated in this study have been deposited to the ProteomeXchange Consortium via the PRIDE30 partner repository under accession code PXD047942. The tissue RNA-seq raw data used in this study are available in the SRA database under accession code PRJNA1082302. The mass spectrometry proteomics data and the tissue RNA-seq data generated in this study are provided in the Supplementary Information/Source Data file. Source data are provided with this paper.
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Acknowledgements
We thank the Freiburg Galaxy Team, Björn Grüning, Anika Erxleben, and Rolf Backofen, Bioinformatics, University of Freiburg, Germany, funded by the Deutsche Forschungsgemeinschaft (SFB 992 and SFB 1425, project S3) and German Federal Ministry of Education and Research (BMBF grant 031 A538A RBC [de.NBI]). We thank the European Molecular Biology Laboratory GeneCore (Heidelberg, Germany) for providing sequencing services. This work was supported by the German Research Foundation (FOR2743 to P.F.H. and M.H. #388932620). B.K.F. is a member of CRC1425, funded by the German Research Foundation. The Galaxy server that was used for some calculations is in part funded by the Collaborative Research Center 992 Medical Epigenetics (DFG grant SFB 992/1 2012) and the German Federal Ministry of Education and Research BMBF grant 031 A538A de.NBI-RBC.
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K.F., K.G.R., K.K., J.R., and C.K. performed molecular biology, cell culture, imaging, and immunohistochemistry experiments and data analysis. W.A.L. and A.U. designed, performed, and analyzed (immuno)electron microscopy experiments. M.K., M.M., H.B., and P.F.H. designed and performed mass spectrometry and proteomics data analysis. A.P.K., C.K., and W.S.K. designed and performed isolation of skeletal muscle mitochondria, determination of substrate oxidation rates and measurements of mitochondrial enzymes. K.F. and K.G.R. performed ex vivo Skeletal muscle force measurement. M.P. and G.W. designed, performed and analyzed the rapamycin treatment experiment. D.H. performed analysis with the SarcAsM algorithm. M.W. performed qPCR experiments and data analysis. M.H. performed tissue RNA-Seq analysis. M.H. conceived the study and wrote the manuscript together with B.K.F. All authors edited and approved the submitted paper.
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Filippi, K., Graf-Riesen, K., Kuppusamy, M. et al. Blockage of autophagy causes severe skeletal muscle disruption in a mouse model for myofibrillar myopathy 6. Nat Commun (2026). https://doi.org/10.1038/s41467-026-71749-6
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DOI: https://doi.org/10.1038/s41467-026-71749-6
