Blockage of autophagy causes severe skeletal muscle disruption in a mouse model for myofibrillar myopathy 6
-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.
Authors
- Martin Wiemann (ORCID: https://orcid.org/0000-0002-8230-8601)
- Cornelia Kornblum (ORCID: https://orcid.org/0000-0002-0111-7281)
- Magdalena Podlacha (ORCID: https://orcid.org/0000-0002-7709-5955)
- Daniel Haertter (ORCID: https://orcid.org/0000-0002-9582-6141)
- Kathrin Graf-Riesen
- Martin Matijass
- Henrique Baeta
- Bernd K. Fleischmann (ORCID: https://orcid.org/0000-0002-9202-8363)
- Maithreyan Kuppusamy (ORCID: https://orcid.org/0000-0001-6866-0417)
- Grzegorz Węgrzyn (ORCID: https://orcid.org/0000-0003-4042-7466)
- Wolfgang A. Linke (ORCID: https://orcid.org/0000-0003-0801-3773)
- Wolfram S. Kunz (ORCID: https://orcid.org/0000-0003-1113-3493)
- Pitter F. Huesgen (ORCID: https://orcid.org/0000-0002-0335-2242)
- Kenichi Kimura (ORCID: https://orcid.org/0000-0002-0363-8865)
- Michael Hesse (ORCID: https://orcid.org/0000-0002-7518-0224)
- Alexei P. Kudin
- Kerstin Filippi
- Jens Reimann
- Andreas Unger
Institutions
- University of Bonn (DE)
- University of Tsukuba (JP)
- University of Freiburg (DE)
- Forschungszentrum Jülich (DE)
- University Hospital Bonn (DE)
- University of Gdańsk (PL)
- Ruhrlandklinik (DE)
- Universitätsmedizin Göttingen (DE)
- Essen University Hospital (DE)
- Life & Brain (Germany) (DE)
- University of Duisburg-Essen (DE)
- University of Göttingen (DE)
Publication Details
- Journal
- Nature Communications
- Published
- 2026-04-11
- DOI
- https://doi.org/10.1038/s41467-026-71749-6
- Primary Topic
- Hereditary Neurological Disorders
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- European Molecular Biology Laboratory
- Deutsche Forschungsgemeinschaft
- Bundesministerium für Bildung und Forschung
- Albert-Ludwigs-Universität Freiburg
- German Network for Bioinformatics Infrastructure