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Publications

Journal Article Ahead of print

PubMed: 41965903 DOI: 10.1038/s41467-026-71749-6

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

Nat Commun

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

Affiliations

  • Institute of Physiology I, Medical Faculty, University of Bonn, Bonn, Germany.
  • Central Institute for Engineering, Electronics and Analytics, ZEA-3, Forschungszentrum Jülich, Jülich, Germany. Department Metabolism, Senescence and Autophagy, Research Center One Health Ruhr, University Alliance Ruhr & University Hospital Essen, University Duisburg-Essen, 45147, Essen, Germany.
  • Institute of Physiology II, University of Muenster, Muenster, Germany.
  • Life Science Center for Survival Dynamics, Tsukuba Advanced Research Alliance (TARA), University of Tsukuba, Ibaraki, 305-8577, Japan.
  • Central Institute for Engineering, Electronics and Analytics, ZEA-3, Forschungszentrum Jülich, Jülich, Germany.
  • Institute of Biology II, University of Freiburg, 79104, Freiburg, Germany.
  • Department of Molecular Biology, Faculty of Biology, University of GdaÅ„sk, GdaÅ„sk, Poland.
  • Institute of Pharmacology and Toxicology, University Medical Center Göttingen, Göttingen, Germany.
  • Institute of Experimental Epileptology and Neurocognition, University Bonn Medical Center, 53105, Bonn, Germany. Department of Epileptology, University Bonn Medical Center, 53105, Bonn, Germany.
  • Department of Neurology, University Bonn Medical Center, 53105, Bonn, Germany.
  • CIBSS-Centre for Integrative Biological Signaling Studies, University of Freiburg, 79104, Freiburg, Germany.
  • Institute of Experimental Epileptology and Neurocognition, University Bonn Medical Center, 53105, Bonn, Germany.
  • Department of Epileptology, University Bonn Medical Center, 53105, Bonn, Germany.
  • Institute of Physiology I, Medical Faculty, University of Bonn, Bonn, Germany.

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 BAG3 P209L-GFP, which rapidly develop skeletal muscle weakness unlike controls expressing BAG3 WT-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.

MeSH

Muscular Diseases, Genes, Autophagy, Muscles, Muscle Weakness, Muscle, Skeletal, Sarcomeres