Myofibrillar myopathy type 6 (MFM6) is a rare genetic muscle disease that causes severe muscle weakness and a significantly shortened lifespan due to disruption of muscle protein regulation. Researchers at the University Hospital Bonn (UKB) and the University of Bonn have developed a mouse model of the disease and were able to show that disruption of cell recycling, technically known as autophagy, is the main trigger of the disease. Their findings were published in the journal Nature Communications.
Myofibrillar myopathy type 6 (MFM6) destroys sarcomeres, the smallest units in muscle fibers that control muscle movement and tension. This is caused by a defective BAG3 protein (BAG3_P209L), which is part of the chaperone-associated selective autophagy complex (CASA). This is because BAG3 plays an important role in CASA-regulated autophagy, a process by which damaged proteins are discarded or recycled within cells. Affected people suffer rapidly progressive muscle weakness, damage to nerves outside the brain and spinal cord, and sometimes heart failure. The most common cause of death is respiratory failure due to skeletal muscle weakness, and the average life expectancy is approximately 20 years.
Mouse model reproduces key features of the disease
To better mimic and study the myocardial and skeletal muscle pathology observed in patients, we developed a novel humanized mouse model of MFM6. Point mutations in the genetic material render BAG3 unable to function as an auxiliary chaperone in the CASA complex, and loss of its function leads to accumulation of damaged muscle proteins and consequent sarcomere disruption. We found that these mice clearly showed signs of muscle weakness and were therefore an ideal model to study MFM6 pathology in skeletal muscle. It is of particular interest to investigate the differences between skeletal and cardiac muscle, as skeletal muscle is a tissue that can regenerate via its own stem cells. This is because the latter lack stem cells and have low regenerative ability. ”
PD Michael Hesse, PhD, corresponding author, UKB Institute of Physiology 1 and University of Bonn
Therapeutic approaches to improve muscle function
In this study, the researchers observed sarcomere degradation, inflammation, and loss of mitochondria (the powerhouses of cells) in skeletal muscle, which reduced the force of muscle contraction by about 90 percent. Additionally, impaired protein synthesis was observed, as was a block in autophagy and mitophagy, processes by which mitochondria are specifically degraded.
“Until now, it was unclear whether mitochondrial defects were a cause or a consequence of this disease,” said lead author Kerstin Filippi. “We were able to show in a mouse model that BAG3 aggregation and loss of BAG3 function primarily inhibit autophagy, thereby causing muscle degeneration.” This is because only targeted induction of autophagy using the immunosuppressant rapamycin led to significant improvements in motor function. Gene therapy in skeletal muscle that reduced the amount of mutated BAG3_P209L protein also significantly improved muscle function. “This success shows that we have found a useful mouse model to test new gene therapy approaches to cure this devastating disease,” said Professor Bernd Fleischmann, research group leader at the UKB First Institute of Physiology and member of the TRA ‘Life & Health’ at the University of Bonn.
Participating institutions and funding:
In addition to the Daiichi Physiological Institute, the Department of Neurology and the Department of Epilepsy of Bonn University Hospital also participated in the study. Partners also include the Jülich Research Center, the University of Münster, the University of Freiburg, the University of Göttingen, the University of Cologne, the University of Gdańsk in Poland, and the University of Tsukuba in Japan. This study was funded by the German Research Foundation (DFG) as part of the research group “Cellular protection mechanisms against mechanical stress.”
sauce:
Bonn University Hospital (UKB)
Reference magazines:
Filippi, K. Others. (2026). In mouse models of myofibrillar myopathy, blockade of autophagy leads to severe skeletal muscle destruction6. Nature Communications. DOI: 10.1038/s41467-026-71749-6. https://www.nature.com/articles/s41467-026-71749-6
