In myofibrillar myopathy type 6 (MFM6), the sarcomeres—the smallest units of the muscle fiber responsible for muscle movement and tension—break down. This is triggered by a defective BAG3 protein (BAG3_P209L), which is part of the chaperone-associated selective autophagy complex (CASA). This is because BAG3 plays a key role in CASA-regulated autophagy, a process in which damaged proteins are disposed of or recycled within the cell. Affected individuals suffer from 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 their life expectancy is approximately 20 years.

Mouse model replicates key features of the disease
“To better mimic and thus study the cardiac and skeletal muscle pathologies observed in patients, we developed a novel humanized mouse model for MFM6. Due to a point mutation in the genetic material, BAG3 was no longer able to fulfill its function as a co-chaperone in the CASA complex, and its loss of function leads to the accumulation of damaged muscle proteins and consequently to the breakdown of sarcomeres,” says corresponding author PD Dr. Michael Hesse from the Institute of Physiology 1 at the UKB and the University of Bonn. “We found that these mice exhibit clear signs of muscle weakness and therefore represent an ideal model for investigating the MFM6 pathomechanism in skeletal muscle. Since skeletal muscle is a tissue that can regenerate via its own stem cells, it is particularly interesting to investigate the differences between skeletal and cardiac muscle, as the latter lacks stem cells and has poor regenerative capacity.”
Therapeutic approaches for improving muscle function
In the study, the researchers observed sarcomere degradation, inflammation, and defects in the mitochondria—the powerhouses of the cells—in the skeletal muscles, which reduced the muscles’ contractile force by about 90 percent. In addition, impaired protein synthesis was observed, as well as blocked autophagy and mitophagy, a process in which mitochondria are specifically broken down.

“Until now, it was unclear whether the defects in mitochondria were a cause or a consequence of the disease,” says lead author Kerstin Filippi. “We were able to show in a mouse model that BAG3 aggregates and the loss of BAG3 function primarily impair autophagy, thereby driving muscle degeneration.” This is because only the targeted induction of autophagy using the immunosuppressant rapamycin led to significantly improved motor function. Gene therapy in skeletal muscle, which reduced the amount of the mutated BAG3_P209L protein, also significantly improved muscle function. Research group leader Prof. Dr. Bernd Fleischmann from the Institute of Physiology I at the UKB and a member of the TRA “Life & Health” at the University of Bonn states: “This success shows that we have found a useful mouse model for testing new gene therapy approaches to cure this devastating disease.”

Participating institutions and funding:
In addition to the Institute of Physiology I, the Departments of Neurology and Epileptology at the University Hospital Bonn were also involved in the study. Partners also include the Jülich Research Center, the Universities of Münster, Freiburg, Göttingen, and Cologne, as well as the University of Gdańsk in Poland and the University of Tsukuba in Japan. The study was funded by the German Research Foundation (DFG), including as part of the research group “Cellular Protection Mechanisms Against Mechanical Stress.”