An enzyme called Ubiquitin-specific peptidase 5 is a key factor in protein quality in heart muscle cells

Dilated cardiomyopathy is a pathological enlargement of one or both heart chambers, including the atria. The resulting restriction of heart function is caused by structural damage to heart muscle cells. The consequence is heart failure, which can lead to death without a heart transplant. Existing therapeutic options can usually not stop or reverse the progression of the disease.
In search of new therapeutic approaches, researchers from the department of Thomas Braun at the Max Planck Institute for Heart and Lung Research have investigated the molecular processes of protein degradation in heart muscle cells. Yvonne Eibach and Silke Kreher, both first authors of the study, together with their research partners, discovered disturbances in the process that serves the disposal of defective or no longer needed proteins.
Defective or no longer needed proteins are connected with chains of a molecule called Ubiquitin and thus marked for disposal. The disposal takes place in so-called proteasomes, which are a cellular waste disposal factory. Before the proteins are fed into this factory, the Ubiquitin chains are split off and the chains must be split into their individual parts. If this does not happen, the entire waste disposal process collapses. Responsible for the splitting of Ubiquitin chains is the enzyme Ubiquitin-specific peptidase 5 (USP5), which occurs in a specific form in heart muscle cells. The enzyme is crucial for the recycling of Ubiquitin and thus ensures a balance between protein synthesis and degradation.
Low USP5 levels trigger cardiomyopathy
The Bad Nauheimer researchers now found in animal studies with mice that low USP5 levels trigger dilated cardiomyopathy. "Through a genetic intervention, we were able to specifically knock out USP5 in heart muscle cells of adult animals. If USP5 was then missing, a dilated cardiomyopathy developed in the following," reported Silke Kreher. Co-author Yvonne Eibach adds: "Using magnetic resonance imaging as a imaging method, we were able to impressively demonstrate that in these animals the entire heart was significantly enlarged and the pumping performance was severely restricted." Under the microscope, the researchers also found increased protein deposits, which is a direct consequence of the disrupted degradation of proteins, as these cannot find their way into the proteasomes without USP5.
From mice to men
The Bad Nauheimer researchers were particularly interested in evaluating the clinical relevance of the findings. "For this, we examined heart biopsies from patients with dilated cardiomyopathy, which were provided by the adjacent Kerkhoff Clinic," said Eibach. "And indeed, we found that in the hearts of patients the USP5 level was significantly reduced. We also found the protein aggregates that we had observed in the mice in the diseased heart muscle cells of patients," explained Kreher.Department head Thomas Braun summarized the data as follows: "Our study highlights the role of Ubiquitin recycling in dilated cardiomyopathy for the first time, for which USP5 is essential." The Bad Nauheimer researchers hope to find new therapeutic options through this: "We assume that inhibition of USP5 degradation or therapeutic increase of USP5 concentration in heart muscle cells will reduce protein aggregation and thus at least slow down the progression of the disease," said Braun.
Yvonne Eibach, Silke Kreher, Mareike S. Poetsch, Ay Lin Kho, Ulrich Gaertner, Christoph S. Clemen, Rolf Schröder, Kai Guo, Hendrik Milting, Benjamin Meder, Michael Potente, Manfred Richter, Andre Schneider, Silke Meiners, Mathias Gaute, Thomas Braun
In Germany, animal research is primarily carried out in the areas of basic research, medicine and veterinary medicine. Animal research can also be required to identify factors that pose a risk to the environment. The toxicity of chemicals is also investigated using animal research. It is a legal requirement that all’active substances are tested in animal experiments for effectiveness and side effects.