An enzyme called Ubiquitin-specific peptidase 5 is a key factor in protein quality in heart muscle cells
A disrupted protein degradation process in heart muscle cells can lead to a range of severe heart diseases. In the case of dilated cardiomyopathy, a pathological enlargement of the heart chambers, researchers at the Max Planck Institute for Heart and Lung Research in Bad Nauheim have now identified a cause: a low level of the enzyme Ubiquitin-specific peptidase 5 (USP5) leads to an accumulation of Ubiquitin in heart muscle cells and the formation of protein aggregates, which trigger heart diseases. Increasing USP5 levels in heart muscle cells protects the heart from harmful degradation processes, offering a perspective for new therapies.
Low USP5 concentration leads to heart muscle weakness. The figure shows images of hearts using magnetic resonance imaging (MRI). While the heart of the control animal (right) is healthy in terms of size and thickness of the heart wall, a low USP5 concentration leads to dilatation of the heart and muscle weakness (dilated cardiomyopathy, left).
© MPI for Heart and Lung Research
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
Schematic representation of the mode of action of USP5 in the heart. In the healthy heart, USP5 organises the recycling of defective proteins. If the USP5 concentration is too low, recycling no longer works. This leads to damaged heart muscle cells and thus to dilated cardiomyopathy.
© Created in BioRender. Eibach, Y. (2023)
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.
Further experiments should clarify the importance of USP5 in heart diseases and investigate whether increased production of USP5 can lead to therapeutic improvements: "We have used a genetic intervention to cause heart muscle cells to produce USP5 in excess and then subjected the animals to increased pressure loads," said Kreher. Such increased pressure loads are found, for example, in high blood pressure and in narrowing of heart valves. "Animals with increased USP5 production coped much better with the increased pressure load and showed significantly fewer harmful degradation processes in the heart. Ultimately, the animals fared much better than the control animals," added Eibach.
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.
