• © Michael Radke, Max Delbrück Center

    © Michael Radke, Max Delbrück Center

    08.09.2026

    Hidden switch in the heart: Berlin research opens new avenues against heart disease

The heart is a master of adaptation. To respond to changing demands, its cells are constantly running finely tuned molecular processes. One of the most important regulators is the protein RBM20. Researchers at the Max Delbrück Center in Brain City Berlin have now discovered that this protein is regulated far more complexly than previously assumed, identifying a possible new target for the treatment of serious heart disease. The findings have been published in Nature Communications.

A molecular spring in the heart muscle

RBM20 controls a process known as alternative splicing, through which a cell can produce different messenger RNA molecules from the same gene. Together with other proteins, RBM20 regulates the production of titin, a giant molecule that acts like a molecular spring, keeping the heart muscle elastic. Defects in the RBM20 gene can impair this elasticity and are associated with serious cardiomyopathies and heart failure.

The "Translational Cardiology and Functional Genomics" research group led by Professor Michael Gotthardt at the Max Delbrück Center has now discovered, together with colleagues, a previously unknown gene switch: the RBM20 gene can be activated from different starting points, generating differently structured RNA and protein molecules known as isoforms.

An unexpected result

The discovery came from an experiment that was designed to show something else entirely. The team developed a mouse model in which the genetic code for the starting point of RBM20 transcription was altered. The researchers expected this to completely block production of the protein. Instead, the mice continued to produce RBM20, albeit in a shorter isoform. "That completely surprised us," says Dr Michael Radke, one of the study's first authors.

Further analyses of heart tissue from mice, rats and human cardiac patients revealed that the RBM20 gene has multiple transcription start points, and that the balance between isoforms is particularly tightly regulated around the time of birth, when the heart transitions from foetal to adult function.

Disease-specific patterns

The findings in human heart tissue were particularly revealing. In hypertrophic cardiomyopathy, where the heart muscle thickens significantly, the overall amount of RBM20 was elevated, driven mainly by an increase in the shorter isoform. In dilated cardiomyopathy, where the heart enlarges and loses pumping capacity, both isoforms were elevated compared with healthy tissue, with the longer isoform being especially prominent.

"These results show that heart cells regulate RBM20 in a far more complex way than we previously thought," says Gotthardt, the study's last author. "It is not just about how much of the protein is produced, but also which isoform it is."

A target for more precise therapies

RBM20 is already used as a target for drugs against cardiomyopathies. The new findings could significantly refine this approach. "RBM20 is known as a disease gene and is already an important drug target for cardiomyopathies and heart failure," says Radke. "Our study suggests that future therapeutic strategies may need to consider not only how much RBM20 is produced, but also which isoform is involved."

Deliberately intervening in the isoform balance could help to influence heart muscle stiffness more precisely while reducing unwanted side effects, says Gotthardt. Further studies will investigate the functions of the RBM20 isoforms in larger patient cohorts and disease models.

For Brain City Berlin, the study is a further example of how the close integration of basic and translational research at the Max Delbrück Center leads to findings with immediate clinical relevance.

 

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