Non-coding RNA protects the heart against dangerous arrhythmias

TRDN-AS influences calcium release in cardiac muscle cells and thereby the electrical stability of the heart

To the point

• The noncoding RNA TRDNAS helps keep the heart's rhythm stable by controlling the production of triadin protein variants that regulate calcium release in heart muscle cells. Reduced TRDNAS levels can disrupt calcium balance and increase the risk of dangerous arrhythmias.
• Calcium triggers heart muscle contraction and relaxation, with triadin protein variants playing a key role. TRDNAS ensures the heart produces the correct triadin variant; without it, a skeletal muscle variant (TRISK95) appears, impairing calcium control.
• Patients with dilated cardiomyopathy show lower TRDNAS and higher levels of TRISK95, especially those with documented arrhythmias, linking TRDNAS deficiency to heart rhythm disturbances.
• A new understanding of arrhythmia development: TRDNAS regulates triadin gene transcription to favor the heart-specific protein variant and suppress the skeletal muscle variant, offering a new understanding of arrhythmia development and potential early risk identification.

The heartbeat is controlled by electrical impulses that travel along the heart muscle. Disruptions in this coordinated transmission of electrical signals underlie cardiac arrhythmias and, in many cases, heart failure. Scientists at the Max Planck Institute for Heart and Lung Research, together with collaborators, have now shown that the non-coding RNA TRDN-AS is reduced in patients with dilated cardiomyopathy. At the same time, they detected an atypical variant of the protein triadin, particularly in patients with cardiac arrhythmias. This variant disrupts calcium regulation in cardiac muscle cells and can thereby trigger electrical changes in the heart.

The role of calcium

For the heart to beat regularly, its muscle cells must contract precisely with every heartbeat and then relax again. Calcium plays a central role in this process. With each heartbeat, calcium is released from a storage compartment inside the cardiac muscle cell, triggering contraction. The calcium is then transported back into the storage compartment.

The protein triadin is involved in this finely coordinated process. Triadin occurs in different variants. In the heart, a specific variant characteristic of cardiac muscle cells is normally produced. Scientists at the Max Planck Institute for Heart and Lung Research in Bad Nauheim, together with colleagues from Bad Oeynhausen and the universities in Munich, Marburg and Grenoble, have now identified a mechanism that influences which triadin variants are produced in cardiac muscle cells.

At the centre of this mechanism is TRDN-AS, a so-called long non-coding RNA (lncRNA). Unlike conventional messenger RNA, it does not contain a blueprint for a protein. Instead, it can influence the activity of other genes. TRDN-AS is transcribed in the opposite direction to the TRDN gene, which contains the blueprint for triadin.

“We were able to show, by analysing samples from human hearts, that patients with dilated cardiomyopathy have less TRDN-AS than a healthy control group,” explains Thomas Böttger, head of the study. At the same time, a triadin variant that normally occurs primarily in skeletal muscle was detected in the cardiac muscle cells of these patients. “This variant, known as TRISK95, was particularly pronounced in patients in whom cardiac arrhythmias had been documented,” says Theresa Hofmann, first author of the study.

The research team conducted further experiments to determine whether the altered activity of TRDN-AS was actually the cause of these changes. To this end, they specifically switched off TRDN-AS in human cardiac muscle cells derived from stem cells. This resulted in a marked shift in the production of triadin variants in favour of the TRISK95 variant characteristic of skeletal muscle. “At the same time, calcium regulation changed: calcium was released from the storage compartments more rapidly and was subsequently taken up again more rapidly,” says Hofmann. In addition, spontaneous calcium releases occurred in one third of the TRDN-AS-deficient cardiac muscle cells examined; these were not observed in control cells.

Studies in mice also confirmed the importance of this mechanism. When the production of TRDN-AS in the heart was prevented, the triadin variant characteristic of skeletal muscle was produced in greater amounts. The cardiac muscle cells exhibited spontaneous calcium releases and calcium oscillations. Over time, these animals developed cardiac arrhythmias and eventually also displayed signs of heart failure.

Finally, the researchers in Bad Nauheim were able to elucidate the molecular mechanism. “TRDN-AS influences the transcription of the triadin gene. It normally ensures that only the shorter triadin variant characteristic of the heart is produced, while suppressing the production of the longer variant characteristic of skeletal muscle,” says Hofmann. “With our study, we describe a new link between non-coding RNA and the generation of different protein variants,” says Böttger. The mechanism identified here may contribute to the development of arrhythmias in patients with pre-existing heart conditions. In conclusion, Böttger says that the scientists hope the study has identified an approach that could, in the future, help to identify patients at increased risk of cardiac arrhythmias at an early stage.