Reducing nuclear damage improves heart function and survival in mice

Reducing damage to the nuclei of heart muscle cells improved heart function and extended survival in mice with a form of inherited heart disease, according to a new study led by Cornell researchers. The findings point to new approaches for understanding and potentially treating LMNA-related dilated cardiomyopathy, a disease that leads to heart failure and sudden cardiac death.

The study, published in Circulation Research, was directed by Jan Lammerding, a professor in the Meinig School of Biomedical Engineering in the Cornell Duffield College of Engineering and a member of the Weill Institute for Cell and Molecular Biology, and jointly led by Noam Zuela-Sopilniak and Julien L.P. Morival in his group. Co-corresponding author Iwijn De Vlaminck is also a professor in the Meinig School.

LMNA-related dilated cardiomyopathy is an inherited heart disease caused by mutations in the LMNA gene, which encodes lamin A and lamin C, proteins that help maintain the structural integrity of a cell’s nucleus. Although researchers have identified a link between LMNA mutations and heart disease, they do not completely understand the cellular mechanisms that lead to heart damage.

“We know that mutations in the LMNA gene cause heart disease, but we don’t fully understand how on a cellular level, which makes it difficult to develop effective therapies for the disease,” said Lammerding.

In their mouse model, after the researchers removed LMNA in heart muscle cells, signs of nuclear rupture in a subset of heart muscle cells were seen. The researchers found these ruptures activated an inflammatory response resembling the body’s reaction to an infection, even though no virus was present, leading to damage.

“Over time, this response results in scarring of the heart tissue that affects its function and ability to pump blood,” Lammerding said. “We suspect that the damage to the nucleus also triggers additional changes in the heart muscle cell that impair its function, contributing to the rapid heart failure.”

To reduce nuclear damage, the team used an engineered protein called DN KASH to disrupt the LINC complex, a structure that transmits mechanical forces from the rest of the cell to the nucleus. By reducing those forces on the fragile lamin A/C-deficient nuclei, the researchers prevented nuclear rupture and the harmful inflammatory signaling associated with it.

“Our approach reduced the damage to the nuclei with the lamin deletion by more than half,” he said. “This was sufficient to reduce much of the pathogenic signaling associated with nuclear damage, reducing the immune response and scarring of the heart, and most importantly, restore almost normal cardiac function and extend survival of the mice from weeks to over a year.”

The researchers also found that reducing nuclear rupture restored the activity of more than half the genes whose activity had been altered by the loss of the lamin A/C structural proteins. The intervention improved outcomes even though lamin A/C remained depleted within cells. This suggests that many harmful changes in cells occur as a consequence of nuclear damage, rather than directly from the loss of lamin A/C proteins, Lammerding said.

Analyzing existing data sets from human hearts with LMNA-related cardiomyopathy, the researchers found gene expression signatures similar to those seen in the mouse model but emphasized that further research is needed.

The findings may also have implications beyond inherited heart disease.

“Recent findings suggest that even in other, more common heart issues, such as myocardial infarction or even normal aging, some muscle cell nuclei become more fragile and rupture, which could contribute to cardiac dysfunction,” Lammerding said.

“Our work suggests that reducing nuclear damage or targeting pathogenic signals triggered by nuclear damage could substantially improve cardiac function in those conditions too. We are excited to explore this further.”

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