Nucleoli as drivers of nuclear remodelling in cardiomyocytes during Heart Failure

Abstract

Cardiomyocyte mechanotransduction has traditionally focused on the sarcomere and cytoskeleton, yet emerging evidence highlights the nucleus as an active mechanical responder. To adapt to the dynamic mechanical environment, the nucleus forms nuclear invaginations (NIs), double-membrane folds that provide structural support to chromatin and incorporate nuclear pore complexes to facilitate nucleo-cytoplasmic transport, including Ca2+ transport. However, how these structures are formed is not yet understood. We leveraged advances in high-resolution microscopy, mechanical stimulation, rat models and human samples, to study the formation, function and remodelling of cardiac NIs in Heart Failure (HF). Here, we demonstrate that the formation of NI in cardiomyocytes is regulated by both, cytoskeleton such as actin and detyrosinated microtubules as well as intranuclear nucleolar interactions with NI disruption resulting in elevated baseline nuclear Ca2+. In a 16-week post-Myocardial Infarction (MI) end-stage HF rat model, as well as in human Dilated Cardiomyopathy samples, a marked reduction in NIs was observed. Importantly, NI loss was already evident at 8 weeks post-MI, preceding detectable cytoskeletal stiffening. At this stage, we observed increased DNA damage in the peri-nucleolar region, accompanied by nucleolar remodelling and a shift in nucleolar biomechanical properties. In conclusion, preserving nucleolar integrity emerges as a potential target for intervention.