Unraveling the nexus of nesprin in dilated cardiomyopathy: From molecular insights to therapeutic prospects

Dilated cardiomyopathy is a complex and debilitating heart disorder characterized by the enlargement and weakening of the cardiac chambers, leading to impaired contractility and heart failure. Nesprins, a family of nuclear envelope spectrin repeat proteins that include isoforms Nesprin-1/-2, are integral components of the LInker of Nucleoskeleton and Cytoskeleton complex. They facilitate the connection between the nuclear envelope and the cytoskeleton, crucial for maintaining nuclear architecture, migration and positioning, and mechanical transduction and signaling. Nesprin-1/-2 are abundantly expressed in cardiac and skeletal muscles.They have emerged as key players in the pathogenesis of dilated cardiomyopathy. Mutations in synaptic nuclear envelope-1/2 genes encoding Nesprin-1/-2 are associated with dilated cardiomyopathy, underscoring their significance in cardiac health. This review highlights the all known cases of Nesprin-1/-2 related dilated cardiomyopathy, focusing on their interactions with the nuclear envelope, their role in mechanical transduction, and their influence on gene expression. Moreover, it delves into the underlying mechanisms through which Nesprin dysfunction disrupts nuclear-cytoskeletal coupling, leading to abnormal nuclear morphology, impaired mechanotransduction, and altered gene regulation. The exploration of Nesprin's impact on dilated cardiomyopathy offers a promising avenue for therapeutic interventions aimed at ameliorating the disease. This review provides a comprehensive overview of recent advancements in understanding the pivotal role of Nesprins in dilated cardiomyopathy research.