skNAC, a new player protecting the heart from failure through maintenance of cardiomyocyte integrity

Abstract Background Cardiac hypertrophy initially serves as an adaptive response to maintain cardiac output under conditions of pressure overload, such as hypertension or aortic stenosis. However, sustained stress ultimately triggers maladaptive remodeling, leading to contractile dysfunction and heart failure (HF). Myocardial hypertrophy is characterized by increased protein synthesis and extensive sarcomeric reorganization, both key features of the remodeling process. The muscle-specific nascent polypeptide-associated complex alpha isoform (skNAC) is a regulator essential for proper sarcomere organization during cardiac development. Despite its well-established role in cardiac development, the contribution of skNAC to pathological hypertrophy and the progression to heart failure in the adult heart remains largely unknown. Purpose This study aimed to investigate skNAC role in pressure overload–induced cardiac hypertrophy and heart failure. Methods skNAC expression and regulation were investigated in neonatal rat ventricular cardiomyocytes (NRVMs) stimulated with the pro-hypertrophic agent phenylephrine, in mice subjected to transverse aortic constriction (TAC) or angiotensin II infusion, and in human cardiac biopsies of patients suffering from aortic stenosis. skNAC silencing was achieved using siRNA in NRVMs, while plasmid-mediated overexpression was performed to assess the protective effects of increased skNAC levels. In parallel, cardiomyocyte-specific constitutive and inducible skNAC knockout mice (αMHC-Cre and αMHC-MerCreMer) were generated to evaluate the effects of skNAC deletion under basal and TAC conditions. Cardiac structure and function were analyzed by echocardiography. skNAC localization and interactions were examined by confocal immunofluorescence and proximity ligation assays. Cardiomyocyte ultrastructure was assessed by electron microscopy. Results skNAC expression was reduced in all in vitro and in vivo models of cardiac hypertrophy. A similar decrease in skNAC expression was observed in human samples displaying cardiac hypertrophy. This decrease was associated with reduced expression of the RNA-binding proteins Rbm24 and Rbm20, which regulate skNAC pre-mRNA splicing. skNAC silencing induced basal cardiomyocyte hypertrophy, whereas plasmid-mediated overexpression prevented phenylephrine-induced hypertrophy. Cardiomyocyte-specific skNAC deletion induced basal hypertrophy, left ventricular dilation and systolic dysfunction, leading to severe dilated cardiomyopathy and lethality, TAC surgery accelerating this phenotype. At the cellular level, skNAC colocalized with ribosomes at the Z-disks, and its deletion led to sarcomere disorganization and increased autophagic processes. Conclusion Based on our findings, skNAC is essential for preserving sarcomere integrity and cardiomyocyte homeostasis. Loss of skNAC drives maladaptive remodeling leading to heart failure, highlighting its potential as a novel therapeutic target.