skNAC is a Key Driver of Cardiomyocyte Integrity Against Pathological Cardiac Hypertrophy and Heart Failure

BACKGROUND: Myocardial hypertrophy caused by chronic pressure overload eventually leads to heart failure. Increased protein synthesis and sarcomere reorganization are crucial elements of cardiac remodeling under such conditions. The muscle-specific nascent polypeptide-associated complex alpha isoform (skNAC) is a protein essential for proper sarcomere organization during development. However, its role in hypertrophy and heart failure in adults remains unexplored. We investigated the function of skNAC in pressure overload-induced hypertrophy and heart failure. METHODS: skNAC expression was assessed in neonatal rat ventricular cardiomyocytes (NRVMs) stimulated with phenylephrine, in human cardiac biopsies, and in mice subjected to transverse aortic constriction (TAC) or angiotensin II infusion. The impact of siRNA-mediated skNAC silencing was evaluated in NRVMs, while constitutive and inducible cardiomyocyte-specific skNAC knockout mouse models were generated to examine the long-term effects of skNAC deletion under both basal and TAC conditions. Immunofluorescence confocal microscopy and proximity ligation assay were used to assess skNAC localization and interactions, while electron microscopy was employed to analyze the consequences of skNAC deletion on cardiomyocyte ultrastructure. RESULTS: skNAC expression was reduced in phenylephrine-treated NRVMs and in mice subjected to TAC or angiotensin II, due to decreased expression of the RNA-binding proteins Rbm24 and Rbm20, which regulate skNAC pre-mRNA splicing. Consistently, skNAC expression inversely correlated with cardiac hypertrophy and NT-proBNP levels in humans. Cardiomyocyte-specific skNAC deletion generated basal hypertrophy, severe systolic dysfunction, and premature death, which were further exacerbated by TAC surgery, leading to rapid dilated cardiomyopathy and lethality. skNAC strongly colocalized with ribosomes, and its deletion caused sarcomere disorganization and an autophagic response. Conversely, skNAC overexpression prevented phenylephrine-induced hypertrophy in NRVMs. CONCLUSIONS: Our results demonstrate that skNAC is essential for preserving sarcomere integrity and cardiomyocyte homeostasis. Its downregulation drives pathological remodeling and heart failure, positioning skNAC as a promising therapeutic target.