lncRNA Lockd promotes cardiomyocyte proliferation via Eno1/beta-catenin/Myc axis

Abstract

Neonatal mouse hearts exhibit a transient regenerative capacity that enables recovery from injury and certain pathological stresses; however, their response to pathological hypertrophic stimuli remains poorly defined. Here, we show that neonatal hearts within the regenerative window are protected from isoproterenol-induced pathological hypertrophy and maintain cardiac function, whereas hearts beyond this window develop hypertrophy and functional impairment. Resistance to hypertrophic stress during the regenerative phase was associated with robust cardiomyocyte proliferation, which was largely absent in the non-regenerative phase. Transcriptomic profiling identified the long non-coding RNA Lockd as the most upregulated transcript during the regenerative window, in an E2F1-dependent manner. Cardiomyocyte-specific AAV9-mediated overexpression of Lockd in non-regenerative neonatal hearts attenuated isoproterenol-induced hypertrophy, preserved cardiac function, and restored cardiomyocyte proliferative capacity. Mechanistically, Lockd directly interacted with and stabilized α-enolase (ENO1), leading to enhanced β-catenin stability, nuclear accumulation, and induction of the pro-proliferative target gene Myc. Consistently, Eno1 knockdown impaired β-catenin signaling, Myc expression, and cardiomyocyte proliferation. These findings identify Lockd as a key mediator of regenerative resistance to pathological hypertrophic stress in the neonatal heart.