Lnc-mg regulates cardiomyocyte contraction and promotes functional recovery after ischemic injury

Abstract

Aim: Persistent loss of cardiomyocyte contractile function is a major driver of cardiac dysfunction following myocardial infarction (MI). Long noncoding RNAs (lncRNAs) have emerged as important regulators of cardiac biology, yet their contribution to maintenance of myocardial contractility remains incompletely understood. To address this question, we investigated the role of the muscle-enriched lncRNA lnc-mg in cardiomyocyte contractility and its underlying molecular basis.

Methods: Ardiomyocyte-specific lnc-mg knockout mice were generated to investigate the physiological function of lnc-mg in the heart. Cardiac function, exercise capacity, myocardial tissue contractility, and single-cardiomyocyte contractility were assessed by echocardiography, treadmill testing, the Myostation-intact system, and the IonOptix platform, respectively. RNA-seq of myocardial tissue, bioinformatic prediction, RNA immunoprecipitation, molecular docking, immunofluorescence, and analysis of published cardiac MBNL1 CLIP-seq data were used to investigate the underlying molecular mechanism. Finally, Adeno-associated virus 9 (AAV9)-mediated overexpression of lnc-mg in cardiomyocytes was evaluated in a mouse model of MI.

Results:Lnc-mg was highly enriched in cardiomyocytes and progressively increased during postnatal cardiac development. Cardiomyocyte-specific deletion of lnc-mg impaired left ventricular systolic function, exercise capacity, and contractility at both the myocardial tissue and single-cardiomyocyte levels. Consistent with these functional abnormalities, lnc-mg deficiency was accompanied by coordinated suppression of gene programs governing sarcomere organization, myofibril assembly, actomyosin organization, and muscle contraction. MBNL1 was identified as an lnc-mg-associated RNA-binding protein. The nuclear localization of MBNL1 was reduced following lnc-mg deficiency, and MBNL1-bound cardiac transcripts are enriched for cardiomyocyte contractile gene programs. Importantly, AAV9-mediated lnc-mg overexpression in cardiomyocytes preserved cardiac systolic function, attenuated chronic fibrotic remodeling, and improved myocardial tissue contractility after MI.

Conclusion: Our study identifies lnc-mg as a previously unrecognized regulator of cardiomyocyte contractile function and suggests that an lnc-mg-MBNL1-associated mechanism may contribute to the maintenance of cardiac contractile gene programs. These observations provide a rationale for further investigation of lnc-mg as a potential therapeutic target for preserving myocardial contractility after ischemic injury.

Keywords

Long non-coding RNA / myocardial infarction / myocardial contractility / cardiac function

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