Myosin Light-Chain 4 Gene-Transfer Attenuates Atrial Fibrosis While Correcting Autophagic Flux Dysregulation

Authors

Yuan Zhong
Kai Tang
Stanley Nattel
Ming Zhai
Shiyu Gong
Qing Yu
Yanxi Zeng
Guangxi E
Nuerbiyemu Maimaitiaili
Jun Wang
Yawei Xu
Wenhui Peng
Hailing Li

Publication Date

4-1-2023

Journal

Redox Biology

Abstract

OBJECTIVES: To determine the role of MYL4 regulation of lysosomal function and its disturbance in fibrotic atrial cardiomyopathy.

BACKGROUND: We have previously demonstrated that the atrial-specific essential light chain protein MYL4 is required for atrial contractile, electrical, and structural integrity. MYL4 mutation/dysfunction leads to atrial fibrosis, standstill, and dysrhythmia. However, the underlying pathogenic mechanisms remain unclear.

METHODS AND RESULTS: Rats subjected to knock-in of a pathogenic MYL4 mutant (p.E11K) developed fibrotic atrial cardiomyopathy. Proteome analysis and single-cell RNA sequencing indicate enrichment of autophagy pathways in mutant-MYL4 atrial dysfunction. Immunofluorescence and electron microscopy revealed undegraded autophagic vesicles accumulated in MYL4

CONCLUSIONS: MYL4 regulates autophagic flux in atrial cardiomyocytes via lysosomal mobility. MYL4 overexpression attenuates MYL4 p.E11K induced fibrotic atrial cardiomyopathy, while correcting autophagy and lysosomal function. These results provide a molecular basis for MYL4-mutant induced fibrotic atrial cardiomyopathy and identify a potential biological-therapy approach for the treatment of atrial fibrosis.

Keywords

Animals, Rats, Atrial Fibrillation, Autophagy, Cardiomyopathies, Fibrosis, Lysosomes, Myosin Light Chains, Myosins

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Associated Data

PMID: 36645977