The RNA-binding protein Quaking is essential for cardiac homeostasis and function by regulating Morf4l2 splicing

Area of Science:

• Cardiovascular Biology
• Molecular Cardiology
• RNA Splicing Mechanisms

Background:

• Reduced Qki levels are observed in failing human and mouse hearts, suggesting a role in cardiac disease.
• The precise molecular and functional consequences of Qki downregulation in adult heart tissue are not well understood.

Purpose of the Study:

• To investigate the impact of Qki knockdown on adult heart function and molecular pathways.
• To elucidate the mechanism by which Qki deficiency leads to cardiac pathology.

Main Methods:

• Adeno-associated virus serotype 9 (AAV9)-mediated short hairpin RNA (shRNA) delivery to knock down Qki in adult mouse hearts.
• Global transcriptomic analysis (RNA-seq) to identify dysregulated splicing events.
• Analysis of MORF4L2 splicing in human heart RNA-seq datasets.
• Experimental models of cardiac cachexia induced by colon cancer.

Main Results:

• Qki knockdown in adult mice resulted in rapid cardiac malfunction, atrophy, apoptosis, heart failure, and death.
• Significant dysregulation of 996 alternative splicing events was observed, including the exclusion of Morf4l2 exon 3, leading to increased Morf4l2Δex3.
• Lower MORF4L2 exon 3 splice junction counts correlated with lower QKI levels in human hearts.
• Knockdown of Morf4l2Δex3 rescued Qki knockdown-induced cardiac cachexia and improved cardiac function.
• Morf4l2Δex3 was elevated in a cancer-induced cardiac cachexia model, and its inhibition ameliorated cardiac cachexia.

Conclusions:

• Qki knockdown in the adult heart induces cardiac cachexia through aberrant Morf4l2 splicing.
• Targeting Morf4l2Δex3 demonstrates therapeutic potential for inhibiting cancer-induced cardiac cachexia.