Metabolic remodeling and cardiac dysfunction in left ventricular noncompaction: Insights from the MYH7 Q315R model

TL;DR

This study explores how a specific genetic mutation in the MYH7 gene causes metabolic changes and heart dysfunction in a mouse model of left ventricular noncompaction.

Contribution

The study introduces a novel mouse model of LVNC with the MYH7 Q315R mutation and reveals new insights into its metabolic pathophysiology.

Findings

Mice with the MYH7 Q315R mutation show impaired heart function and excessive ventricular trabeculations.

Metabolic analysis shows suppressed glycolysis, lipid oxidation, and TCA cycle activity in these mice.

Altered metabolic pathways suggest a shift toward anaerobic glycolysis and impaired nucleic acid synthesis.

Abstract

Left ventricular noncompaction (LVNC) is a form of cardiomyopathy characterized by excessive trabeculation and a thin compacted myocardial layer. Variants in MYH7, which encodes the β-myosin heavy chain, are among the most commonly identified genetic causes of LVNC. Despite its clinical relevance, the metabolic disturbances associated with LVNC remain poorly understood, and the pathophysiological mechanisms have not been investigated in an animal model of MYH7-related LVNC. To address this gap, we generated a mouse model carrying the human MYH7 Gln315Arg (Q315R) variant, a representative mutation linked to LVNC. Mice with the MYH7 Q315R variant exhibited key features of LVNC, including impaired diastolic function, reduced contractility, and excessive trabeculations extending across the ventricular walls. Metabolomic analysis revealed significant metabolic remodeling, characterized by suppressed glycolysis, lipid oxidation, and tricarboxylic acid (TCA) cycle activity. Levels of key intermediates, including glucose-6-phosphate, pyruvate, and acetyl-CoA, were reduced, along with downregulated expression of glycolytic and mitochondrial genes. Additionally, alterations in the pentose phosphate pathway indicated impaired nucleic acid synthesis, while an increased lactate-to-pyruvate ratio suggested a metabolic shift toward anaerobic glycolysis. This study underscores the critical role of metabolic inflexibility—marked by suppression of glycolysis, lipid metabolism, and TCA cycle activity—in the pathophysiology of LVNC. Targeting these dysregulated metabolic pathways, particularly by enhancing mitochondrial function and restoring metabolic adaptability, presents a potential therapeutic strategy for LVNC treatment.

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