dATP elevation induces myocardial metabolic remodeling to support improved cardiac function.

Area of Science:

• Cardiovascular Biology
• Mitochondrial Metabolism
• Molecular Cardiology

Background:

• Systolic heart failure is characterized by reduced myocardial contractility and impaired metabolic flexibility.
• Elevated deoxy ATP (dATP) in cardiomyocytes (CMs) has shown potential to improve contractility.
• The impact of dATP elevation on cardiac metabolism remained largely unexplored.

Purpose of the Study:

• To investigate the effects of elevated deoxy ATP (dATP) on cardiac metabolism and function.
• To explore the potential of proteolysis-resistant ribonucleotide reductase (RNR) for therapeutic applications in heart failure.
• To elucidate the mechanisms by which dATP influences cardiomyocyte contractility and metabolic flexibility.

Main Methods:

• Development of proteolysis-resistant versions of ribonucleotide reductase (RNR) for sustained dATP elevation.
• Generation of a transgenic mouse model (TgRRB) with elevated dATP levels in cardiomyocytes.
• Utilized pharmacological approaches and targeted metabolomic profiling to assess cardiac function and metabolism.
• Examined mitochondrial structure, specifically cristae density and activity, using electron microscopy.

Main Results:

• TgRRB mice exhibited robust improvement in cardiac function with dATP/ATP levels elevated to approximately 1%.
• Elevated dATP in CMs increased basal respiratory rates by promoting more active myosin states.
• Metabolomic analysis revealed a significant shift towards oxidative phosphorylation in TgRRB-CMs.
• Increased mitochondrial cristae density and activity correlated with enhanced respiratory capacity.

Conclusions:

• Deoxy ATP (dATP) plays a critical role in modulating myosin states, thereby enhancing cardiomyocyte contractility.
• Elevated dATP induces metabolic flexibility in cardiomyocytes, promoting a shift towards oxidative phosphorylation.
• Targeting dATP levels presents a promising therapeutic strategy for improving cardiac function in heart failure.