Cardiac Urea Cycle Activation by Time-Restricted Feeding Protects Against Pressure Overload-Induced Heart Failure

Area of Science:

• Cardiovascular Biology
• Metabolic Regulation
• Nutritional Science

Background:

• Heart failure is a major global health concern requiring new treatments.
• Time-restricted feeding (TRF) shows promise for preventing and treating heart disease.
• The role of amino acids and the urea cycle in cardiac function needs further elucidation.

Purpose of the Study:

• To investigate the cardioprotective effects of TRF in heart failure.
• To explore the mechanisms underlying TRF's benefits, focusing on amino acid metabolism and the urea cycle.
• To assess the relevance of these findings in human patients with cardiac dysfunction.

Main Methods:

• Utilized mouse models of heart failure with different stages.
• Performed metabolomic profiling of circulating and cardiac metabolites.
• Conducted cardiac-specific argininosuccinate lyase (ASL) knockout studies.
• Analyzed arteriovenous gradients of metabolites in human hearts.

Main Results:

• TRF conferred protection against heart failure in mice.
• TRF increased circulating amino acids and activated cardiac amino acid utilization and the urea cycle via ASL.
• Cardiac ASL upregulation by TRF is mediated by transcription factor Yin Yang 1.
• Impaired amino acid utilization and urea cycle activity were observed in human hearts with reduced function.

Conclusions:

• TRF is a potential therapeutic strategy for heart failure.
• The cardiac urea cycle, particularly ASL, plays a vital role in TRF-mediated cardioprotection.
• Restoring amino acid metabolism and urea cycle function may be beneficial for patients with heart failure.