Catestatin improves heart metabolic flexibility by promoting mitochondrial structure and function.

Area of Science:

• Cardiovascular Biology
• Metabolic Regulation
• Molecular Cardiology

Background:

• Hypertension is a primary driver of cardiomyopathy and heart failure.
• Cardiomyocyte metabolic inflexibility contributes significantly to heart failure.
• Catestatin (CST) is known for hypotensive and cardioprotective effects, but its impact on cardiac metabolism is unexplored.

Purpose of the Study:

• To investigate the effects of Catestatin (CST) on cardiac metabolism.
• To elucidate the molecular mechanisms underlying CST's cardioprotective actions.
• To identify gene signatures regulated by CST in the context of cardiac function.

Main Methods:

• Transcriptomic analysis using Boolean implication relationships in CST-supplemented CST knockout (CST-KO) mice.
• Validation of gene signatures with public patient datasets.
• Assessment of glucose and fatty acid uptake, immunoprecipitation, mass spectrometry, molecular simulation, and mitochondrial function assays.

Main Results:

• CST treatment rescued cardiac gene signatures in CST-KO mice, involving fibroblasts, cardiomyocytes, and macrophages.
• CST restored metabolic flexibility by shifting cardiac energy utilization from glucose to fatty acids.
• CST binds to ATP synthase, enhancing mitochondrial membrane potential and ATP production.

Conclusions:

• Catestatin (CST) is a key regulator of cardiac metabolism and mitochondrial function.
• CST treatment effectively restores metabolic flexibility in the heart.
• CST demonstrates potential as a therapeutic agent for heart failure by targeting cardiac metabolism.