Creatine kinase overexpression improves ATP kinetics and contractile function in postischemic myocardium

Area of Science:

• Biochemistry
• Cardiovascular Physiology
• Molecular Biology

Background:

• Myocardial ischemia reduces adenosine triphosphate (ATP) availability, limiting post-ischemic mechanical function.
• Creatine kinase (CK) is crucial for maintaining cardiac energy reserves.
• Augmenting ATP synthesis during and after ischemia is challenging.

Purpose of the Study:

• To test if overexpressing the myofibrillar isoform of creatine kinase (CKM) in the heart improves ATP delivery in ischemic-reperfused hearts.
• To determine if CKM overexpression enhances functional recovery after ischemia.

Main Methods:

• Isolated, retrograde-perfused hearts from control and CKM-overexpressing mice were subjected to global ischemia and reperfusion.
• Cardiac function (rate pressure product, RPP) was monitored.
• Phosphorus-31 nuclear magnetic resonance ((31)P-NMR) and biochemical assays measured CK flux and intracellular pH (pH(i)).

Main Results:

• Baseline CK flux was significantly higher in CKM hearts.
• End-ischemic pH(i) was higher in CKM hearts, indicating reduced acidosis.
• Post-ischemic phosphocreatine, CK flux, and functional recovery (RPP) were significantly improved in CKM hearts, with reduced lactate dehydrogenase release.

Conclusions:

• Augmenting cardiac CKM expression attenuates ischemic acidosis and reduces injury.
• Increased CKM improves high-energy phosphate content and CK ATP synthesis rate in post-ischemic myocardium.
• CKM overexpression significantly enhances the recovery of contractile function in ischemic-reperfused hearts.