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An increase in the myocardial PCr/ATP ratio in GLUT4 null mice
Robert G Weiss1, John C Chatham, Dimitrios Georgakopolous
1Cardiology Division, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. rgweiss@rad.jhu.edu
Insights
Transgenic mice lacking GLUT4 (G4N) showed a 60% increase in heart creatine phosphate to ATP ratio (PCr/ATP). This novel finding in cardiac energetics suggests a new genetic approach for boosting myocardial creatine levels.
Area of Science:
- Biochemistry
- Cardiovascular Physiology
- Molecular Biology
Background:
- Myocardial high-energy phosphates, adenosine triphosphate (ATP) and creatine phosphate (PCr), are crucial for cardiac function.
- The PCr/ATP ratio is typically conserved but decreases in pathological conditions like ischemia and heart failure.
- No previous reports documented an increased cardiac PCr/ATP ratio.
Purpose of the Study:
- To investigate the in vivo cardiac energetics in transgenic mice lacking glucose transporter type 4 (G4N).
- To determine if the absence of GLUT4 affects myocardial high-energy phosphate levels, specifically the PCr/ATP ratio.
- To explore novel mechanisms for modulating myocardial energy metabolism.
Main Methods:
- Studied in vivo energetics in GLUT4-deficient (G4N) mice and wild-type (WT) littermates.
- Utilized three different experimental settings, including intact animals, to confirm findings.
- Measured myocardial creatine (CR), ATP, ADP, and phosphocreatine (PCr) concentrations.
Main Results:
- G4N mice exhibited a significant 60% increase in the myocardial PCr/ATP ratio compared to WT mice.
- This increase was cardiac-specific and attributed to elevated total cardiac creatine concentrations in G4N.
- Levels of ATP, ADP, and calculated free energy of ATP hydrolysis (-DG(-ATP)) remained unchanged between G4N and WT mice.
- Expression of the creatine transporter (CreaT) was preserved in G4N cardiac tissue.
Conclusions:
- G4N mice demonstrate a unique, significant elevation in the cardiac PCr/ATP ratio.
- This finding suggests a novel genetic strategy for increasing myocardial creatine levels.
- The preserved creatine transport indicates that elevated creatine levels are due to intrinsic factors within the G4N model.
Abstract:
ATP and creatine phosphate (PCr) are prime myocardial high-energy phosphates. Their relative concentrations are conserved among mammalian species and across a range of physiologic cardiac workloads. The cardiac PCr/ATP ratio is decreased with several pathologic conditions, such as ischemia and heart failure, but there are no reports of an increase in the cardiac PCr/ATP ratio in any species or with interventions. We studied the in vivo energetics in transgenic mice lacking expression of the glucose transport protein GLUT4 (G4N) and observed a significant 60% increase in the myocardial PCr/ATP ratio in G4N that was confirmed in three different experimental settings including intact animals. The higher PCr/ATP in G4N is cardiac-specific and is due to higher total cardiac creatine (CR) concentrations in G4N than in wild-type (WT). However, [ATP], [ADP], and -DG(-ATP) did not differ between the strains. Expression of the creatine transport protein (CreaT) that is responsible for creatine uptake in myocytes was preserved in G4N cardiac tissue. These observations demonstrate, for the first time to our knowledge, that G4N manifest a unique increase in the cardiac PCr/ATP ratio, which suggests a novel genetic strategy for increasing myocardial creatine levels.