Abstract 12652: Creatine Kinase Over-expression Improves ATP Kinetics in Failing Hypertrophied Hearts
Although reduced rates of ATP synthesis through the creatine kinase (CK) reaction, the primary myocardial energy reservoir, are observed in hypertrophied and failing hearts (HF), prior pharmacologic attempts to augment depressed CK metabolites have failed to improve energy delivery. We generated mice that overexpress the myofibrillar isoform of CK (CKM) in cardiac-specific, conditional fashion to test the hypothesis that enhanced CK activity increases ATP delivery via CK in HF. CKM mice were generated using a tet-off system and fed a diet containing doxycycline (650mg/kg diet). Gene induction was achieved by termination of doxycycline diet four weeks prior to the study. Pressure-overload hypertrophy was induced surgically in control and CKM mice by thoracic aortic constriction (TAC). A combination of biochemical assays and 31P nuclear magnetic resonance magnetization transfer at 11.75T were used to measure cardiac phosphocreatine/ATP ratio (PCr/ATP), pseudo first-order rate constant (kf) of the forward CK reaction, the rate of ATP synthesis via CK (CK flux), and CK activity in isolated, perfused hearts. In the absence of TAC (no-TAC), CKM hearts had three-fold higher kf, CK flux and CK activity compared to control hearts with no significant differences in PCr/ATP (Table). Nine weeks post-TAC, PCr/ATP, kf, CK flux and CK activity were reduced in control-TAC vs. no-TAC, while TAC-CKM hearts had significantly higher PCr/ATP, kf, CK flux and CK activity than control-TAC despite a comparable degree of ventricular hypertrophy. These observations demonstrate that augmenting CK expression offers a strategy for improving cardiac ATP kinetics and limiting energy depletion in pressure-overload hypertrophy.
- © 2010 by American Heart Association, Inc.