The creatine kinase energy transport system in the failing mouse heart

Abstract

Characteristic alterations of the creatine kinase (CK) system are found in animal models of heart failure and in man, and may contribute to contractile dysfunction. Despite widespread use, such changes have yet to be described in the mouse. We therefore examined mouse models of transverse aortic constriction (TAC) and of coronary artery ligation (CAL) and measured CK system changes during hypertrophy and heart failure development. Methods and results: C57BL/6 mice were subjected to TAC or sham surgery and sacrificed after 2–10 weeks according to echocardiographic criteria of myocardial hypertrophy and function. Echocardiographic and haemodynamic indices showed clear progression from normal to heart failure. However, only mice with established congestive heart failure had LV total creatine concentration and total CK activity significantly lower than sham (11% and 30% lower respectively). There were corresponding decreases in the activities of the mito-, MM-, and MB-CK isozymes, while the BB isoform remained unchanged. To determine whether these changes were model specific, a second cohort of mice were subjected to CAL or sham operation and followed for 4–8 weeks. Quantitative changes in total creatine, total CK activity, Mito-CK and MM-CK activities were similar between CAL and TAC mice. Quantitative analysis of mRNA by real-time PCR indicated a decrease in creatine transporter gene expression, which may provide a mechanism for the reduced total creatine concentration. We conclude that mice are a suitable model for studying the relationship between the CK system and heart failure, with qualitative changes similar to those occurring in larger animals and man.