Cardiac Over-Expression Of Creatine Kinase Improves Function In Failing Myocytes

Aims: Abnormal energy metabolism contributes to heart failure (HF) and the failing heart is energy starved. Here we tested whether augmented CK energy metabolism improves myocyte dysfunction in experimental HF. Methods and Results: We tested the response to the β-agonist isoproterenol (2.5 nM, ISO) in cardiomyocytes isolated from wild-type (WT) mice and mice over-expressing cardiac myofibrillar and mitochondrial CK (CK-M and CK-mito) from sham and HF (8 wk transverse aortic constriction, TAC) hearts, to dissect whether over-expressing CK-M or CK-mito might alter myocyte function at baseline or after an increase in energetic demand. At baseline, there were no differences in sarcomere fractional shortening (FS) or whole Ca2+ transient amplitude in response to ISO among sham WT, CK-M or CK-mito myocytes. However, ISO impact on FS, Ca2+ transient, time to 50 Ca2+ decay, and sarcomere re-lengthening were all reduced in WT TAC hearts, consistent with prior reports. Conversely, over-expressing CK-M or CK-mito rescued ISO-induced inotropy in TAC myocytes. No sizable differences in ISO response were noticed in cells obtained from sham WT, CK-M or CK-mito hearts. To test whether over-expressing CK-M or CK-mito confers a degree of protection against acute oxidative stress, non-TAC myocytes were exposed to H2O2 (50 μM for 10 min). The interval between the beginning of H2O2 superfusion and the appearance of an irreversible arrhythmia was measured. WT and CK-M myocytes showed a similar response (359±87s vs. 370±60s, n=5), whereas in CK-mito this interval was prolonged (580±74s). Conclusions: Over-expressing CK-M and CK-mito under failing-TAC conditions improves myocyte contraction and relaxation, likely through preserved Ca2+ handling; however, only the up-regulation of CK-mito can effectively buffer ROS, especially those of mitochondrial origin.