Overexpression of mitochondrial creatine kinase preserves cardiac energetics without ameliorating murine chronic heart failure

Fang Cao,Craig A Lygate,Mahon L Maguire,Sevasti Zervou,Debra J Mcandrew,Jürgen E Schneider,Stefan Neubauer,Hannah A Lake

doi:10.1007/s00395-020-0777-3

Abstract

Mitochondrial creatine kinase (Mt-CK) is a major determinant of cardiac energetic status and is down-regulated in chronic heart failure, which may contribute to disease progression. We hypothesised that cardiomyocyte-specific overexpression of Mt-CK would mitigate against these changes and thereby preserve cardiac function. Male Mt-CK overexpressing mice (OE) and WT littermates were subjected to transverse aortic constriction (TAC) or sham surgery and assessed by echocardiography at 0, 3 and 6 weeks alongside a final LV haemodynamic assessment. Regardless of genotype, TAC mice developed progressive LV hypertrophy, dilatation and contractile dysfunction commensurate with pressure overload-induced chronic heart failure. There was a trend for improved survival in OE-TAC mice (90% vs 73%, P = 0.08), however, OE-TAC mice exhibited greater LV dilatation compared to WT and no functional parameters were significantly different under baseline conditions or during dobutamine stress test. CK activity was 37% higher in OE-sham versus WT-sham hearts and reduced in both TAC groups, but was maintained above normal values in the OE-TAC hearts. A separate cohort of mice received in vivo cardiac 31P-MRS to measure high-energy phosphates. There was no difference in the ratio of phosphocreatine-to-ATP in the sham mice, however, PCr/ATP was reduced in WT-TAC but preserved in OE-TAC (1.04 ± 0.10 vs 2.04 ± 0.22; P = 0.007). In conclusion, overexpression of Mt-CK activity prevented the changes in cardiac energetics that are considered hallmarks of a failing heart. This had a positive effect on early survival but was not associated with improved LV remodelling or function during the development of chronic heart failure.

Highlights

Effective treatments for chronic heart failure often act to reduce cardiac energy demand by lowering afterload and/ or heart rate (e.g. β-adrenergic antagonists, ACE inhibitors and diuretics)
Total creatine kinase activity was 37% higher in overexpressing mice (OE)-sham compared to WT-sham hearts (Table 1)
Values were lower in both transverse aortic constriction (TAC) groups, but only in OE hearts was total creatine kinase (CK) activity maintained above normal WT levels

Summary

Introduction

Effective treatments for chronic heart failure often act to reduce cardiac energy demand by lowering afterload and/ or heart rate (e.g. β-adrenergic antagonists, ACE inhibitors and diuretics). PCr is relatively smaller and less polar than ATP allowing it to accumulate to higher levels and act as an energy transport and buffering system, capable of regenerating ATP when demand outstrips supply. This reaction is catalysed by cytosolic CK isoforms, such as muscle (M-CK), that are often functionally coupled to major ATP-using enzymes (e.g. myosin ATPase, SERCA) [40]

Methods

Results

Conclusion