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

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.

• Authors: Fang Cao, Mahon L Maguire, Debra J McAndrew, Hannah A Lake, Stefan Neubauer, Sevasti Zervou, Jürgen E Schneider, Craig A Lygate
• Journal: Basic research in cardiology (Basic Res Cardiol) Vol. 115 Issue 2 Pg. 12 (01 10 2020) ISSN: 1435-1803 [Electronic] Germany
• PMID: 31925563 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Creatine Kinase, Mitochondrial Form

Topics

• Animals
• Chronic Disease
• Creatine Kinase, Mitochondrial Form (genetics, metabolism)
• Disease Models, Animal
• Energy Metabolism
• Heart Failure (enzymology, genetics, pathology, physiopathology)
• Hypertrophy, Left Ventricular (enzymology, genetics, pathology, physiopathology)
• Male
• Mice, Inbred C57BL
• Mice, Transgenic
• Mitochondria, Heart (enzymology, genetics, pathology)
• Myocytes, Cardiac (enzymology, pathology)
• Signal Transduction
• Ventricular Dysfunction, Left (enzymology, genetics, pathology, physiopathology)
• Ventricular Function, Left
• Ventricular Remodeling