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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.

SUBMITTER: Cao F

PROVIDER: S-EPMC6954138 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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

Cao Fang F Maguire Mahon L ML McAndrew Debra J DJ Lake Hannah A HA Neubauer Stefan S Zervou Sevasti S Schneider Jürgen E JE Lygate Craig A CA

Basic research in cardiology 20200110 2

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 w ...[more]

PMID: 31925563

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Project description:Muscle ring finger-1 (MuRF1) is a muscle-specific protein implicated in the regulation of cardiac myocyte size and contractility. MuRF2, a closely related family member, redundantly interacts with protein substrates, and hetero-dimerizes with MuRF1. Mice lacking either MuRF1 or MuRF2 are phenotypically normal whereas mice lacking both proteins develop a spontaneous cardiac and skeletal muscle hypertrophy indicating cooperative control of muscle mass by MuRF1 and MuRF2. In order to identify the role that MuRF1 plays in regulating cardiac hypertrophy in vivo, we created transgenic mice expressing increased amounts of cardiac MuRF1. Adult MuRF1 transgenic (Tg+) hearts exhibited a non-progressive thinning of the left ventricular wall and a concomitant decrease in cardiac function. Experimental induction of cardiac hypertrophy by trans-aortic constriction (TAC) induced rapid failure of MuRF1 Tg+ hearts. Microarray analysis identified that the levels of genes associated with metabolism (and in particular mitochondrial processes) were significantly altered in MuRF1 Tg+ hearts, both at baseline and during the development of cardiac hypertrophy. Surprisingly, ATP levels in MuRF1 Tg+ mice did not differ from wild type mice despite the depressed contractility following TAC. To explain this discrepancy between the ongoing heart failure and maintained ATP levels in MuRF1 Tg+ hearts, we compared the level and activity of creatine kinase (CK) between wild type and MuRF1 Tg+ hearts. Although mCK and CK-M/B protein levels were unaffected in MuRF1 Tg+ hearts, total CK activity was significantly inhibited. We conclude that MuRF1’s inhibition of CK activity leads to increased susceptibility to heart failure following TAC, demonstrating for the first time that MuRF1 regulates cardiac energetics in vivo. Keywords: Genetic modification, physiological manipulation. Three-condition experiment, MuRF1 Tg+ vs. WT mice. Biological replicates: 4 WT baseline, 3 MuRF1 Tg+ baseline, cardiac overpressure hypertrophy induced by trans-aortic banding at 1 week (3 WT, 3 MurF Tg) and 4 weeks (3 WT, 3 MurF Tg), hearts harvested. One replicate per array.

Project description:BackgroundAbnormalities in cardiac energy metabolism occur in heart failure (HF) and contribute to contractile dysfunction, but their role, if any, in HF-related pathologic remodeling is much less established. CK (creatine kinase), the primary muscle energy reserve reaction which rapidly provides ATP at the myofibrils and regenerates mitochondrial ADP, is down-regulated in experimental and human HF. We tested the hypotheses that pathologic remodeling in human HF is related to impaired cardiac CK energy metabolism and that rescuing CK attenuates maladaptive hypertrophy in experimental HF.MethodsFirst, in 27 HF patients and 14 healthy subjects, we measured cardiac energetics and left ventricular remodeling using noninvasive magnetic resonance 31P spectroscopy and magnetic resonance imaging, respectively. Second, we tested the impact of metabolic rescue with cardiac-specific overexpression of either Ckmyofib (myofibrillar CK) or Ckmito (mitochondrial CK) on HF-related maladaptive hypertrophy in mice.ResultsIn people, pathologic left ventricular hypertrophy and dilatation correlate closely with reduced myocardial ATP levels and rates of ATP synthesis through CK. In mice, transverse aortic constriction-induced left ventricular hypertrophy and dilatation are attenuated by overexpression of CKmito, but not by overexpression of CKmyofib. CKmito overexpression also attenuates hypertrophy after chronic isoproterenol stimulation. CKmito lowers mitochondrial reactive oxygen species, tissue reactive oxygen species levels, and upregulates antioxidants and their promoters. When the CK capacity of CKmito-overexpressing mice is limited by creatine substrate depletion, the protection against pathologic remodeling is lost, suggesting the ADP regenerating capacity of the CKmito reaction rather than CK protein per se is critical in limiting adverse HF remodeling.ConclusionsIn the failing human heart, pathologic hypertrophy and adverse remodeling are closely related to deficits in ATP levels and in the CK energy reserve reaction. CKmito, sitting at the intersection of cardiac energetics and redox balance, plays a crucial role in attenuating pathologic remodeling in HF. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT00181259.

Project description:BACKGROUND:The role of coronary microvascular disease and its impact on functional and energetic reserve in heart failure with preserved ejection fraction (HFpEF) remains unclear. We hypothesized that in response to submaximal pharmacologic stress (dobutamine), patients with HFpEF have impairment in left ventricular (LV) myocardial mechanical (external work [EW]), energetic (myocardial O2 consumption [MVO2]), and myocardial blood flow (MBF) reserve. We further assessed whether coupling of MBF to EW is impaired in HFpEF and associated with compensatory increases or pathological decreases in myocardial O2 extraction. Lastly, we assessed whether coupling of MVO2 to EW (mechanical efficiency) was impaired in HFpEF. METHODS AND RESULTS:In prospectively enrolled patients with HFpEF (n=19) and age/sex-matched healthy controls (n=19), we performed 11C-acetate positron emission tomography assessing MVO2 and MBF at rest and during dobutamine infusion. EW was calculated as stroke volume (echo)×end-systolic pressure×heart rate. At rest, compared with controls, patients with HFpEF had higher LV EW, MVO2, and MBF. With dobutamine, LV EW, MVO2, and MBF increased in both HFpEF and controls; however, the magnitude of increases was significantly smaller in HFpEF. In both groups, MBF increased in relation to EW, but in HFpEF, the slope of the relationship was significantly smaller than in controls. Myocardial O2 extraction was increased in HFpEF. Mechanical efficiency was similar in HFpEF and controls. In a post hoc analysis, HFpEF patients with LV hypertrophy (n=10) had significant reductions in LV mechanical efficiency relative to controls. CONCLUSIONS:In HFpEF during submaximal dobutamine stress, there is myocardial mechanical-, energetic- and flow-reserve dysfunction with impaired coupling of blood flow to demand and slight increases in myocardial O2 extraction. These findings provide evidence that coronary microvascular dysfunction is present in HFpEF, limits O2 supply relative to demand, and is associated with reserve dysfunction.

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

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

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