In vivo creatine kinase reaction kinetics at rest and stress in type II diabetic rat heart

Abstract

The effects of type II diabetes on cardiac creatine kinase (CK) enzyme activity and/or flux are unknown. We therefore measured steady‐state phosphocreatine (PCr) and adenosine triphosphate (ATP) content and forward CK reaction kinetic parameters in Zucker Diabetic Fatty (ZDF) rat hearts, a type II diabetes research model. At baseline the PCr to ATP ratio (PCr/ATP) was significantly lower in diabetic heart when compared with matched controls (1.71 ± 0.21 vs. 2.26 ± 0.24, P < 0.01). Furthermore, the forward CK reaction rate constant (kf) was higher in diabetic animals (0.52 ± 0.09 s−1 vs. 0.35 ± 0.06 s−1, P < 0.01) and CK flux calculated as a product of PCr concentration ([PCr]) and kf was similar between two groups (4.32 ± 1.05 μmol/g/s vs. 4.94 ± 1.23 μmol/g/s, P = 0.20). Dobutamine administration resulted in similar increases in heart rate (~38%) and kf (~0.12 s−1) in both groups. No significant change in PCr and ATP content was observed with dobutamine. In summary, our data showed reduced PCr/ATP in diabetic myocardium as an indicator of cardiac energy deficit. The forward CK reaction rate constant is elevated at baseline which might reflect a compensatory mechanics to support energy flux through the CK shuttle and maintain constant ATP supply. When hearts were stimulated similar increase in kf was observed in both groups thus it seems that CK shuttle does not limit ATP supply for the range of workload studied.

Decreased ATP production and myocardial contractile reserve in metabolic heart disease

“…Of note, our findings are consistent with those of Bashir et al [34], who likewise found that the forward CK reaction rate constant was higher and CK flux was preserved in hearts from diabetic Zucker Diabetic Fatty (ZDF) rats. Taken together with the findings in the ZDF rat, our data suggest that a decrease in CK activity is not a major driver of cardiac energetic deficiency in the cardiomyopathy of MHD, but rather, support the thesis proposed by Bashir et al [34] that the increase in the CK rate constant is a compensatory response that helps to maintain a normal flux through CK in the face of a decrease in [PCr] [34]. Interestingly, in other models of HFpEF such as pressure overload [48] and hypertrophic cardiomyopathy [47] CK flux is decreased, suggesting that the energetic profile in “HFpEF” may be heterogeneous and related to the underlying etiology.…”

“…[PCr] and the [PCr]/[ATP] ratio are decreased in animal models of systolic heart failure [30-32] and humans with systolic failure due to dilated cardiomyopathy [32,33]. More limited data suggest that [PCr] is also decreased in animals [34] and humans with MHD due to type 2 diabetes [35] or obesity [8]. The functional importance of a decrease in [PCr] has been linked to a thermodynamic limitation for Ca 2+ handling [24,27].…”

“…Likewise, [PCr] is decreased in MHD, suggesting that an energy deficiency also exists in MHD [10,12,34,41]. However, it is not known whether the energy deficit in MHD, as reflected by a decrease in [PCr], is sufficient to contribute to pump dysfunction.…”

Rapid, ‐insensitive, dual‐band quasi‐adiabatic saturation transfer with optimal control for complete quantification of myocardial ATP flux

“…The results of the experimental studies conducted here nevertheless are in quantitative agreement with previously reported values of : our compares to in the in vivo healthy control rat heart 7 and in the healthy human heart 11 . For concentrations, we have [PCr] = 11.58 ± 0.69 mM vs 11.5 ± 1.01 mM 34 and [ATP]=7.31 ± 0.52 mM versus 6.75 ± 0.5 mM in perfused rat heart.…”

“…However, while the use of saturation transfer experiments can provide quantitative measurements of , and and , it is the forward CK flux reaction that has been extensively studied in the heart, in part owing to the poor SNR of cardiac 31 P‐MRS wherein PCr, having the highest SNR, provides the most accessible readout in the saturation transfer experiment in clinical settings. This remains highly biologically relevant because metabolic dysregulation plays a key role in common heart diseases, 4 and as a consequence, the forward CK rate constant has additionally been associated with cardiac metabolic health, with reductions in reported in conditions ranging from obesity 5,6 and diabetes 7 to heart failure 8,9 and myocardial infarction 10 . Thus far, this is the only rate constant currently routinely measurable in the human heart in vivo.…”