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Creatine kinase–mediated improvement of function in failing mouse hearts provides causal evidence the failing heart is energy starved
Ashish Gupta, … , Gary Gerstenblith, Robert G. Weiss
Ashish Gupta, … , Gary Gerstenblith, Robert G. Weiss
Published December 27, 2011
Citation Information: J Clin Invest. 2012;122(1):291-302. https://doi.org/10.1172/JCI57426.
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Research Article Cardiology

Creatine kinase–mediated improvement of function in failing mouse hearts provides causal evidence the failing heart is energy starved

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Abstract

ATP is required for normal cardiac contractile function, and it has long been hypothesized that reduced energy delivery contributes to the contractile dysfunction of heart failure (HF). Despite experimental and clinical HF data showing reduced metabolism through cardiac creatine kinase (CK), the major myocardial energy reserve and temporal ATP buffer, a causal relationship between reduced ATP-CK metabolism and contractile dysfunction in HF has never been demonstrated. Here, we generated mice conditionally overexpressing the myofibrillar isoform of CK (CK-M) to test the hypothesis that augmenting impaired CK-related energy metabolism improves contractile function in HF. CK-M overexpression significantly increased ATP flux through CK ex vivo and in vivo but did not alter contractile function in normal mice. It also led to significantly increased contractile function at baseline and during adrenergic stimulation and increased survival after thoracic aortic constriction (TAC) surgery–induced HF. Withdrawal of CK-M overexpression after TAC resulted in a significant decline in contractile function as compared with animals in which CK-M overexpression was maintained. These observations provide direct evidence that the failing heart is “energy starved” as it relates to CK. In addition, these data identify CK as a promising therapeutic target for preventing and treating HF and possibly diseases involving energy-dependent dysfunction in other organs with temporally varying energy demands.

Authors

Ashish Gupta, Ashwin Akki, Yibin Wang, Michelle K. Leppo, V.P. Chacko, D. Brian Foster, Viviane Caceres, Sa Shi, Jonathan A. Kirk, Jason Su, Shenghan Lai, Nazareno Paolocci, Charles Steenbergen, Gary Gerstenblith, Robert G. Weiss

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Figure 7

Functional response to adrenergic stress.

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Functional response to adrenergic stress.
Effects of dobutamine stress o...
Effects of dobutamine stress on heart rate (HR; A and B), EF (C and D), and LV ESV (E and F) in sham (A, C, and E) and TAC animals (B, D, and F) in both control (gray bars) and CK-M “on” (black bars) animals (n = 6–10 in each group). The change induced by dobutamine (as percentage of baseline values) is shown in the right plot of each panel. Note that although the contractile response of control and CK-M overexpressing animals was similar under sham conditions (A, C, and E), the dobutamine-induced changes in mean EF and ESV were significantly greater in CK-M TAC hearts than in control TAC hearts (B, D, and F). Results are mean ± SD. ‡P < 0.005, **P < 0.001.
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