Abstract
Hypertrophic cardiomyopathy (HCM) is associated with cardiac hypertrophy, diastolic dysfunction, and sudden death. Recently, it has been suggested that inefficient energy utilization could be a common molecular pathway of HCM-related mutations. We have previously generated transgenic Sprague–Dawley rats overexpressing a truncated cardiac troponin T (DEL-TNT) molecule, displaying typical features of HCM such as diastolic dysfunction and an increased susceptibility to ventricular arrhythmias. We now studied these rats using 31P magnetic resonance spectroscopy (MRS). MRS demonstrated that cardiac energy metabolism was markedly impaired, as indicated by a decreased phosphocreatine to ATP ratio (−31%, p < 0.05). In addition, we assessed contractility of isolated cardiomyocytes. While DEL-TNT and control cardiomyocytes showed no difference under baseline conditions, DEL-TNT cardiomyocytes selectively exhibited a decrease in fractional shortening by 28% after 1 h in glucose-deprived medium (p < 0.05). Moreover, significant decreases in contraction velocity and relaxation velocity were observed. To identify the underlying molecular pathways, we performed transcriptional profiling using real-time PCR. DEL-TNT hearts exhibited induction of several genes critical for cardiac energy supply, including CD36, CPT-1/-2, and PGC-1α. Finally, DEL-TNT rats and controls were studied by radiotelemetry after being stressed by isoproterenol, revealing a significantly increased frequency of arrhythmias in transgenic animals. In summary, we demonstrate profound energetic alterations in DEL-TNT hearts, supporting the notion that inefficient cellular ATP utilization contributes to the pathogenesis of HCM.
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Acknowledgements
The authors thank Ulrike Oehl and Jutta Krebs for their excellent technical support.
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N.F. was supported by the Bundesministerium für Bildung und Forschung, Germany (Nationales Genomforschungsnetz: NGFN2 and NGFNplus: 01650836), U.F. and J.S. were supported by the SFB 612 “Molekulare Analyse kardiovaskulärer Funktionen and Funktionsstörungen”, Teilprojekt Z2, and the DFG project SCHR154/9.
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Supplemental Figure
Stimulation of WT and DEL-TNT cardiomyocytes with 10 nm isoproterenol [ISO] led to a significant increase of fractional shortening in WT and DEL-TNT cardiomyocytes. After 1 h of glucose depletion, DEL-TNT cells that were stimulated with isoproterenol revealed a significant decrease in fractional shortening (−47% ± 6.2%) that was comparable to the decrease of FS in DEL-TNT CMs that were not stimulated with ISO (−46% ± 9.8%). In contrast, WT CMs revealed no significant decrease in FS after 1-h glucose depletion with or without ISO stimulation. Data are mean values ± SEM. *p < 0.05, †p < 0.01, ‡p < 0.001 (DOC 20.0 kb)
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Luedde, M., Flögel, U., Knorr, M. et al. Decreased contractility due to energy deprivation in a transgenic rat model of hypertrophic cardiomyopathy. J Mol Med 87, 411–422 (2009). https://doi.org/10.1007/s00109-008-0436-x
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DOI: https://doi.org/10.1007/s00109-008-0436-x