Decreased contractility due to energy deprivation in a transgenic rat model of hypertrophic cardiomyopathy.
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-1alpha. 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.
Luedde
Mark
M
Department of Cardiology, University of Heidelberg, Germany.
Flögel
Ulrich
U
Knorr
Maike
M
Grundt
Christina
C
Hippe
Hans-Joerg
HJ
Brors
Benedikt
B
Frank
Derk
D
Haselmann
Uta
U
Antony
Claude
C
Voelkers
Mirko
M
Schrader
Juergen
J
Most
Patrick
P
Lemmer
Bjoern
B
Katus
Hugo A
HA
Frey
Norbert
N
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000235:genetics / Q000503:physiopathology; D002312:Cardiomyopathy, Hypertrophic / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D048429:Cell Size; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004734:Energy Metabolism / Q000235:genetics / Q000502:physiology*; D020869:Gene Expression Profiling; D020022:Genetic Predisposition to Disease; D006801:Humans; D008279:Magnetic Resonance Imaging / Q000379:methods; D008854:Microscopy, Electron; D008929:Mitochondria, Heart / Q000648:ultrastructure; D009119:Muscle Contraction / Q000235:genetics / Q000502:physiology*; D009154:Mutation; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism / Q000502:physiology; D010725:Phosphocreatine / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D055647:Rats, Transgenic; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020107:Troponin T / Q000235:genetics
D020107:Troponin T; D010725:Phosphocreatine; D000255:Adenosine Triphosphate