Mitochondrial creatine kinase is critically necessary for normal myocardial high-energy phosphate metabolism.
The individual functional significance of the various creatine kinase (CK) isoenzymes for myocardial energy homeostasis is poorly understood. Whereas transgenic hearts lacking the M subunit of CK (M-CK) show unaltered cardiac energetics and left ventricular (LV) performance, deletion of M-CK in combination with loss of sarcomeric mitochondrial CK (ScCKmit) leads to significant alterations in myocardial high-energy phosphate metabolites. To address the question as to whether this alteration is due to a decrease in total CK activity below a critical threshold or due to the specific loss of ScCKmit, we studied isolated perfused hearts with selective loss of ScCKmit (ScCKmit(-/-), remaining total CK activity approximately 70%) using (31)P NMR spectroscopy at two different workloads. LV performance in ScCKmit(-/-) hearts (n = 11) was similar compared with wild-type hearts (n = 9). Phosphocreatine/ATP, however, was significantly reduced in ScCKmit(-/-) compared with wild-type hearts (1.02 +/- 0.05 vs. 1.54 +/- 0.07, P < 0.05). In parallel, free [ADP] was higher (144 +/- 11 vs. 67 +/- 7 microM, P < 0.01) and free energy release for ATP hydrolysis (DeltaG(ATP)) was lower (-55.8 +/- 0.5 vs. -58.5 +/- 0.5 kJ/mol, P < 0.01) in ScCKmit(-/-) compared with wild-type hearts. These results demonstrate that M- and B-CK containing isoenzymes are unable to fully substitute for the loss of ScCKmit. We conclude that ScCKmit, in contrast to M-CK, is critically necessary to maintain normal high-energy phosphate metabolite levels in the heart.
Department of Medicine, Medical University of Würzburg, Josef-Schneider Strasse 2, 97070 Würzburg, Germany. spindler@mail.uni-wuerzburg.de
Matthias
M
Spindler
Reinhard
R
Niebler
Helga
H
Remkes
Michael
M
Horn
Titus
T
Lanz
Stefan
S
Neubauer
D000818:Animals; D002304:Cardiac Pacing, Artificial; D003402:Creatine Kinase / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D052281:Creatine Kinase, Mitochondrial Form; D004734:Energy Metabolism; D005260:Female; D006321:Heart / Q000502:physiology; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout / Q000235:genetics; D009206:Myocardium / Q000378:metabolism*; D010710:Phosphates / Q000378:metabolism*; D012016:Reference Values; D012518:Sarcomeres / Q000378:metabolism; D016277:Ventricular Function, Left
D007527:Isoenzymes; D010710:Phosphates; D003402:Creatine Kinase; D052281:Creatine Kinase, Mitochondrial Form