Mitochondrial creatine kinase is critically necessary for normal myocardial high-energy phosphate metabolism

2002 ◽  
Vol 283 (2) ◽  
pp. H680-H687 ◽  
Author(s):  
Matthias Spindler ◽  
Reinhard Niebler ◽  
Helga Remkes ◽  
Michael Horn ◽  
Titus Lanz ◽  
...  
Keyword(s):  
Creatine Kinase ◽  
Energy Homeostasis ◽  
Atp Hydrolysis ◽  
High Energy ◽  
Left Ventricular ◽  
Critical Threshold ◽  
Wild Type ◽  
High Energy Phosphate ◽  
The Individual ◽  
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 ∼70%) using31P 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 μM, P < 0.01) and free energy release for ATP hydrolysis (Δ G 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.

Myocardial high-energy phosphate metabolism is altered after treatment with anthracycline in childhood

2000 ◽  
Vol 10 (6) ◽  
pp. 610-617 ◽  
Author(s):  
Andrea B. Eidenschink ◽  
Gerrit Schröter ◽  
Stefan Müller-Weihrich ◽  
Heiko Stern
Keyword(s):  
Adenosine Triphosphate ◽  
High Energy ◽  
Left Ventricular ◽  
Control Group ◽  
Left Ventricular Myocardium ◽  
Resonance Spectroscopy ◽  
Phosphate Metabolism ◽  
High Energy Phosphate ◽  
High Energy Phosphate Metabolism

AbstractObjectivesWe aimed to investigate whether changes in high-energy phosphate metabolism after treatment of children and young adults with anthracycline can be demonstrated non-invasively by 31P magnetic resonance spectroscopy.BackgroundAbnormal myocardial energy metabolism has been suggested as a mechanism for anthracycline-induced cardiotoxicity. Deterioration in such has been shown in animal studies by resonance spectroscopy.MethodsWe studied 62 patients, with a mean age of 13.5 ±5 years,3.7±4.3 years after a cumulative anthracycline dose of 270±137 mg/m2. Normal echocardiographic findings had been elicited in 54 patients. The control group consisted of 28 healthy subjects aged 20±7 years. Resonance spectrums of the anterior left ventricular myocardium were obtained at 1.5 Tesla using an image-selected in vivo spectroscopy localization technique.ResultsThe ratio of phosphocreatine to adenosine triphosphate after blood correction was 1.09±0.43 for the patients, and 1.36±0.36 (mean±SD)for controls (p = 0.005), with a significantly reducedmean ratio even in the subgroup of patients with normal echocardiographic results ( l.11 ± 0. 44 versus1.36±0.36, p=0.01). The ratio did not correlate with the cumulative dose of anthracycline. The ratio of phosphodiester to adenosine triphosphate was similar in patients and controls (0.90±0.56 versus 0.88±0.62).ConclusionsIn patients treated with anthracyclines in childhood, myocardial high-energy phosphate metabolism may be impaired even in the absence of cardiomyopathy. Our data support the concept that anthracycline-induced cardiotoxicity is not clearly dose dependent.

Oxidative capacity in failing hearts

2003 ◽  
Vol 285 (2) ◽  
pp. H541-H548 ◽  
Author(s):  
Guangrong Gong ◽  
Jingbo Liu ◽  
Peihua Liang ◽  
Tao Guo ◽  
Qingsong Hu ◽  
...  
Keyword(s):  
Ventricular Hypertrophy ◽  
Atp Synthesis ◽  
Oxidative Capacity ◽  
High Energy ◽  
Left Ventricular ◽  
High Energy Phosphate ◽  
Mitochondrial Uncoupling ◽  
Aortic Banding ◽  
High Workload ◽  
High Energy Phosphate Metabolism

Although high-energy phosphate metabolism is abnormal in failing hearts [congestive heart failure (CHF)], it is unclear whether oxidative capacity is impaired. This study used the mitochondrial uncoupling agent 2,4-dinitrophenol (DNP) to determine whether reserve oxidative capacity exists during the high workload produced by catecholamine infusion in hypertrophied and failing hearts. Left ventricular hypertrophy (LVH) was produced by ascending aortic banding in 21 swine; 9 animals developed CHF. Basal myocardial phosphocreatine (PCr)/ATP measured with 31P NMR spectroscopy was decreased in both LVH and CHF hearts (corresponding to an increase in free [ADP]), whereas ATP was decreased in hearts with CHF. Infusion of dobutamine and dopamine (each 20 μg · kg–1 · min–1 iv) caused an approximate doubling of myocardial oxygen consumption ([Formula: see text]) in all groups and decreased PCr/ATP in the normal and LVH groups. During continuing catecholamine infusion, DNP (2–8 mg/kg iv) caused further increases of [Formula: see text] in normal and LVH hearts with no change in PCr/ATP. In contrast, DNP caused no increase in [Formula: see text] in the failing hearts; the associated decrease of PCr/ATP suggests that DNP decreased the mitochondrial proton gradient, thereby causing ADP to increase to maintain adequate ATP synthesis.

scholarly journals High-Energy Phosphate Metabolism and Creatine Kinase in Failing Hearts

Circulation ◽  
2001 ◽  
Vol 103 (11) ◽  
pp. 1570-1576 ◽  
Author(s):  
Yun Ye ◽  
Guangrong Gong ◽  
Koichi Ochiai ◽  
Jingbo Liu ◽  
Jianyi Zhang
Keyword(s):  
Creatine Kinase ◽  
High Energy ◽  
Phosphate Metabolism ◽  
High Energy Phosphate ◽  
High Energy Phosphate Metabolism

Fasudil prevents KATP channel-induced improvement in postischemic functional recovery

2005 ◽  
Vol 288 (6) ◽  
pp. H3011-H3015 ◽  
Author(s):  
Kenya Nishizawa ◽  
Paul E. Wolkowicz ◽  
Tadashi Yamagishi ◽  
Ling-Ling Guo ◽  
Martin M. Pike
Keyword(s):  
Diastolic Pressure ◽  
Rho Kinase ◽  
High Energy ◽  
Left Ventricular ◽  
High Energy Phosphate ◽  
Cellular Processes ◽  
Rat Hearts ◽  
Perfused Rat Hearts ◽  
Rock Activity ◽  
Mechanical Recovery

Whereas activation of ATP-dependent potassium (KATP) channels greatly improves postischemic myocardial recovery, the final effector mechanism for KATP channel-induced cardioprotection remains elusive. RhoA is a GTPase that regulates a variety of cellular processes known to be involved with KATP channel cardioprotection. Our goal was to determine whether the activity of a key rhoA effector, rho kinase (ROCK), is required for KATP channel-induced cardioprotection. Four groups of perfused rat hearts were subjected to 36 min of zero-flow ischemia and 44 min of reperfusion with continuous measurements of mechanical function and 31P NMR high-energy phosphate data: 1) untreated, 2) pinacidil (10 μM) to activate KATP channels, 3) fasudil (15 μM) to inhibit ROCK, and 4) both fasudil and pinacidil. Pinacidil significantly improved postischemic mechanical recovery [39 ± 16 vs. 108 ± 4 mmHg left ventricular diastolic pressure (LVDP), untreated and pinacidil, respectively]. Fasudil did not affect reperfusion LVDP (41 ± 13 mmHg) but completely blocked the marked improvement in mechanical recovery that occurred with pinacidil treatment (54 ± 15 mmHg). Substantial attenuation of the postischemic energetic recovery was also observed. These data support the hypothesis that ROCK activity plays a role in KATP channel-induced cardioprotection.

Sign in / Sign up

Export Citation Format

Share Document