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PubMed1988

Use of creatine kinase MB isoenzyme for diagnosing myocardial infarction when total creatine kinase activity is high.

The usefulness of measuring creatine kinase MB isoenzyme for diagnosing myocardial infarction when activities of total creatine kinase are very high is unclear. We conducted a retrospective study in an urban hospital that serves a largely indigent population. We concentrated on 146 patients whose creatine kinase activity was greater than 1000 U/L (upper limit of normal: 165 U/L for women and 225 U/L for men), with MB isoenzyme greater than 10 U/L and less than 5% of total creatine kinase. The positive predictive value of MB isoenzyme (isoimmune method) values greater than 10 U/L was between 11.6% and 56.8% when the value for total creatine kinase exceeded 1000 U/L. Using different values (MB greater than 4% of total creatine kinase) as positive for myocardial infarction would have resulted in far fewer false-positives, but 10 cases of myocardial infarction would have been missed. The most appropriate cutoff value for MB isoenzyme in this population (total creatine kinase greater than 1000 U/L) was found to be greater than 2% of total creatine kinase.

Adolescent↗

PubMed2004

Neuroprotective mechanisms of creatine occur in the absence of mitochondrial creatine kinase.

There is substantial evidence that creatine administration exerts neuroprotective effects both in vitro and in vivo. The precise mechanisms for these neuroprotective effects however are as yet unclear. We investigated whether creatine administration could exert neuroprotective effects in mice deficient in ubiquitous mitochondrial creatine kinase (UbMi-CK). UbMi-CK-deficient mice showed increased sensitivity to 1-methyl-1, 2, 3, 6-tetrahydropyridine (MPTP)-induced dopamine depletion and loss of tyrosine hydroxylase (TH) stained neurons. Isolated mitochondria from these mice showed no alterations in calcium retention, oxygen utilization, membrane potential, or swelling in response to a calcium challenge. Creatine administration significantly increased brain concentrations of both creatine and PCr in the UbMi-CK knockout mice. Creatine administration to the UbMi-CK-deficient mice exerted significant neuroprotective effects against MPTP toxicity that were comparable in magnitude to those seen in wild-type mice. These results suggest that the neuroprotective effects of creatine are not mediated by an effect on UbMi-CK to inhibit the mitochondrial permeability transition, and are more likely to be mediated by maintenance of appropriate ATP/ADP and PCr/Cr levels.

3,4-Dihydroxyphenylacetic Acid↗

PubMed2004

Distinct cellular expressions of creatine synthetic enzyme GAMT and creatine kinases uCK-Mi and CK-B suggest a novel neuron-glial relationship for brain energy homeostasis.

The creatine/phosphocreatine shuttle system, as catalysed reversibly by creatine kinases, is thought to be essential for the storing and buffering of high phosphate-bound energy in tissues with high energy demand. In the present study, we aimed to clarify the cellular system of creatine biosynthesis and its energy metabolism in the mouse brain by immunohistochemistry for creatine biosynthetic enzyme S-adenosylmethionine:guanidinoacetate N-methyltransferase (GAMT), ubiquitous mitochondrial creatine kinase (uCK-Mi) and brain-type cytoplasmic creatine kinase (CK-B). GAMT was expressed highly in oligodendrocytes and olfactory ensheathing glia and moderately in astrocytes, whereas GAMT was very low in neurons and microglia. By contrast, uCK-Mi was expressed selectively in neurons and localized in their mitochondria in dendrites, cell bodies, axons and terminals. The distinct and almost complementary distribution of GAMT and uCK-Mi suggests that the creatine in neuronal mitochondria is derived not only from the circulation, but also from local glial cells associated with these neuronal elements. By contrast, CK-B was selective to astrocytes among glial populations, and was exclusive to inhibitory neurons among neuronal populations. Interestingly, these cells with high CK-B immunoreactivity are known to be highly resistant to acute energy loss, such as hypoxia and hypoglycemia. Considering that phosphocreatine generates ATP much faster than the processes of glycolysis and oxidative phosphorylation, the highly regulated cellular expressions of creatine biosynthetic and metabolic enzymes suggest that the creatine/phosphocreatine shuttle system plays a role in brain energy homeostasis through a novel neuron-glial relationship.

Animals↗

PubMed2002

Myocellular creatine and creatine transporter serine phosphorylation after starvation.

BACKGROUND: Myocellular creatine, which is critically important for normal energy metabolism, increases in rat gastrocnemius muscle after starvation via unknown mechanisms. Creatine (Cr) uptake across plasma membranes is governed by a single, specific transporter (CrTr) that shares 50% amino acid sequence identity with GABA/choline/betaine transporters whose functions are modulated by phosphorylation. METHODS: Gastrocnemius muscle was collected from adult male Sprague-Dawley (225-250 g) rats that were randomized to receive normal rat chow and distilled water ad libitum (CTL) or distilled water alone for 4 days (STV). Total Cr, phosphocreatine (PCr), free Cr, and ATP were measured luminometrically. CrTr protein expression and protein serine and tyrosine phosphorylation and mRNA expression were determined using immunoprecipitation and quantitative Western blotting and reverse transcription polymerase chain reaction (RT-PCR) analyses, respectively. Guanidinoacetate methyltransferase (GAMT) activity, guanidinoacetic acid (GAA) content, creatine kinase (CK) activity, and creatinine (Crn) content were assayed luminometrically or spectrophotometrically. Creatine transporter uptake activity was also measured in skeletal muscle membrane vesicles. Data were analyzed by t test. RESULTS: Total Cr and free Cr increased 26 and 280% in STV (32.3 +/- 1.0 and 12.9 +/- 1.4 vs 25.7 +/- 1.1 and 3.4 +/- 0.9 micromol/g wet wt, mean +/- SEM, respectively, P < 0.01) whereas PCr content decreased 18% (18.6 +/- 0.8 vs 22.8 +/- 0.9 micromol/g wet wt, STV vs CTL P < 0.05). CrTr protein and mRNA expression, ATP, GAA, CK, GAMT, and protein tyrosine phosphorylation of CrTr were not significantly different between the two groups. However, protein serine phosphorylation of CrTr was significantly reduced by 30% (P < 0.05) and creatine uptake activity was significantly increased (P < 0.05) in starved animals. CONCLUSION: Increases in myocellular creatine content after starvation are associated with reduced serine phosphorylation of the creatine transporter.

Animals↗

PubMed1991

Adult rat cardiomyocytes cultured in creatine-deficient medium display large mitochondria with paracrystalline inclusions, enriched for creatine kinase.

In adult regenerating cardiomyocytes in culture, in contrast to fetal cells, mitochondrial creatine kinase (Mi-CK) was expressed. In the same cell, two populations of mitochondria, differing in shape, in distribution within the cell and in content of Mi-CK, could be distinguished. Immunofluorescence studies using antibodies against Mi-CK revealed a characteristic staining pattern for the two types of mitochondria: giant, mostly cylindrically shaped, and, as shown by confocal laser light microscopy, randomly distributed mitochondria exhibited a strong signal for Mi-CK, whereas small, "normal" mitochondria, localized in rows between myofibrils, gave a much weaker signal. Transmission EM of the giant mitochondria demonstrated paracrystalline inclusions located between cristae membranes. Immunogold labeling with anti-Mi-CK antibodies revealed a specific decoration of these inclusions for Mi-CK. Addition of 20 mM creatine, the substrate of Mi-CK, to the essentially creatine-free culture medium caused the disappearance of the giant cylindrically shaped mitochondria as well as of the paracrystalline inclusions, accompanied by an increase of the intracellular level of total creatine. Replacement of creatine in the medium by the creatine analogue and competitor beta-guanidinopropionic acid caused the reappearance of the enlarged mitochondria. It is believed that the accumulation of Mi-CK within the paracrystalline inclusions, similar to those observed in certain myopathies, represents a compensatory effect of the cardiomyocytes to cope with a metabolic stress situation caused by low intracellular total creatine levels.

Animals↗

PubMed1982

Characterization of an atypical creatine kinase from human heart tissue, with properties similar to those of mitochondrial creatine kinase.

The 600 X g particulate fraction, obtained from the homogenates of human heart muscle, contained large quantities of an atypical creatine kinase (CK-Z). Creatine kinase Z migrated cathodically relative to CK-MM on agarose gel electrophoresis, and was not inhibited by antibodies directed against human CK-MM and CK-BB. Creatine kinase Z had an apparent Km for Mg-ADP and creatine phosphate of 0.04 mmol/l and 1.3 mmol/l, respectively. This enzyme existed in two molecular forms; one form of molecular weight 33 000-38 000 in the presence of a buffer containing Tris-HCl (0.05 mol/l), EDTA (0.001 mol/l), and 2-mercaptoethanol (0.010 mol/l), pH 8.0; and another form having a molecular weight of 62 000-68 000 in the presence of a buffer containing sodium phosphate (0.020 mol/l) and EDTA (0.001 mol/l), pH 8.0. Creatine kinase Z had biochemical properties which were different from those of the other soluble creatine kinase isoenzymes (MM, MB and BB), but similar to those reported for mitochondrial creatine kinases isolated from other animal tissues.

Creatine Kinase↗

PubMed1984

Creatine kinase in regulation of heart function and metabolism. I. Further evidence for compartmentation of adenine nucleotides in cardiac myofibrillar and sarcolemmal coupled ATPase-creatine kinase systems.

In isolated and purified cardiac myofibrillar and sarcolemmal preparations, the route of movement of ADP produced in the Mg2+-ATPase reactions was studied by investigating the efficiency of competition between the endogenous creatine kinase and exogenous pyruvate kinase reactions. In the homogeneous control system composed of hexokinase and glucose as ATPase, soluble creatine kinase rapidly rephosphorylated ADP produced in the presence of 1 mM ATP, but the addition of pyruvate kinase in an increasing amount inhibited the reaction of creatine release from phosphocreatine and symmetrically increased the rate of pyruvate production from phosphoenol pyruvate. At a pyruvate-kinase/creatine-kinase activity ratio (PK/CK) of 50, all ADP was used by the pyruvate kinase. In myofibrillar and sarcolemmal preparations containing particulate creatine kinase, the creatine kinase reaction was much less efficiently suppressed by pyruvate kinase, and at PK/CK = 50 half-maximal release of creatine was still observed. The rate of immediate myofibrillar MgADP rephosphorylation in the endogenous creatine-kinase reaction was observed to be governed by the concentration of phosphocreatine in accordance with the kinetics of this enzyme. The physiological significance of these findings is discussed.

Adenine Nucleotides↗

PubMed1990

Application and validation of an ion-exchange high-performance liquid chromatographic method for measuring adenine nucleotides, creatine and creatine phosphate in mouse brain.

We have modified and applied an ion-exchange high-performance liquid chromatographic method for measuring adenine nucleotides (adenosine monophosphate, adenosine diphosphate and adenosine triphosphate) as well as creatine and creatine phosphate in brain tissue. There was a linear relationship between the area of each peak and the amount of standard injected onto the column in the concentration range 0.5-25 nmol per 50 microliters. The concentrations of creatine phosphate and creatine were not stable in a standard mixture for 20 h at 4 degrees C unless the pH of the standard mixture was adjusted to neutral. We therefore strongly recommended the neutralization of all standard mixtures and samples before storage. The measurements of adenine nucleotides, creatine and phosphate in control mouse brain determined by this method agreed well with an enzymic method of nucleotide measurement. Furthermore, both methods detected similar decreases in the concentrations of adenosine triphosphate and creatine phosphate, together with concomitant increases in the concentrations of adenosine diphosphate, adenosine monophosphate and creatine when mice were placed under anoxic conditions (either 30 s or 2 min); these changes were greater after 2 min of anoxia than after 30 s of anoxia.

Adenine Nucleotides↗

PubMed2004

Presence of normal creatine in the muscle of a patient with a mutation in the creatine transporter: a case study.

To date, more than seven families have been reported who carry a mutation in the X-linked creatine-transporter (CrT) gene. The resulting lack of creatine in the brain is associated with mental retardation, severe expressive language disorder, mild epilepsy, and a complete absence of Cr in the brain (measured using MRS). Conversely, these patients had no observable cardiac or musculo-skeletal deficits. In this case study, a 22-year-old patient underwent surgical repair for scoliosis. Proton MRS of this patient's brain demonstrated the near-absence of creatine and phosphocreatine within the cerebral white and deep gray matter structures. Cerebral atrophy was noted with serial MRI examinations. Subsequent genetic and metabolic analysis showed some biochemical anomalies consistent with a CrT deficiency. The mutation in this patient was identified as a deletion at phenylalanine 107 (delF107). Control muscle biopsies were obtained from archived samples, which had been taken with informed consent during routine muscle biopsies for diagnostic purposes. We determined that the total Cr concentration in the skeletal muscle biopsy was 39.3 +/- 2.94 mmol/kg wet wt., which is not significantly different from non-CrT controls, n = 3 (43.3 +/- 3.57 mmol/kg wet wt.). We conclude that the brain appears to lack the ability to transport creatine when there is a mutation in the CrT gene. However, the muscle utilizes another mechanism for maintaining normal creatine levels. Identifying this alternative creatine-transport mechanism may be useful in treating the neurologic and cognitive impairments of patients with creatine-transporter deficiency.

Adult↗

PubMed1982

Serum myoglobin, creatine kinase and creatine kinase-MB as mutually supportive indices of myocardial infarction and infarct size.

A comparison was made between the appearance of serum myoglobin and creatine kinase in 22 patients with acute myocardial infarction who were admitted to a coronary-care unit within four hours of onset of chest pain. The MB isoenzyme of creatine kinase was measured in 12 patients. The more rapid appearance and disappearance of myoglobin relative to creatine kinase and creatine kinase-MB was confirmed, as was the correspondence between their respective peak values. A significant correlation was also obtained between the area under the myoglobin time-course and the respective peak levels. Whereas creatine kinase activity declined exponentially from a single peak, myoglobin appeared in multiple episodes inadequately represented by a single peak value and having no clear clinical correlation. The role of myoglobin as a diagnostic aid in myocardial infarction is probably limited to its ability to support creatine kinase and creatine kinase-MB as indices of infarct size.

Creatine Kinase↗

PubMed2004

Creatine serum is not as effective as creatine powder for improving cycle sprint performance in competitive male team-sport athletes.

This study examined the effects of supplementation with either creatine monohydrate powder in solution (CP) or a widely available creatine serum (CS) on performance in a repeated maximal sprint cycling test (10 x 6 seconds, 24-second passive rest between sprints). Using a randomized, double-blind, crossover design, 11 competitive male athletes supplemented with creatine in 2 forms according to the manufacturer's recommendations on 2 separate occasions. The 2 supplementation protocols were (a) 20 g.day(-1) x 6 days of creatine powder in solution plus a placebo serum (CP) or (b) 5 ml.day(-1) x 6 days of creatine serum plus a placebo powder (CS). Subjects completed 2 familiarization trials before the 6-day supplementation period. A repeated maximal sprint cycling test was performed prior to and immediately postsupplementation. A 7-week washout period separated the 2 supplementation protocols. Subjects' total work (9.6%) and peak power (3.4%) in the cycle sprint improved significantly (p < 0.05) after loading with CP, but there was little change after loading with CS. The present data support previous research findings showing an ergogenic effect of CP supplementation but indicate that supplementation with CS does not affect sprint cycling performance. Although the levels of creatine in each formulation were not determined, a substantial conversion of creatine into creatinine has been reported in many formulations and may explain the present findings.

Adult↗

PubMed1998

Creatine metabolism in the seminiferous epithelium of rats. I. Creatine synthesis by isolated and cultured cells.

The testis synthesizes creatine from both arginine and glycine precursors, but when rat testicular tissue is separated into seminiferous tubules and interstitial cells, creatine synthesis occurs only in the tubular fraction. The purpose of the work presented here was to define the locus of creatine synthesis within the seminiferous tubules, by using cell separation and culture techniques to examine synthesis in the Sertoli cells and germ cells. The total creatine content, in the cellular compartment and incubation medium, of Sertoli-germ cell co-cultures and of Sertoli cell-enriched cultures, largely free of germ cells, increased by similar amounts over a 24 h incubation period. Sertoli cell-enriched cultures incorporated radioactivity from L-[guanidino-14C]arginine and [1-14C]glycine into both creatine and its biosynthetic precursor, guanidinoacetic acid. Isolated germ cells did not incorporate radioactivity from L-[guanidino-14C]arginine into either creatine or guanidinoacetic acid when incubated at a similar density and protein concentration under similar conditions. It is concluded that the synthesis of creatine observed in isolated rat seminiferous tubules occurs within the Sertoli cells and not the germ cells.

Animals↗

PubMed1986

[Physiological role of the creatine kinase system and the problem of regulating the activity of mitochondrial creatine kinase].

The review contains the analysis of present-day concepts on the physiological role of the creatine kinase system. A hypothesis on the buffering functions of the creatine kinase system which ensures a constant ATP level in cells and a hypothesis according to which phosphocreatine is a macroergic phosphate carrier from mitochondria to the sites of their utilization are considered. In connection with the creatine phosphate carrier hypothesis according to which the transport function of the creatine kinase system is provided for by an effective function of mitochondrial creatine kinase, feasible mechanisms of mitochondrial creatine kinase activity regulation are considered: as a result of creation of local concentration of nucleotide substrates as well as changes in the properties of creatine kinase itself which may result from the enzyme conversion from the membrane-bound to the free form or from the interconversion of oligomeric forms of the enzyme.

Adenosine Triphosphate↗

PubMed1985

Higher homolog and N-ethyl analog of creatine as synthetic phosphagen precursors in brain, heart, and muscle, repressors of liver amidinotransferase, and substrates for creatine catabolic enzymes.

Tissues of chicks fed 5% N-methyl-3-guanidinopropionate (N-amidino-N-methyl-beta-alanine) for 12 days accumulated the following amounts of free plus phosphorylated derivatives as mumol/g, wet weight: brain, 5.5; heart, 7.3; leg muscle, 21.0; and breast muscle, 24.4. Since total creatine levels remained nearly the same in brain, N-methyl-3-guanidinopropionate-P provided brain with a supplemental reservoir of high energy phosphate. Tissues of rats fed 2% N-ethylguanidinoacetate (N-amidino-N-ethylglycine) accumulated large amounts of N-ethylguanidinoacetate-P, which has thermodynamic properties similar to creatine-P and is the kinetically most reactive synthetic phosphagen yet described. N-Ethylguanidinoacetate derivatives replaced creatine derivatives mole-for-mole, and the fraction of synthetic to total phosphagen after 19 days was 60% in heart, 54% in slow oxidative muscle, 42% in fast glycolytic muscles, and 22% in brain. N-Ethylguanidinoacetate served as a false end product co-repressor of liver arginine:glycine amidinotransferase levels in both chicks and chick embryos; N-methyl-3-guanidinopropionate and N-propylguanidinoacetate were relatively inactive. Creatinine amidohydrolase reversibly cyclized both N-ethylguanidinoacetate and N-propylguanidinoacetate with even lower Km values than for creatine derivatives, but it did not react significantly with N-methyl-3-guanidinopropionate, 3-guanidinopropionate, or 1-carboxy-methyl-2-imino-imidazolidine (cyclocreatine). Creatine amidinohydrolase also hydrolyzed N-acetimidoylsarcosine, but was relatively unreactive toward N-ethylguanidinoacetate, N-methyl-3-guanidinopropionate, 3-guanidinopropionate, and cyclocreatine. Amidinohydrolase can therefore be used to remove interfering creatine in assays of tissues for coexisting N-ethylguanidinoacetate or N-methyl-3-guanidinopropionate. Assays are now available to follow changes during metabolic stresses of any combination or all of the following phosphagens accumulated by the same tissue: creatine-P, N-ethylguanidinoacetate-P, cyclocreatine-P, N-methyl-3-guanidinopropionate-P, and homocyclocreatine-P.

Amidinotransferases↗

PubMed1979

[Creatine kinase and creatine isoenzyme activities in newborn. Development of the organ-typical isoenzyme pattern during the fetal period (author's transl)].

The activity of the creatine kinase isoenzyme was measured in the serum of 133 healthy newborn. In contrast to the conditions in the adult, a normal range of 0-45 U/1 was found. No creatine kinase BMB activities were established. The increased creatine kinase-MB activities in newborn could be explained by means of an examination of the creatine kinase isoenzyme pattern in the skeleton muscle of foetuses and newborn. Depending upon the gestation age, creatine kinase-MB activity levels were found amounting to as much as a multiple of ten of the adult levels. Due to the deviation of the creatine kinase isoenzyme distribution in the organ tissue of newborn, identified in this study for the first time, creatine kinase-MB activity seems to be unsuitable as an indicator of myocardial damage during the neonatal period.

Creatine Kinase↗

PubMed1979

[Sensitivity of creatine kinase and creatine kinase MB in myocardial infarction. Evaluation of a new optimized standard method (author's transl)].

In 70 patients with confirmed transmural myocardial infarction the sensitivity of creatine kinase and creatine kinase MB at different times after admission was investigated by 364 measurements. Beside the number of correctly positive results the optimized standard method hitherto used was compared with the new optimized standard method with N-acetylcystein as activator. During the first 12 hours after admission the percentage of correctly positive results was 64,4% for creatine kinase (GSH) and 86,7% for creatine kinase (NAC). The sensitivity of cretine kinase MB, however, was found to be 71,1% (GSH) and 86,7% (NAC). With respect to the poor specifity of creatine kinase the sensitivity of creatine kinase MB, especially when using the new optimized standard method is superior. Similar results were established 24 and 48 hours after admission. Creatine kinase MB only fails in detection of myocardial infarction if the stroke is older than 3 days or if the enzyme activity determination intervals are too long.

Acetylcysteine↗

PubMed1979

[Creatine kinase and creatine kinase isoenzyme MB: determination of normal values and values for myocardial infarct, using the new, optimized method with N-acetyl cysteine as the activator (author's transl)].

Preliminary results are reported for the determination of creatine kinase and its isoenzyme MB in healthy individuals and in patients with acute, transmural myocardial infarct, using N-acetyl cysteine as the activator of the enzyme. In healthy individuals, the upper normal limit for creatine kinase activity was 54 U/l; the decision level for the presence of creatine kinase MB activity 9 U/l. The limiting values were only slightly different from those for the GSH-activated creatine kinase, and the results with the old and new methods showed a linear relationship with a slope of 1.0. The differences in the activation of creatine kinase MM by GSH and by N-acetyl cysteine are discussed; the activities obtained for creatine kinase and creatine kinase-MB by the GSH-activation method cannot simply be recalculated to give the appropriate values of the N-acetyl cysteine activation method.

Acetylcysteine↗

PubMed2001

Creatine kinase: a role for arginine-95 in creatine binding and active site organization.

Sequence homology analysis reveals that arginine-95 is fully conserved in 29 creatine kinases sequenced to date, but fully conserved as a tyrosine residue in 16 arginine kinases. Site-directed mutants of rabbit muscle creatine kinase (rmCK) were prepared in which R95 was replaced by a tyrosine (R95Y), alanine (R95A), or lysine (R95K). Kinetic analysis of phosphocreatine formation for each purified mutant showed that recombinant native rmCK and all R95 mutants follow a random-order, rapid-equilibrium mechanism. However, we observed no evidence for synergism of substrate binding by the recombinant native enzyme, as reported previously [Maggio et al., (1977) J. Biol. Chem. 252, 1202-1207] for creatine kinase isolated directly from rabbit muscle. The catalytic efficiencies of R95Y and R95A are reduced approximately 3000- and 2000-fold, respectively, compared to native enzyme, but that of R95K is reduced only 30-fold. The major contribution to the reduction of the catalytic efficiency of R95K is a 5-fold reduction in the affinity for creatine. This suggests that while a basic residue is required at position 95 for optimal activity, R95 is not absolutely essential for binding or catalysis in CK. R95Y has a significantly lower affinity for creatine than the native enzyme, but it also displays a somewhat lower affinity for MgATP and 100-fold reduction in k(cat). Interestingly, R95A appears to bind either creatine or MgATP first with affinities similar to those for the native enzyme, but it has a 10-fold lower affinity for the second substrate, suggesting that replacement of R95 by an alanine disrupts the active site organization and reduces the efficiency of formation of the catalytically competent ternary complex.

Amino Acid Substitution↗