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PubMed1994

Effects of the creatine analogue beta-guanidinopropionic acid on skeletal muscles of mice deficient in muscle creatine kinase.

To evaluate the effects of phosphocreatine (PCr) and creatine (Cr) depletion on skeletal muscles of mice deficient in muscle creatine kinase (M-CK), we have fed mutant mice a diet containing the creatine analogue beta-guanidinopropionic acid (beta GPA). After 8-10 weeks of feeding, accumulation of the creatine analogue in M-CK-deficient muscles was comparable to that observed in muscles of wild-type mice. Strikingly, and unlike wild types, mutants did not accumulate phosphorylated beta GPA, indicating that MM-CK is the only muscle CK isoform which can phosphorylate beta GPA. In M-CK-deficient muscles there was respective depletion of PCr, Cr and ATP levels to 31, 41 and 83% of normal. The average cross-sectional area of type 2B fibres in gastrocnemius muscles was very much reduced and was similar to type 1 and type 2A fibres which maintained their normal size. The maximal isometric twitch force developed by gastrocnemius-plantaris-soleus (GPS) muscle complexes of beta GPA-treated mutants was reduced by about 30%, but these muscles showed an increased fatigue resistance during 1 and 5 Hz contraction. Mitochondrial enzyme activities in the upper hind limb musculature of null mutants were 20-35% increased by the beta GPA diet. Altogether, these results provide evidence that certain functions of the creatine kinase/phosphocreatine (CK/PCr) system are not eliminated solely by the loss of M-CK.

Animals↗

PubMed1996

The utilisation of creatine and its analogues by cytosolic and mitochondrial creatine kinase.

We have investigated the utilisation of four analogues of creatine by cytosolic Creatine Kinase (CK), using 31P-NMR in the porcine carotid artery, and by mitochondrial CK (Mt-CK), using oxygen consumption studies in isolated heart mitochondria and skinned fibers. Porcine carotid arteries were superfused for 12 h with Krebs-Henseleit buffer at 22 degrees C, containing 11 mM glucose as substrate, and supplemented with either 20 mM beta-guanidinopropionic acid (beta-GPA), methyl-guanidinopropionic acid (m-GPA), guanidinoacetic acid (GA) or cyclocreatine (cCr). All four analogues entered the tissue and became phosphorylated by CK as seen by 31 P-NMR, Inhibition of oxidative metabolism by 1 mM cyanide after accumulation of the phosphorylated analogue resulted in the utilisation of PCr, beta-GPA-P, GA-P and GA-P over a similar time course (approximately 2 h), despite very different kinetic properties of these analogues in vitro. cCr-P was utilised at a significantly slower rate, but was rapidly dephosphorylated in the presence of both 1 mM iodoacetate and cyanide (to inhibit both glycolysis and oxidative metabolism respectively). The technique of creatine stimulated respiration was used to investigate the phosphorylation of the analogues by Mt-CK, Isolated mitochondria were subjected to increasing [ATP], whereas skinned fibres received a similar protocol with increasing [ADP]. There was a significant stimulation of respiration by creatine and cCr in isolated mitochondria (decreased K(m) and increased Vmax vs control), but none by GA, mGPA or beta-GPA (also in skinned fibres), indicating that these latter analogues were not utilised by Mt-CK. These results demonstrate differences in the phosphorylation and dephosphorylation of creatine and its analogues by cytosolic CK and Mt-CK in vivo and in vitro.

Adenosine Diphosphate↗

PubMed2005

The creatine kinase system in human skin: protective effects of creatine against oxidative and UV damage in vitro and in vivo.

Cutaneous aging is characterized by a decline in cellular energy metabolism, which is mainly caused by detrimental changes in mitochondrial function. The processes involved seem to be predominantly mediated by free radicals known to be generated by exogenous noxes, e.g., solar ultraviolet (UV) radiation. Basically, skin cells try to compensate any loss of mitochondrial energetic capacity by extra-mitochondrial pathways such as glycolysis or the creatine kinase (CK) system. Recent studies reported the presence of cytosolic and mitochondrial isoenzymes of CK, as well as a creatine transporter in human skin. In this study, we analyzed the cutaneous CK system, focusing on those cellular stressors known to play an important role in the process of skin aging. According to our results, a stress-induced decline in mitochondrial energy supply in human epidermal cells correlated with a decrease in mitochondrial CK activity. In addition, we investigated the effects of creatine supplementation on human epidermal cells as a potential mechanism to reinforce the endogenous energy supply in skin. Exogenous creatine was taken up by keratinocytes and increased CK activity, mitochondrial function and protected against free oxygen radical stress. Finally, our new data clearly indicate that human skin cells that are energetically recharged with the naturally occurring energy precursor, creatine, are markedly protected against a variety of cellular stress conditions, like oxidative and UV damage in vitro and in vivo. This may have further implications in modulating processes, which are involved in premature skin aging and skin damage.

Administration, Topical↗

PubMed1980

Cryoenzymic studies on the transition-state analog complex creatine kinase . ADPMg . nitrate . creatine.

Concomitant with the formation of the transition state analog complex creatine kinase . ADPMg . nitrate . creatine [Milner-White, E. J. and Watts, D. C. (1971) Biochem. J. 122, 727--740] there results a large difference spectrum. The shape of the spectrum was characteristic of tryptophan exposure. The kinetics of formation and final amplitude of the spectrum were studied at -15 degrees C using a stopped-flow apparatus. The results obtained allowed for a plausible reaction pathway for nitrate fixation: the ordered addition of nitrate and creatine to the binary enzyme-ADPMg complex, a slow protein isomerization and the final addition of a molecule each of nitrate and creatine. The kinetic parameters for the formation of the transition state analog complex were compared with those already known for the overall reaction obtained under the same conditions [Barman, T. E., Brun, A. and Travers, F. (1980) Dur. J. Biochem. 110, 397--403]. This comparison revealed a striking analogy between the two processes. This suggests that the conformation of creatine kinase in the analog complex is very similar to that in the transition state complex on the catalytic pathway.

Adenosine Diphosphate↗

PubMed2002

X-linked creatine deficiency syndrome: a novel mutation in creatine transporter gene SLC6A8.

Among creatine deficiency syndromes, an X-linked condition related to a defective creatine transport into the central nervous system has been described recently. Hallmarks of the disease are the absence of a creatine signal at brain spectroscopy, increased creatine levels in blood and urine, ineffectiveness of oral supplementation, and a mutation in the SLC6A8 (Online Mendelian Inheritance in Man [OMIM] 300036) creatine transporter gene. We report on a patient in whom a novel mutation (1221-1223delTTC) was identified.

Administration, Oral↗

PubMed1998

Creatine kinase and creatine kinase isoenzyme responses to heat stress.

During this investigation the effects of heat acclimation and exercise on creatine kinase and creatine kinase BB isoenzyme responses in various tissues and serum of male Sprague-Dawley rats were ascertained. Forty rats were randomly divided into two groups of 20 rats each. One group was housed at 22+/-1 degrees C and the other at 33+/-1 degrees C. Each of the two groups were subdivided into two subgroups of ten rats each. One subgroup of each group was subjected to a programme of treadmill running of progressive intensity over a period of 6 weeks at the temperature at which it was housed while the other served as a resting control. At the end of the acclimation programme the rats were running at 23 m/min for 80 min. On the day of sacrifice all four subgroups were subjected to a discontinuous exercise protocol (10 min running alternated by a 2-min rest period; repeated three times) at 30+/-1 degrees C on a rodent treadmill at 23 m/min. The tissues investigated were kidney, heart and muscle. The rats were anaesthetized with pentobarbital sodium (6 mg/100 g body mass) injected intraperitoneally. The tissues were freeze-clamped and stored in liquid air until analysed. The body temperature of the four subgroups at the end of the experimental protocol were not significantly different. Acclimation at 33+/-1 degrees C resulted in significantly lower creatine kinase activity levels. Exercise at 30+/-1 degrees C also resulted in decreased creatine kinase activity levels in both acclimated groups. A similar trend was observed regarding creatine kinase BB isoenzyme activity levels, especially in kidney.

Acclimatization↗

PubMed1978

[Creatine kinase isoenzymes: idiopathic occurrence of creatine kinase BB activities in patient serum (author's transl)].

By differentiation of creatine kinase isoenzyme activities in sera using immunological methods the published data about occurrence of creatine kinase BB activities in patients with different diseases or after surgical treatment, respectively, cannot be verified in general. With a frequency in the order of magnitude of 1 : 1000 in the serum of old patients (age 57 to 85 years with one exception), however, creatine kinase BB activities can be measured. The range of activities is 15 to 234 U/1, or 19 to 94% of total creatine kinase activities, respectively. At the present time there is no possibility to correlate this phenomenon to any specific disease. These cases are detected by abnormally high results of CK-MB activity measurements with the immunoinhibition test (range 60 to 202% of total creatine kinase activities) which lead to a repeated analysis using immunoprecipitation. The results of all CK-BB patients investigated till now are presented and discussed.

Adult↗

PubMed2001

Supplemental creatine may decrease serum homocysteine and abolish the homocysteine 'gender gap' by suppressing endogenous creatine synthesis.

Creatine synthesis is responsible for the large majority of the methyl group transfers in normal hepatic metabolism, and is significantly greater in men than in women. Since methyl group depletion impairs the efficiency of homocysteine disposal, it is believed that the comparatively high rate of creatine synthesis in men is primarily responsible for the 'gender gap' in homocysteine levels. Adequate supplemental intakes of creatine can suppress creatine synthesis by inhibiting expression of the enzyme arginine-glycine transamidase. Thus, it is proposed that creatine supplementation may represent a practical strategy for decreasing plasma homocysteine levels.

Animals↗

PubMed2001

X-linked creatine-transporter gene (SLC6A8) defect: a new creatine-deficiency syndrome.

We report the first X-linked creatine-deficiency syndrome caused by a defective creatine transporter. The male index patient presented with developmental delay and hypotonia. Proton magnetic-resonance spectroscopy of his brain revealed absence of the creatine signal. However, creatine in urine and plasma was increased, and guanidinoacetate levels were normal. In three female relatives of the index patient, mild biochemical abnormalities and learning disabilities were present, to various extents. Fibroblasts from the index patient contained a hemizygous nonsense mutation in the gene SLC6A8 and were defective in creatine uptake. The three female relatives were heterozygous for this mutation in SLC6A8, which has been mapped to Xq28.

Amino Acid Sequence↗

PubMed1990

Optimised function for determining time to peak creatine kinase and creatine kinase-MB as non-invasive reperfusion indicators after thrombolytic therapy in acute myocardial infarction.

STUDY OBJECTIVE: The aim of the study was to investigate the use of an optimised function to approximate and interpolate the time course of serum creatine kinase and creatine kinase-MB values after thrombolytic therapy in acute myocardial infarction. DESIGN: A three parameter interpolating function was developed which approximates the time course of serum enzyme levels. In the proposed function, time to peak creatine kinase and maximum of creatine kinase determined from raw data were used as starting parameters of the non-linear interpolation routine, thus providing ideal starting conditions for the iteration. The efficacy of the function was compared with that of three other functions cited in published reports (log-normal distribution function, modified gamma density function, three compartment function). SUBJECTS: Serum enzyme data from 20 patients with acute myocardial infarction were used in the comparisons. The patients have all been treated with anisoylated plasminogen streptokinase activator complex. RESULTS: In comparison with the other models, deviations of the experimental model function from the raw data were minimal. The fit remained stable for time intervals between blood samples of up to 6 h. CONCLUSIONS - Due to its numerical stability, the function outlined in this study is suitable for large clinical reperfusion trials. In the case of uncomplicated infarctions without thrombolytic therapy, the area under the creatine kinase activity curve could be directly calculated in terms of maximum activity and time to peak.

Anistreplase↗

PubMed2002

New creatine transporter assay and identification of distinct creatine transporter isoforms in muscle.

Despite the pivotal role of creatine (Cr) and phosphocreatine (PCr) in muscle metabolism, relatively little is known about sarcolemmal creatine transport, creatine transporter (CRT) isoforms, and subcellular localization of the CRT proteins. To be able to quantify creatine transport across the sarcolemma, we have developed a new in vitro assay using rat sarcolemmal giant vesicles. The rat giant sarcolemmal vesicle assay reveals the presence of a specific high-affinity and saturable transport system for Cr in the sarcolemma (Michaelis-Menten constant 52.4 +/- 9.4 microM and maximal velocity value 17.3 +/- 3.1 pmol x min(-1) x mg vesicle protein(-1)), which cotransports Cr into skeletal muscle together with Na(+) and Cl(-) ions. The regulation of Cr transport in giant vesicles by substrates, analogs, and inhibitors, as well as by phorbol 12-myristate 13-acetate and insulin, was studied. Two antibodies raised against COOH- and NH(2)-terminal synthetic peptides of CRT sequences both recognize two major polypeptides on Western blots with apparent molecular masses of 70 and 55 kDa, respectively. The highest CRT expression occurs in heart, brain, and kidney, and although creatine kinase is absent in liver cells, CRT is also found in this tissue. Surprisingly, immunofluorescence staining of cultured adult rat heart cardiomyocytes with specific anti-CRT antibodies, as well as cell fractionation and cell surface biotinylation studies, revealed that only a minor CRT species with an intermediate molecular mass of approximately 58 kDa is present in the sarcolemma, whereas the previously identified major CRT-related protein species of 70 and 55 kDa are specifically located in mitochondria. Our studies indicate that mitochondria may represent a major compartment of CRT localization, thus providing a new aspect to the current debate about the existence and whereabouts of intracellular Cr and PCr compartments that have been inferred from [(14)C]PCr/Cr measurements in vivo as well as from recent in vivo NMR studies.

Animals↗

PubMed1981

Effects of creatine administration on experimental liver fibrosis and on creatine and phosphocreatine content of rat muscle.

Creatine administration has no effect on the induction of liver cirrhosis caused by CCl4 in the rat. The muscle creatine content decreases in rats given CCl4 and this change is not modified by creatine treatment. Administered on its own it depresses the level of muscle creatine in normal rats. Creatinine administration increases the uptake of radioactive creatine by the muscle.

Animals↗

PubMed1983

Red cell creatine in term and preterm, adequate and small for gestational age newborns after normal pregnancy or risk conditions. I. Statistical analysis of creatine in various groups of newborns.

The red cell creatine concentration was determined in 174 newborns (cord blood) and in 50 healthy adults. Normal values for term adequate for gestational age newborns without intrauterine and perinatal risk (n = 53) were established to lie significantly above those for adults. Newborns after risk pregnancies had higher mean creatine concentrations than those born after uneventful gestation. Small for gestational age (SGA) infants proved to have the lowest creatine concentration of all newborn groups. The creatine values of our SGA children suggested that not more than 20% of them had chronic intrauterine hypoxia. It is concluded that red cell creatine at birth may serve to characterize in retrospect erythropoietic dynamics in cases of intrauterine growth retardation and intrauterine risk.

Creatine↗

PubMed1983

Red cell creatine in term and preterm, adequate and small for gestational age newborns after normal pregnancy or risk conditions. II. Mathematical analysis of 12 risk conditions in relation to the creatine level at birth.

Univariate and multivariate analysis of variance and discriminant analysis were performed on newborns with respect to the level of red cell creatine at birth (cord blood) and 12 risk conditions occurring during the last trimester of gestation and birth. 111 of the 174 newborns studied had been at risk. The factor "small for gestational age" (SGA) showed to have a negative coefficient of discriminant function, i.e. it contributes to lower creatine values at birth. Other risks are shown to raise the creatine level. For "adequate for gestational age" (AGA) newborns "Rh-incompatibility", "toxoplasmosis", "premature and/or prolonged rupture of the membranes", "complications of the umbilical cord" and - to a minor degree - "pyelonephritis of the mother", "threatened premature labour", and "toxemia of pregnancy" were shown to be significant risks leading towards high red cell creatine concentrations in cord blood. For the SGA infants "preterm birth", "threatened premature labour", "green amniotic fluid" and "toxemia of pregnancy" were the most important risks relating to high creatine levels of red cells at birth.

Analysis of Variance↗

PubMed1989

Direct determination of creatine kinase equilibrium constants with creatine or cyclocreatine substrate.

The equilibrium constants of two reactions catalyzed by rabbit muscle creatine kinase with creatine or cyclocreatine as substrate were determined by 31P-NMR. The value of the equilibrium constant with creatine as substrate was 172.10(7) M(-1) in agreement with previous work (Veech, R.L., Lawson, J.W.R., Cornell, W. and Krebs, H.A. (1979) J. Biol. Chem 254, 6538-6547). The value with cyclocreatine was 5.62.10(7) M(-1) and the ratio of the two constants is 30.6. It was possible to determine the ratio of the two equilibrium constants in a reaction mixture containing both substrates since it was found that the 31P resonances of P-creatine and P-cyclocreatine were well resolved. The ratio of K1/K2 determined in such experiments was 34.6, of the same order as previously reported by Annesley and Walker (Annesley, T.M. and Walker, J.B. (1977) Biochem. Biophys. Res. Commun. 74, 185-190).

Adenosine Diphosphate↗

PubMedDate not supplied

[Creatine and phosphocreatine concentrations and creatine phosphokinase activity in the hearts of dogs with restricted coronary blood flow].

Alterations in some patterns of energy metabolism, which are essential for energy transport in myocardial cells, were studied in dogs with local artificial impairment by 70% of coronary circulation. In this case activity of creatine phosphokinase and content of creatine phosphate were decreased, particularly in the ischemic zone, but creatine concentration was unaltered. Possible role of creatine is discussed not only as a regulator of systolic pressure but also as an indicator of the functional state of myocardium.

Animals↗

PubMed1988

Isolation of four rat creatine kinase genes and identification of multiple potential promoter sequences within the rat brain creatine kinase promoter region.

Rat genes encoding muscle creatine kinase (gene ckm) and brain creatine kinase (gene ckb) have been cloned. The two genes have an identical intron-exon distribution, although introns of the ckb gene are much smaller than those for ckm. The complete nucleotide sequence has been determined for the ckb gene. 5'-Flanking sequences have been compared for both ckm and ckb. The ckb gene has a structurally complex 5'-flanking region with multiple TATA and CAAT sequences suggesting that the gene may contain overlapping promoter elements. Examination of ckb RNA from brain tissue provides no evidence for the existence of more than one set of transcriptional start points. The ckm and ckb genes show little homology in the 5'-flanking regions, although we observed some sequence conservation in the regions immediately surrounding the CAAT and TATA sequences. The rat genome also contains two other creatine kinase-like sequences which may represent processed pseudogenes or mitochondrial creatine kinase.

Amino Acid Sequence↗

PubMed1998

Identification of the creatine binding domain of creatine kinase by photoaffinity labeling.

A new photoaffinity probe with a benzophenone group, N-dibenzylphospho-N'-(4-benzoyl)-benzylguanidine (BzPG), has been synthesized on the basis on our previously described creatine kinase bisubstrate analog. BzPG is also a bisubstrate type analog whose photoinsertion is inhibited by the natural substrates of creatine kinase. When rabbit CK-MM is irradiated in the presence of BzPG then cleaved by CNBr, one labeled peptide can be purified by reverse phase HPLC and sequenced. This sequence of 31 amino acids (Ala30-Val60) contains a region which could be responsible for isoenzyme selectivity and another one just preceding the 11 amino acid peptide (Asp61-Thr70) very recently described as a putative creatine binding site. This second peptide was deduced from the comparison of 18 amino acid sequence alignments. We proposed the creatine binding site to be essentially a peptide from Lys39 to Val71.

Animals↗