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PubMed2002

Novel mitochondrial creatine transport activity. Implications for intracellular creatine compartments and bioenergetics.

Immunoblotting of isolated mitochondria from rat heart, liver, kidney, and brain with antibodies made against N- and C-terminal peptide sequences of the creatine transporter, together with in situ immunofluorescence staining and immunogold electron microscopy of adult rat myocardium, revealed two highly related polypeptides with molecular masses of approximately 70 and approximately 55 kDa in mitochondria. These polypeptides were localized by immunoblotting of inner and outer mitochondrial membrane fractions, as well as by immunogold labeling in the mitochondrial inner membrane. In addition, a novel creatine uptake via a mitochondrial creatine transport activity was demonstrated by [(14)C]creatine uptake studies with isolated mitochondria from rat liver, heart, and kidney showing a saturable low affinity creatine transporter, which was largely inhibited in a concentration-dependent manner by the sulfhydryl-modifying reagent NEM, as well as by the addition of the above anti-creatine transporter antibodies to partially permeabilized mitochondria. Mitochondrial creatine transport was to a significant part dependent on the energetic state of mitochondria and was inhibited by arginine, and to some extent also by lysine, but not by other creatine analogues and related compounds. The existence of an active creatine uptake mechanism in mitochondria indicates that not only creatine kinase isoenzymes, but also creatine transporters and thus a certain proportion of the creatine kinase substrates, might be subcellularly compartmentalized. Our data suggest that mitochondria, shown here to possess creatine transport activity, may harbor such a creatine/phosphocreatine pool.

Animals↗
PubMed2001

The effect of 7 days of creatine supplementation on 24-hour urinary creatine excretion.

Since the discovery that oral ingestion of creatine leads to an increase in intramuscular creatine, its supplementation has become widespread. However, the dosage necessary to maximize retention and create significant increases in intramuscular creatine is poorly understood. In this study, 24-hour urinary creatine and creatinine levels of 20 university men's football players and 20 university men's hockey players involved in a resistance-exercise program and supplementing with creatine were collected and analyzed. In a double-blind, randomized design, 10 football players and 10 hockey players were randomly assigned to either the supplement or placebo group. Subjects provided a 24-hour urine sample twice during the study: once prior to supplementation (baseline) and the second 7 days after daily supplementation and resistance exercise. Creatine dosage was 0.1 g x kg(-1) lean body mass. The quantity of creatine ingested was compared with the amount excreted in the urine of those subjects supplementing with creatine and with placebo. Creatinine levels were compared between the first and second urine collection and between groups. Creatine and creatinine concentrations were determined using high-performance liquid chromatography. In 24-hours, 46% of the ingested creatine was excreted. There was no change in creatine levels for placebo subjects. Creatinine levels remained the same within groups at the first and second collection times (p < 0.05). Our findings indicate that when supplementing with dosages of 0.1 g x kg(-1) lean body mass or between 6 and 8 g at a time, approximately half of the ingested creatine gets excreted. Because there was no change in urinary creatinine, it can be assumed that enhanced degradation of creatine did not occur.

Administration, Oral↗
PubMed1994

Kinetics of creatine uptake in the perfused mouse liver: a 31P-n.m.r. study of transgenic mice expressing creatine kinase (CKBB) in the liver.

Transport of creatine in the mouse liver has been investigated in vivo and in the perfused organ. Experiments were carried out with transgenic mice expressing creatine kinase in the liver (brain isoenzyme CKBB; EC 7.2.3.2.) [Koretsky, Brosnan, Chen, Chen and Van Dyke (1990) Proc. Natl. Acad. Sci. U.S.A. 87, 3112-3116] and in the corresponding control mice. The animals were fed a regular chow with or without the addition of 10% creatine (w/w) for 5 days. The kinetics of creatine uptake was measured in the perfused liver by 31P-n.m.r. spectroscopy and biochemical analysis following infusion of creatine at concentrations ranging over 0-15 mM and at an extracellular pH of either 7.40 or 6.40. The results suggest that creatine is actively transported by a pH-dependent mechanism obeying a saturable Michaelis-Menten type of kinetics (Km = 0.80 +/- 0.18 and 5.12 +/- 2.40 mM; Vmax. = 0.57 +/- 0.04 and 1.72 +/- 0.32 mumol.g of liver-1.min-1 at pH 7.40 and 6.40 respectively). Creatine export was evaluated in the perfused liver preloaded with creatine and the results show that less than 2.5 and 5% of the total creatine pool is exported to the perfusate during 80 min of perfusion at pH 7.40 and 6.40 respectively. Taken together, these results seem to explain the observation that creatine accumulates in the mouse liver only when blood creatine is raised by creatine feeding.

Animals↗
PubMedDate not supplied

[Various properties of the creatine transport system and the location of creatine kinase in skeletal muscle mitochondria].

Water and creatine contents were studied in rat skeletal muscle mitochondria after their 5 min. incubation in creatine solutions, pH 7.2 or 8.4. The content of water and creatine in mitochondria was found to be higher at pH 8.4, than at pH 72, the creatine content correlated with the water content. Structural creatine analogues, containing aminogroups with pKa greater than or equal to 9.5 or carboxyl groups, inhibited the infusion of creatine into mitochondria more strongly than substances having aminogroups with pKa less than 5. The penetrating form is creatine amphiion; the effect of pH on the permeability is probably due to the activation of the creatine transmitter. Rat skeletal muscle mitochondria contain creatine kinase at both sides of the inner membrane. This conclusion is based on the fact that under conditions, supplying the direct course of the creatine kinase reaction (the incubation medium contains Ca2+ and creatine; pH 7.8), ADP produces the stimulation of mitochondrial respiration up to the oxygen exhausting in a polarographic unit. Similarly, ADP irreversibly stimulates mitochondrial respiration in the presence of 1 mM EDTA, if EDTA and ADP are added after the preincubation of mitochondria in creatine-containing medium and after accumulating small amounts of Ca2+ by mitochondria.

Adenosine Diphosphate↗
PubMed1988

Velocity of the creatine kinase reaction in the neonatal rabbit heart: role of mitochondrial creatine kinase.

To examine the role of changes in the distribution of the creatine kinase (CK) isoenzymes [BB, MB, MM, and mitochondrial CK (mito-CK)] on the creatine kinase reaction velocity in the intact heart, we measured the creatine kinase reaction velocity and substrate concentrations in hearts from neonatal rabbits at different stages of development. Between 3 and 18 days postpartum, total creatine kinase activity did not change, but the isoenzyme distribution and total creatine content changed. Hearts containing 0, 4, or 9% mito-CK activity were studied at three levels of cardiac performance: KCl arrest and Langendorff and isovolumic beating. The creatine kinase reaction velocity in the direction of MgATP production was measured with 31P magnetization transfer under steady-state conditions. Substrate concentrations were measured with 31P NMR (ATP and creatine phosphate) and conventional biochemical analysis (creatine) or estimated (ADP) by assuming creatine kinase equilibrium. The rate of ATP synthesis by oxidative phosphorylation was estimated with oxygen consumption measurements. These results define three relationships. First, the creatine kinase reaction velocity increased as mito-CK activity increased, suggesting that isoenzyme localization can alter reaction velocity. Second, the reaction velocity increased as the rate of ATP synthesis increased. Third, as predicted by the rate equation, reaction velocity increased with the 3-fold increase in creatine and creatine phosphate contents that occurred during development.

Aging↗
PubMed1984

Creatine kinase expression and creatine phosphate accumulation are developmentally regulated during differentiation of mouse and human monocytes.

We have studied the expression of creatine kinase (CK) and the accumulation of creatine phosphate during the differentiation of human and mouse peripheral blood monocytes. Mouse monocytes cultured for 24 h do not contain detectable levels of CK and creatine phosphate. However, resident tissue macrophages and inflammatory elicited macrophages obtained from the peritoneal cavities of mice have 70 and 300 mU per mg protein of CK activity and contain 3 and 6 mol of creatine phosphate per mol of ATP, respectively. The major isozyme of CK in these cells has been identified as the brain form. These findings suggest that the differentiation of monocytes into macrophages is associated with the expression of CK and the accumulation of creatine phosphate. We have found a similar pattern in human monocytes. Human blood monocytes, maintained in culture for 24 or 48 h, do not contain detectable levels of CK or creatine phosphate. Monocyte-derived macrophages (monocytes maintained in tissue cultures for 1 to 2 wk) have up to 100 mU per mg protein of CK activity and contain 0.5 mol of creatine phosphate per mol of ATP. Human macrophages express multiple isozymes of CK including the brain (BB) and possibly the mitochondrial forms of this enzyme. Thus, the expression of CK and the accumulation of creatine phosphate in human monocytes is induced by their in vitro cultivation. The induction of CK during in vitro cultivation occurs independently of the concentration of creatine in the medium. However, the size of the creatine phosphate pool varies with respect to extracellular creatine concentration. Creatine phosphate and CK are not detectable in freshly isolated human lymphocytes, polymorphonuclear leukocytes or erythrocytes, but are found in freshly isolated human platelets.

Adult↗
PubMed1994

Immunoreactive creatine kinase-MB and creatine kinase isozyme concentrations during treatment of hypothyroid patients.

Using a highly sensitive enzyme immunoassay (EIA) system, we determined creatine kinase isozymes, namely creatine kinase-MB and creatine kinase-MM, in sera of patients suffering from primary hypothyroidism with concomitant signs of myocardial affections before and during treatment. After oral administration of L-thyroxine, the augmented mass concentrations of serum creatine kinase-MB and creatine kinase-MM, and the increased catalytic activity concentrations of serum total creatine kinase and creatine kinase-MB gradually decreased in inverse proportion to the increased concentrations of serum triiodothyronine (T3) and thyroxine (T4). By the 6th to 8th week after treatment, the elevated levels of serum total creatine kinase and creatine kinase-MB catalytic activity concentrations (assayed by a routine method) and serum creatine kinase-MM mass concentrations (assayed by EIA) declined to normal values, while serum T3, T4, and thyroid stimulating hormone attained normal values. Serum creatine kinase-MB mass concentrations (assayed by EIA), however, still remained at the higher level, without complete recovery from myocardial damage, as shown by electrocardiogram (ECG). These data indicate that metabolic distortion still exists in the myocardium, as revealed by the high creatine kinase-MB mass concentration, especially as assayed by EIA, even though the plasma levels of thyroid hormones had returned to normal.

Aged↗
PubMed2001

Creatine supplementation: exploring the role of the creatine kinase/phosphocreatine system in human muscle.

The effect of oral creatine supplementation on high-intensity exercise performance has been extensively studied over the past ten years and its ergogenic potential in young healthy subjects is now well documented. Recently, research has shifted from performance evaluation towards elucidating the mechanisms underlying enhanced muscle functional capacity after creatine supplementation. In this review, we attempt to summarise recent advances in the understanding of potential mechanisms of action of creatine supplementation at the level of skeletal muscle cells. By increasing intracellular creatine content, oral creatine ingestion conceivably stimulates operation of the creatine kinase (CK)/phosphocreatine (PCr) system, which in turn facilitates muscle relaxation. Furthermore, evidence is accumulating to suggest that creatine supplementation can beneficially impact on muscle protein and glycogen synthesis. Thus, muscle hypertrophy and glycogen supercompensation are candidate factors to explain the ergogenic potential of creatine ingestion. Additional issues discussed in this review are the fibre-type specificity of muscle creatine metabolism, the identification of responders versus non-responders to creatine intake, and the scientific background concerning potential side effects of creatine supplementation.

Creatine↗
PubMed1988

A possible role of the creatine phosphate-creatine pool in the regulation of the adenylate pool.

Human lymphoblastoid Raji cells and mouse hybridoma ascites cells incubated with 20 mM creatine showed significant increases in creatine, creatine phosphate and adenine nucleotide levels and in the energy charge. In human erythrocytes in which no variation of the creatine phosphate-creatine pool was observed because of a very low creatine kinase activity, the adenine nucleotide pool and the energy charge were not modified. These observations suggest not only a relationship among the creatine phosphate-creatine pool, the energy charge and the adenylate pool, but also the possibility to increase the energy charge and the adenylate pool in cells with creatine kinase activity by expanding the creatine phosphate-creatine pool.

Adenine Nucleotides↗
PubMed1986

Creatine kinase of heart mitochondria. Control of oxidative phosphorylation by the extramitochondrial concentrations of creatine and phosphocreatine.

Defining how extramitochondrial high-energy phosphate acceptors influence the rates of heart oxidative phosphorylation is essential for understanding the control of myocardial respiration. When the production of phosphocreatine is coupled to electron transport via mitochondrial creatine kinase, the net reaction can be expressed by the balanced equation: creatine + Pi----phosphocreatine + H2O. This suggests that rates of oxygen consumption could be regulated by changes in [creatine], [Pi], or [phosphocreatine], alone or in combination. The effects of altering these metabolites upon mitochondrial rates of respiration were examined in vitro. Rat heart mitochondria were incubated in succinate-containing oxygraph medium (pH 7.2, 37 degrees C) supplemented with five combinations of creatine (1.0-20 mM), phosphocreatine (0-25 mM), and Pi (0.25-5.0 mM). In all cases, the mitochondrial creatine kinase reaction was initiated by additions of 0.5 mM ATP. To emphasize the duality of control, the results are presented as three-dimensional stereoscopic projections. Under physiological conditions, with 5.0 mM creatine, increases in Pi or decreases in phosphocreatine had little influence upon mitochondrial respiration. When phosphocreatine was held constant (15 mM), changes in [creatine] modestly stimulated respiratory rates, whereas Pi again showed little effect. With 1.0 mM Pi, respiration clearly became dependent upon changes in [creatine] and [phosphocreatine]. Initially, respiratory rates increased as a function of [creatine]. However, at [phosphocreatine] values below 10 mM, product "deinhibition" was observed, and respiratory rates rapidly increased to 80% State 3. With 2.0 mM Pi or higher, respiration could be regulated from State 4 to 100% State 3. Overall, the data show how increasing [creatine] and decreasing [phosphocreatine] influence the rates of oxidative phosphorylation when mediated by mitochondrial creatine kinase. Thus, these changes may become secondary cytoplasmic signals regulating heart oxygen consumption.

Animals↗
PubMed1992

Elevation of creatine in resting and exercised muscle of normal subjects by creatine supplementation.

1. The present study was undertaken to test whether creatine given as a supplement to normal subjects was absorbed, and if continued resulted in an increase in the total creatine pool in muscle. An additional effect of exercise upon uptake into muscle was also investigated. 2. Low doses (1g of creatine monohydrate or less in water) produced only a modest rise in the plasma creatine concentration, whereas 5g resulted in a mean peak after 1h of 795 (SD 104) mumol/l in three subjects weighing 76-87 kg. Repeated dosing with 5g every 2h sustained the plasma concentration at around 1000 mumol/l. A single 5g dose corresponds to the creatine content of 1.1 kg of fresh, uncooked steak. 3. Supplementation with 5g of creatine monohydrate, four or six times a day for 2 or more days resulted in a significant increase in the total creatine content of the quadriceps femoris muscle measured in 17 subjects. This was greatest in subjects with a low initial total creatine content and the effect was to raise the content in these subjects closer to the upper limit of the normal range. In some the increase was as much as 50%. 4. Uptake into muscle was greatest during the first 2 days of supplementation accounting for 32% of the dose administered in three subjects receiving 6 x 5g of creatine monohydrate/day. In these subjects renal excretion was 40, 61 and 68% of the creatine dose over the first 3 days. Approximately 20% or more of the creatine taken up was measured as phosphocreatine. No changes were apparent in the muscle ATP content.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed2004

Effects of repeated creatine supplementation on muscle, plasma, and urine creatine levels.

The purpose of this case study was to examine the effects of repeated creatine administration on muscle phosphocreatine, plasma creatine, and urine creatine. One male subject (age, 32 years; body mass, 78.4 kg; height, 160 cm; resistance training experience, 15 years) ingested creatine (20 g.d(-1) for 5 days) during 2 bouts separated by a 30-day washout period. Muscle phosphocreatine was measured before and after supplementation. On day 1 of supplementation, blood samples were taken immediately before and hourly for 5 hours following ingestion of 5 g of creatine, and a pharmacokinetic analysis of plasma creatine was conducted. Twenty-four-hour urine collections were conducted before and for 5 days during supplementation. Muscle phosphocreatine increased 45% following the first supplementation bout, decreased 22% during the 30-day washout period, and increased 25% following the second bout. There were no meaningful differences in plasma creatine pharmacokinetic parameters between bouts 1 and 2. Total urine creatine losses during supplementation were 63.2 and 63.4 g during bouts 1 and 2, respectively. The major findings were that (a) a 30-day washout period is insufficient time for muscle phosphocreatine to return to baseline following creatine supplementation but is sufficient time for plasma and urine creatine levels to return to presupplementation values; (b) postsupplementation muscle phosphocreatine levels were similar following bouts 1 and 2 despite 23% higher presupplementation muscle phosphocreatine before bout 2; and (c) the increased muscle phosphocreatine that persisted throughout the 30-day washout period corresponded with maintenance of increased body mass (+2.0 kg). Athletes should be aware that the washout period for muscle creatine to return to baseline levels may be longer than 30 days in some individuals, and this may be accompanied by a persistent increase in body mass.

Adult↗
PubMed1985

Decreased mitochondrial creatine kinase activity in dystrophic chicken breast muscle alters creatine-linked respiratory coupling.

Dystrophic chicken breast muscle mitochondria contain significantly less mitochondrial creatine kinase than normal breast muscle mitochondria. Breast muscle mitochondria from normal 16- to 40-day-old chickens contain approximately 80 units of mitochondrial creatine kinase per unit of succinate:INT (p-iodonitrotetrazolium violet) reductase, a mitochondrial marker, while dystrophic chicken breast muscle mitochondria contain 36-44 units. Normal chicken heart muscle mitochondria contain about 10% of the mitochondrial creatine kinase per unit of succinate:INT reductase as normal breast muscle mitochondria. The levels in heart muscle mitochondria from dystrophic chickens are not affected significantly. Evidence is presented which shows that the reduced level of mitochondrial creatine kinase in dystrophic breast muscle mitochondria is responsible for an altered creatine linked respiration. First, both normal and dystrophic breast muscle mitochondria respire with the same state 3 and state 4 respiration. Second, the post-ADP state 4 rate of respiration of normal breast muscle mitochondria in the presence of 20 mM creatine continues at the state 3 rate. However, the state 4 rate of dystrophic breast muscle mitochondria and mitochondria from other muscle types with a low level of mitochondrial creatine kinase, such as heart muscle and 5-day-old chicken breast muscle, is slower than the state 3 rate. Third, dystrophic breast mitochondria synthesize ATP at the same rate as normal breast muscle mitochondria but rates of creatine phosphate synthesis in 20-50 mM Pi are reduced significantly. Finally, increasing concentrations of Pi displace mitochondrial creatine kinase from mitoplasts of normal and dystrophic breast muscle mitochondria with the same apparent KD, indicating that the outer surface of the inner mitochondrial membrane and the mitochondrial creatine kinase from dystrophic muscle are not altered.

Adenosine Triphosphate↗
PubMedDate not supplied

[Creatine induction of creatine kinase synthesis in a developing monolayer culture of muscle cells].

Creatine action on the activity of creatine kinase (ATP: creatine-phosphotransferase; EC 2.7.3.2) and the content of water-soluble proteins in the developing monolayer culture of chick myoblasts are studied. Creatine at concentrations of 1.9-10- minus 3-3.8-10- minus 3 M is shown to increase reliably the creatine kinase activity by 1,1--2,9 times and to reduct considerably the content of water-soluble proteins. Lower concentrations of creatine (3.8-10- minus 5 M) also increased the creatine kinase activity but did not change the contents of water-soluble proteins. The creatine effect was maximal at the period preceding the termination of tissue cells differentiation. In the course of the combined effect of both actinomycin D (50 mcg/plate) and creatine (3.8-10- minus 3 M) the creatine kinase activity was much higher than that in the presence of actinomycin D alone which considerably reduced the enzyme activity as well as the contents of water-soluble proteins.

Animals↗
PubMed1996

Carbohydrate ingestion augments creatine retention during creatine feeding in humans.

Blood and urine samples were obtained from four groups of healthy male subjects (A-D, total n = 22) before, during and after ingesting the following: group A, 5 g of creatine in solution; groups B and C, 5 g of creatine and 93 g of simple carbohydrate in solution: group D, a creatine- and carbohydrate-free solution. Subjects ingested the above preparations every 4 h for the remainder of the day and throughout the next day (total daily creatine dose = 20 g), and reported back to the laboratory on day 3 to undergo the same procedures as on day 1. Throughout this time, subjects weighed and recorded all dietary intake, and those in groups B and C ingested a prescribed isoenergetic high carbohydrate diet. Subjects in group C also performed 1 h of cycling exercise at 70% of their maximal oxygen consumption on the morning of each day. On both days 1 and 3, peak plasma creatine concentration, the area under the plasma creatine concentration/time curve and urinary creatine concentration were lower in groups B and C than in group A. Conversely, serum insulin concentration was higher in groups B and C than in A. No differences were evident when comparing groups B and C. These data suggest carbohydrate ingestion augmented creatine retention during creatine feeding and that creatine retention was not further increased when exercise was performed prior to ingestion.

Adult↗