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AbstractTotal creatine (Crtotal = phosphocreatine + creatine) concentrations differ substantially among mammalian skeletal muscle. Bernd Walzel, Oliver Speer, Ernie Boehm, Soren Kristiansen, Sharon Chan, Kierian Clarke, Joseph P. American Journal of Physiology - Endocrinology and Metabolism Published 2 November 2006 Vol.
Electrical field stimulation of isolated, incubated rodent skeletal muscles is a frequently used model to study the effects of contractions on muscle metabolism. Male NMRI mice (n = 118) weighing 35–50 g were purchased from Janvier Breeding Center (Le Genest St.-Isle, France). Incubated muscles were exposed to either electrically induced muscle contractions or electrolyzed incubation medium in the absence of contractions. Soleus and EDL muscles from both legs were excised and incubated in previously electrolyzed or control medium, as described above. Effects of interventions were statistically analyzed with paired (contralateral muscle within one mouse) or unpaired (between mice) Student's t-tests or factorial analysis of variance (ANOVA) depending on the intervention examined. A standard stimulation protocol of 12 min of repeated tetanic stimulations was applied to evaluate the effects of muscle contractions on creatine transport.
Therefore, we decided to perform two series of control experiments to investigate whether the electrical stimulation by the electrodes, and the inherent electrolysis of the oxygenated physiological buffer, would generate the creatine transport-stimulating factor. To investigate whether the formation of ROS is involved in the electrolysis-induced stimulation of muscle creatine transport, we tested the effect of the ROS scavenging enzymes SOD and catalase.
Outside the brain, the major site of norepinephrine and epinephrine synthesis is in adrenal medullary chromaffin cells. Neuronal NOS (nNOS) is constitutively expressed in specific neurons within the brain and spinal cord.
GSH is synthesized in the cytosol of all mammalian cells via the two-step reaction shown in the Figure.
The polyamines are highly cationic molecules that tend to bind nucleic acids with high affinity.
An important intermediate required for the synthesis of spermidine and spermine from putrescine is derived from S-adenosylmethionine (SAM). The AMD1 gene is located on chromosome 6p21 and is composed of 10 exons that generate four alternatively spliced mRNAs that encode four distinct isoforms of the enzyme. The stability of the ODC1 protein also contributes to the level of enzyme activity in cells. Antizyme 2 is encoded by the OAZ2 gene which is located on chromosome 15q22.31 and is composed of 5 exons that generate two alternatively spliced mRNAs that encode two distinct protein isoforms. As discussed, the synthesis of the polyamines is regulated by several independent mechanisms. In this study, this model was used to investigate the effects of electrically stimulated contractions on creatine transport. The effects of muscular activity and exercise on muscle metabolism are often studied using the isolated rodent muscle incubation model. In the contraction experiments, wires were attached to the tendons, and muscles were mounted vertically in an incubation bath between two platinum surface electrodes (Hugo Sachs Electronik, March, Germany) with one tendon attached to a force transducer.
Within the locus coeruleus region of the brain the end product of the pathway is norepinephrine. Segawa syndrome is an autosomal recessive disorder that manifests in early infancy as a DOPA-responsive dystonia. DOPA decarboxylase (also known as aromatic L-amino acid decarboxylase) is encoded by the DDC gene. The major location, within the brain, for norepinephrine synthesis is the locus coeruleus of the brainstem. Outside the brain, dopamine is synthesized in several tissues including the gastrointestinal system where its actions reduce gastrointestinal motility, the pancreas where its actions inhibit insulin synthesis, and in the kidneys where its actions increase sodium excretion and urinary output.
Tryptophan hydroxylase represents the rate-limiting step in serotonin and melatonin synthesis. Histamine is synthesized by the enzymatic decarboxylation of the amino acid histidine by the enzyme L-histidine decarboxylase (HDC). The isoform 1 protein is composed of 662 amino acids and the isoform 2 protein is composed of 629 amino acids.
The NOS1 gene is located on chromosome 12q24.22 and is composed of 35 exons the generate multiple alternatively spliced mRNAs that encode three characterized isoforms. The NOS2 gene is located on chromosome 17q11.2 and is composed of 29 exons that encode a protein of 1153 amino acids. The NOS3 gene is located on chromosome 7q36 and is composed of 29 exons that generate multiple alternatively spliced mRNAs that encode four characterized isoforms.
When intracellular Ca2+ levels rise the calmodulin subunits have an increased affinity for eNOS and nNOS. However, expression of eNOS is also detected in platelets, cardiac myocytes, specific renal tubular epithelial cells, certain neurons within the brain, and in placental syncytio-trophoblast cells.
The cGMP, in turn, activates PKGI isoforms resulting in the phosphorylation of smooth muscle proteins that lead to relaxation. Although predominately induced in macrophages, under appropriate stimulation conditions many other cell types will express the iNOS gene. The formation of guanidinoacetate from these two amino acids is catalyzed by the enzyme glycine amidinotransferase, also called L-arginine:glycine amidinotransferase.
These compounds form conjugates with GSH either spontaneously or enzymatically in reactions catalyzed by members of the glutathione S-transferase (GST) family.
Because of this interaction activity, it is believed that the polyamines are important participants in DNA synthesis, or in the regulation of that process. The SMS gene is located on the X chromosome (Xp22.1) and is composed of 13 exons that generate two alternatively spliced mRNAs encoding SMS isoform 1 (366 amino acids) and SMS isoform 2 (313 amino acids).
The promoter of the ODC1 gene contains elements that are regulated by growth factors, hormones, and tumor promoters. The half-life of ODC protein is short (< 1hr) and this half-life is controlled by proteosomal degradation. In addition to the two different isoforms, the antizyme 1 mRNA contains two in-frame AUG codons that have been shown, in rodents, to be alternatively utilized resulting in differentially localized antizyme 1 isoforms.
In addition to these mechanism of control, intracellular polyamine levels are also regulated via their catabolism. To test this hypothesis, hindlimbs of adult rats were perfused with 0.05–1 mM [14C]creatine for up to 90 min. Soleus and extensor digitorum longus muscles of male NMRI mice (35–50 g) were incubated in an oxygenated Krebs buffer between platinum electrodes.
Electrical field stimulation was obtained by direct currents (100 mA) delivered in tetanic trains of 350 ms duration with a pulse frequency of 50 Hz for soleus and 100 Hz for EDL and a pulse duration of 1 ms (unless otherwise stated).
In some circumstances, when no statistical difference was observed between effects in soleus and EDL, data from both muscle types were pooled for statistical evaluation.
1A, electrically stimulated muscle contractions stimulated creatine transport two- and fourfold in soleus and EDL, respectively.
Within adrenal medulla chromaffin cells, tyrosine is converted to norepinephrine and epinephrine. Two distinct phenotypes are associated with Segawa syndrome, one that manifests very early and presents with symptoms of greater severity, and a later onset less severe type that responds better to L-DOPA therapy. Dopamine β-hydroxylase is a critical vitamin C (ascorbate) and copper (Cu2+)-dependent enzyme. The major brain region for the synthesis of dopamine is the substantia nigra which is located below the posterior hypothalamus and next to the ventral tegmetal area. Within the gastrointestinal tract bacteria also produce histamine via a similar decarboxylation reaction. The HRH1 gene is located on chromosome 3p25 and is composed of 8 exons that generate four alternatively spliced mRNAs all of which encode the same 487 amino acid protein. The heme moiety of one monomer is indeed essential for the process of interdomain electron transfer between NADPH and the flavins (FAD and FMN) to the heme of the opposite monomer.


The calmodulin subunits facilitate the flow of electrons from NADPH to the heme moiety in the oxygenase domain of the enzyme.
The ability of eNOS produced NO to prevent platelet adhesion and aggregation reduces the propensity for the development of abnormal fibrin clots (thrombi) and, therefore, will contribute to a reduced potential for the development of atherosclerosis. Neuronal NOS is also constitutively expressed within the adrenal glands, pancreatic islet cells, epithelial cells of numerous tissues, vascular smooth muscle, skeletal muscle, and renal macula densa cells. Glycine amidinotransfersae is encoded by the GATM gene located on chromosome 15q21.1 and is composed of 12 exons that encode a 423 amino acid protein that localizes to the mitochondria.
The conjugates formed are usually excreted from the cell and, in the case of the liver they are excreted in the bile. In addition to their function in DNA replication, polyamines and polyamine derivatives are involved in the processes of protein synthesis, ion channel function, regulation of gene expression, cell proliferation, and apoptosis (programmed cell death). Production of ODC protein is also regulated at the level of translation by the product of the reaction, putrescine.
However, entry into the proteosome, in the case of ODC, does not require prior ubiquitination. Antizyme 3 is encoded by the OAZ3 gene which is located on chromosome 1q21.3 and is composed of 7 exons that generate three alternatively spliced mRNAs encoding three distinct protein isoforms. Muscles were exposed to [14C]creatine for 30 min after either 12 min of repeated tetanic isometric contractions (contractions) or electrical stimulation of only the buffer before incubation of the muscle (electrolysis). Such in vitro contractions have long been shown to potently stimulate the transport of glucose (14), fatty acids (9), and amino acids (22) in isolated skeletal muscles.A process that is frequently overlooked in electrical field stimulation experiments with incubated muscles is electrolysis. Four minutes after the initial determination of the optimal muscle length (L0), muscles were tetanically stimulated for 12 min in six consecutive blocks of 2 min each. However, the magnitude of creatine transport stimulation depended on the incubation volume: higher volume resulted in a smaller degree of stimulation (Fig. DOPA decarboxylase (also known as aromatic L-amino acid decarboxylase) is encoded by the DDC gene which is located on chromosome7p12.2 and is composed of 18 exons that generate multiple alternatively spliced mRNAs.
The presence of high concentrations of tyrosine in the locus coeruleus and the substantia nigra leads to increased melanin synthesis which confers on these brain regions a dark bluish coloration observable in brain sections. The principal cells that synthesize and release histamine are mast cells and basophils of the immune system, enterochromaffin-like cells of the gastrointestinal system, and neurons.
The HRH2 gene is located on chromosome 5q35.2 and is composed of 8 exons that generate two alternatively spliced mRNAs.
All three NOS enzymes function as homodimers and the interactions of the subunits is required for the process of electron flow from NADPH (bound in the reductase domain of the enzyme), through the various co-factors to the heme moiety which is bound to the N-terminal oxygenase domain of the enzyme.
When intracellular Ca2+ rises it facilitates the binding of the calmodulin subunits to eNOS and nNOS. However, other factors regulate the activity of eNOS that are not related to changes in calcium concentrations. Endothelial cell produced NO can also interfere with leukocyte adhesion to the endothelium thus, further contributing to a reduction in the potential for atherosclerosis. Within the brain the principal functions of nNOS produced NO are in the mediation of long-term synaptic transmission.
The production of large amounts of NO by activation of iNOS expression in macrophages represents the major cytotoxic activity of these cells. Guanidinoacetate it transported to the blood and picked up by heptocytes where it is methylated forming creatine. There are several GST enzymes that are divided into three major families that comprise cytsolic, mitochondrial, and microsomal family members. The ODC1 mRNA contains a long 5'-untranslated region (5'-UTR) that folds into a complex secondary structure. The ability of the proteosome to recognize, and degrade, non-ubiquitinated ODC involves a family of proteins called antizymes.
Antizyme 3 isoform 1 is the longest protein encoded by the OAZ3 gene and the translation of this form of the enzyme begins from a CUG codon and not an AUG codon. The SAT1 gene is located on the X chromosome (Xp22.1) and is composed of 7 exons that generate two alternatively spliced mRNAs. These rates were unaltered by time, insulin concentration, or increased perfusate sodium concentration.
Electrolysis was also investigated in the presence of the reactive oxygen species (ROS) scavenging enzymes superoxide dismutase (SOD) and catalase.
Exposure of a physiological buffer to a 95% O2-5% CO2 gas mixture results in very high Po2 (?700 mmHg).
Uptake of creatine and 2-deoxy-d-glucose was calculated as the difference between the total tissue radioactivity (dpm) and the amount of radioactivity present in the tissue extracellular (inulin or mannitol) space and expressed per milligram wet muscle weight. H2O2 generation was estimated at 6 and 12 min during and in 10-min intervals following electrical stimulation. First, a fixed volume of well-oxygenated buffer was exposed to electrical stimulation (12 min of repeated tetanic stimulation) in the absence of a muscle.
The DDC encoded enzyme is also responsible for the conversion of 5-hydroxytryptophan to serotonin (see next section) and tryptophan to tryptamine. The TPH2 gene is located on chromosome 12q21.1 and is composed of 14 exons that encode a protein (tryptophan 5-hydroxylase 2) of 490 amino acids. The synthesis and storage of histamine by mast cells and basophils represents the greatest store (>90%) of the neurotransmitter. Several proteins, such as caveolin-1 and hsp90, interact with and affect the overall activity of eNOS. Production of NO within the brain, via nNOS, is also important for the central regulation of blood pressure. The NO produced binds to the iron in numerous enzymes that contain the metal in their active sites. The methyl donor for this reation is S-adenosylmethionine (SAM) and the reaction is catalyzed by the enzyme guanidinoacetate N-methyltransferase. The antizyme proteins interact with ODC monomers preventing formation of functional homodimers while simultaneously altering the conformation of the monomers so that they are recognized by the proteosome. The first reaction involves the enzyme deoxyhypusine synthase which transfers the butylamine moiety from spermidine to the specific eIF-5A lysine residue. Conversely, creatine uptake rates were correspondingly decreased among fiber types by lower creatine and sodium concentrations. Both contractions and (to a lesser degree) electrolysis stimulated creatine transport severalfold over basal. Such a condition facilitates the formation of reactive oxygen species (ROS) due to electrolysis, predominantly the hydroxyl radical (·OH) and the superoxide anion radical (O2·?) at the side of the anode and cathode, respectively (18). Hindlimbs were exposed, and soleus and extensor digitorum longus (EDL) muscles from both legs were excised.
During electrolysis experiments, the electrical stimulation protocol was performed in the incubation medium prior to mounting of the muscle, whereafter the muscle was incubated within 1 min after completion of the electrolysis. An aliquot of supernatant containing 400 ?g of total protein (quantitated with the BCA Protein Assay Kit; Pierce) was incubated overnight with 50 ?l of streptavidin-agarose beads (Sigma) at 4°C with gentle agitation. Thereafter, a muscle was placed in the previously electrolyzed buffer, and creatine transport was measured in the absence of electrical stimulation. Within the brain the neurons that synthesize histamine are within the tuberomammillary nucleus of the hypothalamus. The HRH3 gene is located on chromosome 20q13.33 and is composed of 4 exons that encode a 445 amino acid protein. Peripheral production of NO via the action of nNOS, like that produced by the action of eNOS, can effect changes in vascular tone. Examples of NO-inhibited enzymes include the Fe-S cluster-dependent activities of mitochondrial oxidative phosphorylation and ribonucleotide reductase. This latter enzyme is encoded by the GAMT gene located on chromosome 19p13.3 and is composed of 6 exons that generate two alternatively spliced mRNAs that encode isoform a (236 amino acids) and isoform b (269 amino acids).
The human genome contains five GST alpha genes, five mu genes, two omega genes, one pi gene, one sigma gene, two theta genes, and one zeta gene. One domain is a GC-rich sequence, the other is a small functional upstream open reading frame (uORF).


The second reaction involves the enzyme deoxyhypusine hydroxylase which hydroxylates the deoxyhypusine to hypusine. The amount of electrolysis, but not contractile activity, induced (determined) creatine transport stimulation. Reactive oxygen metabolites are known to play an important role in the regulation of cell function in general (8) and skeletal muscle in particular (24). Whenever possible, the intervention (contractions, electrolysis) was performed on the muscles of one leg and the muscles of the other leg served as simultaneous nonstimulated controls, and effects were then analyzed by paired statistical comparison. Dopamine β-hydroxylase is found as both a soluble and a membrane-bound enzyme dependent upon whether or not the signal peptide from the precursor protein is present. The HRH4 gene is located on chromosome 18q11.2 and is composed of 5 exons that generate three alternatively spliced mRNAs.
Following synthesis creatine is released to the blood where is is picked up by the brain and skeletal muscle cells through the action of the SLC family member transporter, SLC6A8. The cytosolic enzymes are functional as dimers and since the alpha and mu proteins can form functional heterodimers, the complexity of functional enzymes is greater than the number of individual subunit genes. Another significant mechanism for regulating ODC1 mRNA translation is particularly important during mitosis.
Antizyme 1 is encoded by the OAZ1 (ornithine decarboxylase antizyme 1) gene which is located on chromosome 19p13.3 and is composed of 5 exons that generate two alternatively spliced mRNAs. In addition to putrescine, the AOC1 encoded enzyme is responsible for the catabolism of histamine and other related biogenic amines. Deoxyhypusine synthase is encoded by the DHPS gene located on chromosome 19p13.2 which is composed of 13 exons that generate three alternatively spliced mRNAs, each of which encode a distinct isoform of the enzyme.
Creatine uptake rates differ among skeletal muscle fiber sections in a manner reasonably assigned to the 58-kDa band of the CrT.
In 1984, Lamb and Webb (17) showed that electrolysis of an oxygenated buffer leads to relaxation of isolated arteries and that this effect is inhibited by scavenging enzymes of ROS. The captured biotinylated proteins were eluted in 50 mM dithiothreitol for 2 h, and CRT expression was quantified as previously described (28).
The phenylethanolamine N-methyltransferase gene (symbol: PNMT) is located on chromosome 17q12 and is composed of 5 exons that generate two alternatively spliced mRNAs, one of which is non-coding, the other encodes a protein of 282 amino acids.
Neuronal NOS is expressed within smooth muscle cells of the penile corpus cavernosum and thus, NO produced by this enzyme is involved in penile erection. These effects of macrophage produced NO explain, to a large degree, the cytotoxic and cytostatic effects of NO on invading parasites as well as on certain tumor cells. Within these cells creatine is phosphorylated by creatine kinases (CK; also called creatine phosphokinase, CPK) that generate the high-energy storage compound, creatine phosphate. Another soluble GST enzyme that is not found in the cytosol is the human GST kappa (κ, K) enzyme (encoded by the GSTK1 gene) that is localized to the peroxisomes. These two mRNAs encode antizyme 1 isoform 1 (228 amino acids) and antizyme 1 isoform 2 (226 amino acids). Furthermore, creatine uptake rates scale inversely with creatine content, with the lowest uptake rate in the fiber type with the highest Crtotal and vice versa.
The electrolysis effects on creatine uptake were completely inhibited by ?-guanidino propionic acid, a competitive inhibitor of (creatine for) the creatine transporter (CRT), and were accompanied by increased cell surface expression of CRT.
Interestingly, further studies have shown that ROS, in particular the superoxide-derived ·OH and R·, play a role in myocardial reperfusion injury (33), and electrolysis became an established method for studying the physiological role of ROS in cardiovascular function. The incubation medium was continuously gassed with a mixture of 95% O2-5% CO2 (resulting in a buffer Po2 of 600–700 mmHg) and maintained at 30°C, and the muscles were allowed to recover without tension for 20 min following the isolation prior to intervention. In short, biotynilated proteins were separated using the NuPAGE polyacrylamide 4–12% Bis-Tris gels system (Invitrogen) and transferred to Protran nitrocellulose membranes by semidry Western blotting. During the second step the enzyme oxidizes the Nω-hydroxy-L-arginine to L-citrulline and NO.
Phosphorylation of eNOS enhances the flow of electrons through the reductase domain of the enzyme. The translation of the functional antizyme 1 proteins is regulated by a polyamine-regulated ribosome frameshifting mechanism. 1A, but after completion of the contraction series the incubation medium was discarded (intended to remove the stimulating factor from the bath), and creatine transport in the previously contracted muscle was determined in a fresh incubation medium.
The predominant effects of NO produced in response to eNOS activiation are vasodilation and inhibition of platelet adhesion and aggregation. The CKM gene is located on chromosome 19q13.32 and is composed of 9 exons that encode a protein of 381 amino acids. The present results indicate that electrical field stimulation of incubated mouse muscles, independently of contractions per se, stimulates creatine transport by a mechanism that depends on electrolysis-induced formation of ROS in the incubation buffer. In incubated rat muscles, direct addition of H2O2 or enzymatic production of ROS using glucose oxidase stimulates glucose transport at micromolar H2O2 concentrations (3, 12). By doing this (contractions alone), no stimulation of creatine transport was observed (Fig.
The CKB gene is located on chromosome 14q32 and is composed of 8 exons that encode a protein of 381 amino acids. The increased creatine uptake is paralleled by an increased cell surface expression of the creatine transporter. Studies in other cell types (human platelets and cultured rabbit epithelial cells) have shown that sodium-dependent transporter systems are also sensitive to stimulation by ROS (2, 4).Creatine and phosphocreatine form an important phosphagen system in mammalian cells with high and fluctuating energy demands. The immunoreactive bands were visualized with a chemiluminescence detection kit (Axon Lab, Switzerland).
Different combinations of the proteins encoded by these two genes generate tissue-specific isoforms of the functional enzymes. Creatine is directly linked to the resynthesis of ATP through the creatine kinase reaction and the phosphocreatine shuttle (30). Elevation of the muscular and neuronal creatine content by oral creatine supplementation has recently been shown to improve muscular performance and to protect against certain muscular and neurodegenerative disorders (13, 31).
This finding suggests that creatine transport stimulation is proportional to the amount of electrolysis. Creatine transport into muscle cells is facilitated by a specific Na+- and Cl?-dependent creatine transporter (CRT).
Elegant studies using one-legged cycling in humans (11, 27) showed that, during a 1-wk oral creatine supplementation period, muscle creatine accumulation was more pronounced in the exercised leg than in the contralateral leg. A: schematic representation of the 4 different interventions prior to creatine transport measurements (results in B).
Evidence of locally regulated metabolite uptake in active muscles has previously been shown for glucose (1) and was confirmed in contemporary in vitro experiments in isolated rodent muscles (14). Different conditions during electrical stimulation included electrolysis (electrical stimulation of buffer prior to incubation of muscle), contractions + electrolysis (electrical stimulation of incubated muscle, as in Fig. In fact, later studies showed that muscle contractions stimulate the translocation and activation of the main glucose transporter (GLUT4) to the plasma membrane by intracellular signals (21; reviewed in Ref. 1), and contractions (electrical stimulation of incubated muscle, but subsequent removal of electrolyzed buffer).
25).The present study hypothesized that isolated muscle contractions stimulate creatine transport in vitro. For this purpose, we exposed isolated, incubated mouse soleus and extensor digitorum longus (EDL) muscles to [14C]creatine during electrical field stimulation.
Additionally, we investigated the possible confounding effect of electrolysis in the study of electrically stimulated contractions in muscle creatine transport and the potential contribution of ROS herein. Finally, we also explored the possible contribution of the sarcolemmal CRT content in this process.



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