Creatine Administration Research Articles

Effect of creatine administration on locomotor activity and stress response in olive flounder (Paralichthys olivaceus)

The creatine kinase system is crucial for maintaining cellular energy homeostasis and plays a role in regulating locomotor behavior in organisms, but its significance in the regulating the motionless behavior in olive flounder is limited. In the first experiment of this study, elevated levels of creatine kinase (CK) activity in the spinal cord were detected in the juvenile group (JG) flounder compared to the adult group (AG) flounder. In the second experiment, to further confirm the involvement of CK in the locomotor behavior, the adult flounder was given an intraperitoneal injection of creatine (150 mg/kg), while the flounder in the control group received a saline solution. After one week post-injection, the behavioral analysis revealed that the flounder in the creatine-treated group displayed higher levels of locomotor activity and a greater number of escape attempts in response to external stimuli when compared to the control group. However, the acute stress response, induced by intraperitoneal injection and characterized by tail beating, was significantly alleviated in the flounder in the creatine-treated group. Additionally, there was an upregulation of the UII and AchR genes in the spinal cord, as well as increased levels of UII and AchR in the muscle tissues of the creatine-treated flounder. However, a reduction in UI mRNA levels was observed in the brain of the flounder. Collectively, our data provide the evidence that the elevated enzyme activity and gene expression of creatine kinase play important roles in off-bottom swimming behavior in the JG flounder. Furthermore, administration of creatine improved the locomotor activity and alleviated the stress response in flounder, which is associated with regulation of the locomotor- and stress-related gene in the brain, spinal cord, and muscle.

Estimating the dosage and feasibility of intranasal administration of creatine.

Creatine dysregulation is present in many psychiatric and neurocognitive conditions, supporting the notion that oral creatine supplementation could constitute a viable treatment for conditions such as dementia, depression, and concussion. We recently proposed an intranasal route of administration (ROA) of creatine as a means of efficiently dosing creatine to achieve absorption across the blood brain barrier while targeting preferential delivery to the brain. Indeed, a subsequent murine study supports that creatine can be absorbed via the nasal ROA. The objective of this project is to refine this ROA and estimate appropriate dosage for research trials. The amount of creatine needed to directly supply the brain is but a small portion of the dose that is administered orally for whole-body saturation. A single dose of creatine is typically 5 g, which results in a calculated blood concentration of 80 mg/dL based upon average adult blood volume. Evidence suggests this is sufficient to raise brain creatine levels. Given the adult brain blood volume of 100‒130 mL, we estimate that a minimum of 80 mg of nasally-administered creatine would need to pass from the nasal cavity across the blood-brain barrier. Even if the nasal columnar epithelium or mucus were to pose a barrier, doubling or tripling the dose would still represent a relatively modest amount of nasally-delivered creatine (e.g., 160‒240 mg) in solution. We predict that the amount of nasally-administered creatine to theoretically raise brain blood concentration to a therapeutic level would be modest and practical.

Intranasal creatine administration increases brain creatine level and improves Barnes maze performance in rats

While skeletal muscle creatine levels can be enhanced by exogenous creatine supplementation, the elevation of brain creatine levels with oral creatine administration remains a challenge due to a lack of effective transportation of creatine through the blood-brain barrier. Intranasal administration can bypass the blood-brain barrier and deliver drugs directly to the brain. The purpose of this study was to assess the effect of intranasal administration of creatine on brain creatine level and cognitive performance. Rats were randomly assigned into three groups intranasal administration group, oral administration group, and control group. The intranasal group exhibited fewer errors and shorter primary latency compared to the control and oral groups, respectively, during the acquisition phase of the Barnes maze. The intranasal group spent a higher percentage of time in the target quadrant during the probe trial compared to the control group. Biochemical measurements showed that the concentration of creatine in the olfactory bulbs, medial prefrontal cortex, and hippocampus of the rats in the intranasal group was higher than in the oral, and control groups. These results indicate that intranasal administration of creatine hydrochloride increases the creatine level in the rat’s brain’s and improves their performance in the Barnes maze.

IMPACT ASSESSMENT OF CREATINE ON MANY PHYSIOLOGICAL AND BIOCHEMICAL SCALES IN MALE RABBITS

Creatine is a substance found naturally in body tissues, especially in the muscles and brain. Creatine is found in the diet, especially in seafood and red meat, and is commonly used to increase muscle mass and improve exercise performance in humans. This research was design to evaluate the effects of creatine administration on many physiological and biochemical parameters. In the method design, 24 mature adult male rabbits are divided at random into four groups as the following: G1 (Group of control): six mature adult of male rabbits orally administered distilled H2O (1ml/animal) by gavage daily, G2 mature adult of male rabbits were orally administration creatine monohydrate (1ml/kg BW) by gavage daily. G 3 mature adult of male rabbits were orally administration creatine monohydrate (2ml/kg BW) by gavage daily. While G4 adult male rabbits were orally administration creatine monohydrate (3ml/kg BW). After 30-days of administration, the rabbits were anaesthetized and blood samples were collected for determination thyroid hormones, liver enzymes, lipid profiles and kidney function (determined by urea, creatinine levels) and serum total protein levels, in the results, the groups that received 1, 2 and 3 ml of creatinine significantly increased but more over increased in group treated with 3 ml of creatinine in all studied parameters such as T4 hormones, liver enzymes, urea, creatinine levels and all lipid profile except TSH, T3, HDL, total protein concentration decreased significantly compared to the control group. In conclusions, the creatine has harmful effect on biochemical and physiological parameters in the creatine-treated group (3ml). In the conclusion that an adverse effect of creatine on the functions of the thyroid gland, liver and kidneys increases in these organs with increase doses.

Beneficial Impact of Semicarbazide-Sensitive Amine Oxidase Inhibition on the Potential Cytotoxicity of Creatine Supplementation in Type 2 Diabetes Mellitus.

Creatine supplementation of the population with type 2 diabetes mellitus (T2DM) combined with an exercise program is known to be a possible therapy adjuvant with hypoglycemic effects. However, excessive administration of creatine leads to the production of methylamine which is deaminated by the enzyme semicarbazide-sensitive amine oxidase (SSAO) and as a result, cytotoxic compounds are produced. SSAO activity and reaction products are increased in the serum of T2DM patients. Creatine supplementation by diabetics will further augment the activity of SSAO. The current review aims to find a feasible way to ameliorate T2DM for patients who exercise and desire to consume creatine. Several natural agents present in food which are involved in the regulation of SSAO activity directly or indirectly are reviewed. Particularly, zinc-α2-glycoprotein (ZAG), zinc (Zn), copper (Cu), histamine/histidine, caffeine, iron (Fe), and vitamin D are discussed. Inhibiting SSAO activity by natural agents might reduce the potential adverse effects of creatine metabolism in population of T2DM.

Restoring Cellular Energetics Promotes Axonal Regeneration and Functional Recovery after Spinal Cord Injury

Axonal regeneration in the central nervous system (CNS) is a highly energy-demanding process. Extrinsic insults and intrinsic restrictions lead to an energy crisis in injured axons, raising the question of whether recovering energy deficits facilitates regeneration. Here, we reveal that enhancing axonal mitochondrial transport by deleting syntaphilin (Snph) recovers injury-induced mitochondrial depolarization. Using three CNS injury mouse models, we demonstrate that Snph-/- mice display enhanced corticospinal tract (CST) regeneration passing through a spinal cord lesion, accelerated regrowth of monoaminergic axons across a transection gap, and increased compensatory sprouting of uninjured CST. Notably, regenerated CST axons form functional synapses and promote motor functional recovery. Administration of the bioenergetic compound creatine boosts CST regenerative capacity in Snph-/- mice. Our study provides mechanistic insights into intrinsic regeneration failure in CNS and suggests that enhancing mitochondrial transport and cellular energetics are promising strategies to promote regeneration and functional restoration after CNS injuries.

Amplified detection of phosphocreatine and creatine after supplementation using CEST MRI at high and ultrahigh magnetic fields

Creatine is an important metabolite involved in muscle contraction. Administration of exogenous creatine (Cr) or phosphocreatine (PCr) has been used for improving exercise performance and protecting the heart during surgery including during valve replacements, coronary artery bypass grafting and repair of congenital heart defects. In this work we investigate whether it is possible to use chemical exchange saturation transfer (CEST) MRI to monitor uptake and clearance of exogenous creatine and phosphocreatine following supplementation. We were furthermore interested in determining the limiting conditions for distinguishing between creatine (1.9 ppm) and phosphocreatine (2.6 ppm) signals at ultra-high fields (21 T) and determine their concentrations could be reliably obtained using Bloch equation fits of the experimental CEST spectra. We have tested these items by performing CEST MRI of hind limb muscle and kidneys at 11.7 T and 21.1 T both before and after intravenous administration of PCr. We observed up to 4% increase in contrast in the kidneys at 2.6 ppm which peaked ~30 min after administration and a relative ratio of 1.3 in PCr:Cr signal. Overall, these results demonstrate the feasibility of independent monitoring of PCr and Cr concentration changes using CEST MRI.

Creatine is Neuroprotective to Retinal Neurons In Vitro But Not In Vivo.

To investigate the neuroprotective properties of creatine in the retina using in vitro and in vivo models of injury. Two different rat retinal culture systems (one containing retinal ganglion cells [RGC] and one not) were subjected to either metabolic stress, via treatments with the mitochondrial complex IV inhibitor sodium azide, or excitotoxic stress, via treatment with N-methyl-D-aspartate for 24 hours, in the presence or absence of creatine (0.5, 1.0, and 5.0 mM). Neuronal survival was assessed by immunolabeling for cell-specific antigens. Putative mechanisms of creatine action were investigated in vitro. Expression of creatine kinase (CK) isoenzymes in the rat retina was examined using Western blotting and immunohistochemistry. The effect of oral creatine supplementation (2%, wt/wt) on retinal and blood creatine levels was determined as well as RGC survival in rats treated with N-methyl-D-aspartate (NMDA; 10 nmol) or high IOP-induced ischemia reperfusion. Creatine significantly prevented neuronal death induced by sodium azide and NMDA in both culture systems. Creatine administration did not alter cellular adenosine triphosphate (ATP). Inhibition of CK blocked the protective effect of creatine. Retinal neurons, including RGCs, expressed predominantly mitochondrial CK isoforms, while glial cells expressed exclusively cytoplasmic CKs. In vivo, NMDA and ischemia reperfusion caused substantial loss of RGCs. Creatine supplementation led to elevated blood and retinal levels of this compound but did not significantly augment RGC survival in either model. Creatine increased neuronal survival in retinal cultures; however, no significant protection of RGCs was evident in vivo, despite elevated levels of this compound being present in the retina after oral supplementation.

Creatine as a Candidate to Prevent Statin Myopathy.

Statins prevent cardiovascular diseases, yet their use is limited by the muscle disturbances they cause. Rarely, statin-induced myopathy is autoimmune, but more commonly it is due to direct muscle toxicity. Available evidence suggests that statin-induced creatine deficiency might be a major cause of this toxicity, and that creatine supplementation prevents it. Statins inhibit guanidinoacetate methyl transferase (GAMT), the last enzyme in the synthesis of creatine; thus, they decrease its intracellular content. Such decreased content could cause mitochondrial impairment, since creatine is the final acceptor of the phosphate group of adenosine triphosphate (ATP) at the end of mitochondrial oxidative phosphorylation. Decreased cellular synthesis of ATP would follow. Accordingly, ATP synthesis is decreased in statin-treated cells. In vitro, creatine supplementation prevents the opening of the mitochondrial permeability transition pore that is caused by statins. Clinically, creatine administration prevents statin myopathy in statin-intolerant patients. Additional research is warranted to hopefully confirm these findings. However, creatine is widely used by athletes with no adverse events, and has demonstrated to be safe even in double-blind, placebo-controlled trials of elderly individuals. Thus, it should be trialed, under medical supervision, in patients who cannot assume statin due to the occurrence of muscular symptoms.

The Effects of Two Different Creatine Formulations on Muscle Bioenergetics in Men

A novel colloidal creatine formulation has been suggested to be superior to creatine monohydrate for improving plasma creatine levels after single-dose administration in animal research. However, if colloidal creatine supremely affects creatine levels in the skeletal muscle and blood of healthy humans remains currently unknown. This double blind, cross-over, randomized, creatine monohydrate-controlled pilot trial evaluated serum and skeletal muscle levels of creatine before and during single-dose colloidal creatine (Creaphil®) administration in five healthy men. Five healthy volunteers aged 24.0 ± 1.7 years (weight 79.2 ± 7.4 kg; height 181.0 ± 5.7 cm) were supplemented with single dose of 5 g of colloidal creatine or creatine monohydrate, with skeletal muscle and serum levels of creatine monitored at baseline and during post-administration for 10 h in five intervals. At each assessment at the lab, the participants completed magnetic resonance spectroscopy for right vastus medialis muscle and clinical chemistry studies. Colloidal formulation resulted in a more powerful rise in vastus medialis creatine levels comparing to creatine monohydrate, as evaluated with the area under the concentration-time curve calculation (108.5 ± 15.9 mM · h vs. 103.3 ± 15.1 mM · h; P = 0.01). This was accompanied by a significantly higher serum creatine level after colloidal creatine administration at 30 min post-administration (158.4 ± 21.2 μmol/L vs. 121.0 ± 38.9 μmol/L; P = 0.05). No participant reported any adverse events during the trial. These results suggest that colloidal creatine is a preferred and safe alternative to creatine monohydrate for improved creatine bioavailability after single-dose administration. However, more studies are needed to evaluate its effectiveness and safety after long-term supplementation.

Effects of Creatine Treatment on Jejunal Phenotypes in a Rat Model of Acidosis.

We investigated the effects of creatine treatment on jejunal phenotypes in a rat model of oxidative stress induced by acidosis. In particular, the activities of some antioxidant enzymes (superoxide dismutase, glutathione peroxidase, catalase, and glutathione reductase), the level of lipid peroxidation, the expression of heat shock proteins (HSP70), and the expression of the major carriers of the cells (Na+/K+-ATPase, sodium-glucose Transporter 1—SGLT1, and glucose transporter 2—GLUT2) were measured under control and chronic acidosis conditions. Creatine did not affect the activity of antioxidant enzymes in either the control or acidosis groups, except for catalase, for which the activity was reduced in both conditions. Creatine did not change the lipid peroxidation level or HSP70 expression. Finally, creatine stimulated (Na+/K+)-ATPase expression under both control and chronic acidosis conditions. Chronic acidosis caused reductions in the expression levels of GLUT2 and SGLT1. GLUT2 reduction was abolished by creatine, while the presence of creatine did not induce any strengthening effect on the expression of SGLT1 in either the control or chronic acidosis groups. These results indicate that creatine has antioxidant properties that are realized through direct interaction of the molecule with reactive oxygen species. Moreover, the administration of creatine seems to determine a functional strengthening of the tissue, making it more resistant to acidosis.

Chronic Acidosis and Oxidative Stress: Protective Effect of Creatine Oral Administration on Rat Jejunum

The protective effect of creatine supplementation on the jejunal epithelium of rats under conditions of oxidative stress induced by chronic acidosis was investigated. In particular, we measured the activities of the main antioxidant enzymes (superoxide dismutase, glutathione peroxidase, catalase, glutathione reductase), the level of lipid peroxidation, the expression of heat shock proteins (HSP70), and the expression of the major carriers of the cells (Na+/K+-ATPase, SGLT1 and GLUT2) in control and chronic acidosis conditions. Creatine did not affect the activity of antioxidant enzymes, nor in control, neither in acidosis, except for catalase, which activity was reduced in both conditions. Creatine did not change the level of lipid peroxidation and the expression of HSP70. Finally, creatine stimulated the expression of (Na+/K+)-ATPase both in control and in chronic acidosis. Chronic acidosis caused a reduction in the expression of GLUT2 and SGLT1. GLUT2 reduction was abolished by creatine, while the presence of creatine did not induce any strengthening effect on the expression of SGLT1, neither in control nor in chronic acidosis. These results indicate that creatine has antioxidant properties that would be realized through direct interaction of the molecule with reactive oxygen species. Moreover, the administration of creatine seems to determine a functional strengthening of the tissue making the tissue more resistant to acidosis.

Subchronic administration of creatine produces antidepressant-like effect by modulating hippocampal signaling pathway mediated by FNDC5/BDNF/Akt in mice

Creatine has been shown to play a significant role in the pathophysiology and treatment of major depressive disorder (MDD) in preclinical and clinical studies. However, the biological mechanisms underlying its antidepressant effect is still not fully elucidated. This study investigated the effect of creatine (p.o.) administered for 21 days in the behavior of mice submitted to tail suspension test (TST), a predictive test of antidepressant activity. Creatine reduced the immobility time in the TST (1–10 mg/kg), without affecting locomotor activity, a finding consistent with an antidepressant profile. Creatine administration increased the ubiquitous creatine kinase (uCK) and creatine kinase brain isoform (CK-B) mRNA in the hippocampus of mice. Taking into account that PGC-1α induces FNDC5/irisin expression mediating BDNF-dependent neuroplasticity, the effect of creatine administration (1 mg/kg, p. o.) on the hippocampal PGC-1α, FNDC5 and BDNF gene expression was investigated. Creatine treatment increased PGC-1α, FNDC5 and BDNF mRNA in the hippocampus as well as BDNF immunocontent. The involvement of BDNF downstream intracellular signaling pathway mediated by Akt, proapoptotic proteins BAX and BAD and antiapoptotic proteins Bcl2 and Bcl-xL was also investigated following creatine treatment. Creatine increased Akt phosphorylation (Ser 473), and Bcl2 mRNA and protein levels, and Bcl-xL mRNA, whereas BAD mRNA was decreased following creatine administration in the hippocampus. Altogether these results indicate that creatine antidepressant-like effect may be dependent on Akt activation and increased expression of the neuroprotective proteins in the hippocampus of mice. The obtained data reinforce the antidepressant property of creatine and highlight the role of these molecular targets in the pathophysiology of MDD.

Effects of creatine supplementation on cognitive function of healthy individuals: A systematic review of randomized controlled trials.

Creatine is a supplement used by sportsmen to increase athletic performance by improving energy supply to muscle tissues. It is also an essential brain compound and some hypothesize that it aids cognition by improving energy supply and neuroprotection. The aim of this systematic review is to investigate the effects of oral creatine administration on cognitive function in healthy individuals. A search of multiple electronic databases was performed for the identification of randomized clinical trials (RCTs) examining the cognitive effects of oral creatine supplementation in healthy individuals. Six studies (281 individuals) met our inclusion criteria. Generally, there was evidence that short term memory and intelligence/reasoning may be improved by creatine administration. Regarding other cognitive domains, such as long-term memory, spatial memory, memory scanning, attention, executive function, response inhibition, word fluency, reaction time and mental fatigue, the results were conflicting. Performance on cognitive tasks stayed unchanged in young individuals. Vegetarians responded better than meat-eaters in memory tasks but for other cognitive domains no differences were observed. Oral creatine administration may improve short-term memory and intelligence/reasoning of healthy individuals but its effect on other cognitive domains remains unclear. Findings suggest potential benefit for aging and stressed individuals. Since creatine is safe, future studies should include larger sample sizes. It is imperative that creatine should be tested on patients with dementias or cognitive impairment.

Neuroprotective Effects of Creatine in the CMVMJD135 Mouse Model of Spinocerebellar Ataxia Type 3.

Mitochondrial dysfunction has been implicated in several neurodegenerative diseases. Creatine administration increases concentration of the energy buffer phosphocreatine, exerting protective effects in the brain. We evaluate whether a creatine-enriched diet would be beneficial for a mouse model of spinocerebellar ataxia type 3, a genetically defined neurodegenerative disease for which no treatment is available. We performed 2 independent preclinical trials using the CMVMJD135 mouse model (treating 2 groups of animals with different disease severity) and wild-type mice, to which 2% creatine was provided for 19 (preclinical trial 1) or 29 (preclinical trial 2) weeks, starting at a presymptomatic age. Motor behavior was evaluated at several time points from 5 to 34 weeks of age, and neuropathological studies were performed at the end of each trial. Creatine supplementation led to an overall improvement in the motor phenotype of CMVMJD135 mice in both trials, rescuing motor balance and coordination and also restored brain weight, mitigated astrogliosis, and preserved Calbindin-positive cells in the cerebellum. Moreover, a reduction of mutant ataxin-3 aggregates occurred despite maintained steady-state levels of the protein and the absence of autophagy activation. Creatine treatment also restored the expression of the mitochondrial mass marker Porin and reduced the expression of antioxidant enzymes Heme oxygenase 1 (HO1) and NAD(P)H Quinone Dehydrogenase 1 (NQO1), suggesting a beneficial effect at the level of mitochondria and oxidative stress. Creatine slows disease progression and improves motor dysfunction as well as ameliorates neuropathology of the CMVMJD135 animals, supporting this as a useful strategy to slow the progression of spinocerebellar ataxia type 3. © 2018 International Parkinson and Movement Disorder Society.

The CREST-E study of creatine for Huntington disease: A randomized controlled trial.

Objective:To investigate whether creatine administration could slow progressive functional decline in adults with early symptoms of Huntington disease.Methods:We conducted a multicenter, randomized, double-blind, placebo-controlled study of up to 40 g daily of creatine monohydrate in participants with stage I and II HD treated for up to 48 months. The primary outcome measure was the rate of change in total functional capacity (TFC) between baseline and end of follow-up. Secondary outcome measures included changes in additional clinical scores, tolerability, and quality of life. Safety was assessed by adverse events and laboratory studies.Results:At 46 sites in North America, Australia, and New Zealand, 553 participants were randomized to creatine (275) or placebo (278). The trial was designed to enroll 650 patients, but was halted for futility after the first interim analysis. The estimated rates of decline in the primary outcome measure (TFC) were 0.82 points per year for participants on creatine, 0.70 points per year for participants on placebo, favoring placebo (nominal 95% confidence limits −0.11 to 0.35). Adverse events, mainly gastrointestinal, were significantly more common in participants on creatine. Serious adverse events, including deaths, were more frequent in the placebo group. Subgroup analysis suggested that men and women may respond differently to creatine treatment.Conclusions:Our data do not support the use of creatine treatment for delaying functional decline in early manifest HD.Clinicaltrials.gov identifier:NCT00712426.Classification of evidence:This study provides Class II evidence that for patients with early symptomatic HD, creatine monohydrate is not beneficial for slowing functional decline.

Neuroprotective Effect of Creatine and Pyruvate on Enzyme Activities of Phosphoryl Transfer Network and Oxidative Stress Alterations Caused by Leucine Administration in Wistar Rats.

Maple syrup urine disease is an autosomal metabolic disease caused by a deficiency of branched-chain α-keto acid dehydrogenase complex activity. In this disease occur the accumulation of the branched-chain amino acids leucine, isoleucine, and valine and their corresponding branched-chain α-keto acids in the tissues and body fluids. The affected patients may present psychomotor development delay and mental retardation. The pathophysiology of maple syrup urine disease is not entirely understood, but leucine seems to be the primary neurotoxic metabolite. Creatine and pyruvate are energetics and antioxidants substances. In this study, we investigated the effects of leucine administration and co-administration of creatine plus pyruvate on several parameters of oxidative stress and phosphoryl transfer network in cerebral cortex and hippocampus of Wistar rats treated from the 8th to the 21st postpartum day. Leucine induced oxidative stress and diminished the activities of pyruvate kinase, adenylate kinase, cytosolic and mitochondrial creatine kinase. Co-administration of creatine plus pyruvate prevented the alterations provoked by leucine administration on the oxidative stress and the enzymes of phosphoryltransfer network. These results indicate that chronic administration of leucine may stimulate oxidative stress and alters the enzymes of phosphoryltransfer network in the cerebral cortex and hippocampus of the rats. It is possible that these effects may contribute, along with other mechanisms, to the neurological dysfunction found in patients affected by maple syrup urine disease. In this case, it is possible that creatine plus pyruvate supplementation could benefit to the patients.

Creatine Enhances Mitochondrial-Mediated Oligodendrocyte Survival After Demyelinating Injury.

Chronic oligodendrocyte loss, which occurs in the demyelinating disorder multiple sclerosis (MS), contributes to axonal dysfunction and neurodegeneration. Current therapies are able to reduce MS severity, but do not prevent transition into the progressive phase of the disease, which is characterized by chronic neurodegeneration. Therefore, pharmacological compounds that promote oligodendrocyte survival could be beneficial for neuroprotection in MS. Here, we investigated the role of creatine, an organic acid involved in adenosine triphosphate (ATP) buffering, in oligodendrocyte function. We found that creatine increased mitochondrial ATP production directly in oligodendrocyte lineage cell cultures and exerted robust protection on oligodendrocytes by preventing cell death in both naive and lipopolysaccharide-treated mixed glia. Moreover, lysolecithin-mediated demyelination in mice deficient in the creatine-synthesizing enzyme guanidinoacetate-methyltransferase (Gamt) did not affect oligodendrocyte precursor cell recruitment, but resulted in exacerbated apoptosis of regenerated oligodendrocytes in central nervous system (CNS) lesions. Remarkably, creatine administration into Gamt-deficient and wild-type mice with demyelinating injury reduced oligodendrocyte apoptosis, thereby increasing oligodendrocyte density and myelin basic protein staining in CNS lesions. We found that creatine did not affect the recruitment of macrophages/microglia into lesions, suggesting that creatine affects oligodendrocyte survival independently of inflammation. Together, our results demonstrate a novel function for creatine in promoting oligodendrocyte viability during CNS remyelination.SIGNIFICANCE STATEMENT We report that creatine enhances oligodendrocyte mitochondrial function and protects against caspase-dependent oligodendrocyte apoptosis during CNS remyelination. This work has important implications for the development of therapeutic targets for diseases characterized by oligodendrocyte death, including multiple sclerosis.

Creatine salts provide neuroprotection even after partial impairment of the creatine transporter

Creatine, a compound that is critical for energy metabolism of nervous cells, crosses the blood-brain barrier (BBB) and the neuronal plasma membrane with difficulty, and only using its specific transporter. In the hereditary condition where the creatine transporter is defective (creatine transporter deficiency) there is no creatine in the brain, and administration of creatine is useless lacking the transporter. The disease is severe and incurable. Creatine-derived molecules that could cross BBB and plasma membrane independently of the transporter might be useful to cure this condition. Moreover, such molecules could be useful also in stroke and other brain ischemic conditions. In this paper, we investigated three creatine salts, creatine ascorbate, creatine gluconate and creatine glucose. Of these, creatine glucose was ineffective after transporter block with guanidine acetic acid (GPA) administration. Creatine ascorbate was not superior to creatine in increasing tissue creatine and phosphocreatine content after transporter impairment, however even after such impairment it delayed synaptic failure during anoxia. Finally, creatine gluconate was superior to creatine in increasing tissue content of creatine after transporter block and slowed down PS disappearance during anoxia, an effect that creatine did not have. These findings suggest that coupling creatine to molecules having a specific transporter may be a useful strategy in creatine transporter deficiency. In particular, creatine ascorbate has effects comparable to those of creatine in normal conditions, while being superior to it under conditions of missing or impaired creatine transporter.

Molecular and metabolic insights of creatine supplementation on resistance training

In recent years the research problem in the field of sports supplementation has changed to explain the metabolic mechanisms by which creatine (Cr) administration enhances the performance of certain sports or simply benefits the muscular adaptation. In this review for first time the biochemical mechanisms of Cr ingestion in a cell signaling insight were analyzed, focusing on energetic bioavailability enhancement and optimization of the temporal and spatial buffering of Cr/PCr/CK system. Moreover, intensification in proliferation and differentiation processes of muscle cells (IGF-I/PI3K/Akt-PKB, SPHK1/MAPK/p38/MRFs, mTOR, cellular swelling, mitotic activity of satellite cells, actin polymerization, and myoblast fusion) and inactivation and/or reduction in the expression of ergolitic metabolites (GSK3β, myostatin and AMPK regulation) were examined. In this way, we explained from a metabolic point of view the increase in muscle mass, strength, fatigue resistance, and performance of high intensity sports after Cr monohydrate supplementation.