Creatine Abstracts 2


Creatine supplementation improves dopaminergic cell survival and protects against MPP+ toxicity in an organotypic tissue culture system.
            (Andres et al., 2005a) Download
Cell replacement therapy using mesencephalic precursor cells is an experimental approach for the treatment of Parkinson's disease (PD). A significant problem associated with this procedure is the poor survival of grafted neurons. Impaired energy metabolism is considered to contribute to neuronal cell death after transplantation. Creatine is a substrate for mitochondrial and cytosolic creatine kinases (CK) and buffers cellular ATP resources. Furthermore, elevated cellular creatine levels facilitate metabolic channeling and show antiapoptotic properties. Exogenous creatine supplementation therefore might offer a tool for improvement of dopaminergic neuron survival. The present study aimed at investigating the effects of creatine on cell survival of rat embryonic day 14 (E14) ventral mesencephalic neurons grown as organotypic free-floating roller tube (FFRT) cultures. We found that the brain-specific isoform of CK (BB-CK) and the ubiquitous mitochondrial isoform (uMt-CK) are expressed at high levels in FFRT cultures and colocalize with tyrosine hydroxylase immunoreactive (TH-ir) cells. Exposure of these cultures to creatine induced an increase in the content of the BB-CK isotype. Creatine (5 mM) administration starting at day in vitro (DIV) 7 resulted in a significant increase (+35%) in TH-ir cell density at DIV21. In addition, we observed that creatine treatment provided neuroprotection against 1-methyl-4-phenyl pyridinium ion (MPP+)-induced TH-ir cell loss in the FFRT culture system, resulting in a significantly higher density (+19%) of TH-ir neurons in creatine-treated cultures compared to corresponding controls. The decrease of TH-ir neurons in the MPP+-treated group corresponded with an increase in immunoreactivity for active caspase-3, an effect that was not seen in the group receiving creatine supplementation. In conclusion, our data imply that creatine administration is beneficial for the survival of TH-ir neurons encountering harmful conditions.


Effects of creatine treatment on survival and differentiation of GABA-ergic neurons in cultured striatal tissue.
            (Andres et al., 2005b) Download
Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder, characterized by a prominent loss of GABA-ergic medium-sized spiny neurons in the caudate putamen. There is evidence that impaired energy metabolism contributes to neuronal death in HD. Creatine is an endogenous substrate for creatine kinases and thereby supports cellular ATP levels. This study investigated the effects of creatine supplementation (5 mm) on cell survival and neuronal differentiation in striatal cultures. Chronic creatine treatment resulted in significant increased densities of GABA-immunoreactive (-ir) neurons, although total neuronal cell number and general viability were not affected. Similar effects were seen after short-term treatment, suggesting that creatine acted as a differentiation factor. Inhibitors of transcription or translation did not abolish the creatine-mediated effects, nor did omission of extracellular calcium, whereas inhibition of mitogen-activated protein kinase and phosphatidylinositol-3-kinase significantly attenuated the creatine induced increase in GABA-ir cell densities. Creatine exhibited significant neuroprotection against toxicity instigated either by glucose- and serum deprivation or addition of 3-nitropropionic acid. In sum, the neuroprotective properties in combination with promotion of neuronal differentiation suggest that creatine has potential as a therapeutic drug in the treatment of neurodegenerative diseases, like HD.

Functions and effects of creatine in the central nervous system.
            (Andres et al., 2008) Download
Creatine kinase catalyses the reversible transphosphorylation of creatine by ATP. In the cell, creatine kinase isoenzymes are specifically localized at strategic sites of ATP consumption to efficiently regenerate ATP in situ via phosphocreatine or at sites of ATP generation to build-up a phosphocreatine pool. Accordingly, the creatine kinase/phosphocreatine system plays a key role in cellular energy buffering and energy transport, particularly in cells with high and fluctuating energy requirements like neurons. Creatine kinases are expressed in the adult and developing human brain and spinal cord, suggesting that the creatine kinase/phosphocreatine system plays a significant role in the central nervous system. Functional impairment of this system leads to a deterioration in energy metabolism, which is phenotypic for many neurodegenerative and age-related diseases. Exogenous creatine supplementation has been shown to reduce neuronal cell loss in experimental paradigms of acute and chronic neurological diseases. In line with these findings, first clinical trials have shown beneficial effects of therapeutic creatine supplementation. Furthermore, creatine was reported to promote differentiation of neuronal precursor cells that might be of importance for improving neuronal cell replacement strategies. Based on these observations there is growing interest on the effects and functions of this compound in the central nervous system. This review gives a short excursion into the basics of the creatine kinase/phosphocreatine system and aims at summarizing findings and concepts on the role of creatine kinase and creatine in the central nervous system with special emphasis on pathological conditions and the positive effects of creatine supplementation.

Creatine supplementation in Parkinson disease: a placebo-controlled randomized pilot trial.
            (Bender et al., 2006) Download
Mitochondrial dysfunction plays a major role in the pathogenesis of Parkinson disease (PD). Creatine (Cr) is an ergogenic compound that exerts neuroprotective effects in animal models of PD. We conducted a 2-year placebo-controlled randomized clinical trial on the effect of Cr in 60 patients with PD. Cr improved patient mood and led to a smaller dose increase of dopaminergic therapy but had no effect on overall Unified Parkinson's Disease Rating Scale scores or dopamine transporter SPECT.

Creatine improves health and survival of mice.
            (Bender et al., 2008) Download
The supplementation of creatine (Cr) has a marked neuroprotective effect in mouse models of neurodegenerative diseases. This has been assigned to the known bioenergetic, anti-apoptotic, anti-excitotoxic, and anti-oxidant properties of Cr. As aging and neurodegeneration share pathophysiological pathways, we investigated the effect of oral Cr supplementation on aging in 162 aged C57Bl/6J mice. Outcome variables included "healthy" life span, neurobehavioral phenotyping, as well as morphology, biochemistry, and expression profiling from brain. The median healthy life span of Cr-fed mice was 9% higher than in control mice, and they performed significantly better in neurobehavioral tests. In brains of Cr-treated mice, there was a trend towards a reduction of reactive oxygen species and significantly lower accumulation of the "aging pigment" lipofuscin. Expression profiling showed an upregulation of genes implicated in neuronal growth, neuroprotection, and learning. These data show that Cr improves health and longevity in mice. Cr may be a promising food supplement to promote healthy human aging.


The influence of creatine supplementation on the cognitive functioning of vegetarians and omnivores.
            (Benton and Donohoe, 2011) Download
Creatine when combined with P forms phosphocreatine that acts as a reserve of high-energy phosphate. Creatine is found mostly in meat, fish and other animal products, and the levels of muscle creatine are known to be lower in vegetarians. Creatine supplementation influences brain functioning as indicated by imaging studies and the measurement of oxygenated Hb. Given the key role played by creatine in the provision of energy, the influence of its supplementation on cognitive functioning was examined, contrasting the effect in omnivores and vegetarians. Young adult females (n 128) were separated into those who were and were not vegetarian. Randomly and under a double-blind procedure, subjects consumed either a placebo or 20 g of creatine supplement for 5 d. Creatine supplementation did not influence measures of verbal fluency and vigilance. However, in vegetarians rather than in those who consume meat, creatine supplementation resulted in better memory. Irrespective of dietary style, the supplementation of creatine decreased the variability in the responses to a choice reaction-time task.

Creatine supplementation improves muscular performance in older women.
            (Gotshalk et al., 2008) Download
Muscle power and strength decrease with age leading to reduced independence and increased health risk from falls. Creatine supplementation can increase muscle power and strength. The purpose of this study was to examine the effects of 7 days of creatine supplementation on body composition, muscular strength, and lower-body motor functional performance in older women. Thirty 58-71 year old women performed three test sessions (T1-T3) each separated by one week. Each session consisted of one repetition maximum tests for bench press and leg press, and isometric hand-grip, tandem gait, upper-body ergometer, and lower-body ergometer tests. Following T2, subjects were assigned to a creatine monohydrate (0.3 g kg body mass(-1) for 7 days) (CR: 63.31 +/- 1.22 year, 160.00 +/- 1.58 cm, 67.11 +/- 4.38 kg) or a placebo (PL: 62.98 +/- 1.11 year, 162.25 +/- 2.09 cm, 67.84 +/- 3.90 kg) supplementation group. CR significantly (P < 0.05) increased bench press (1.7 +/- 0.4 kg), leg press (5.2 +/- 1.8 kg), body mass (0.49 +/- 0.04 kg) and fat free mass (0.52 +/- 0.05) and decreased completion time on the functional tandem gait tests from T2-T3. No significant changes were found for PL on any of the measured variables. No adverse side-effects were reported by either group. Short-term creatine supplementation resulted in an increase in strength, power, and lower-body motor functional performance in older women without any adverse side effects.

Creatine in type 2 diabetes: a randomized, double-blind, placebo-controlled trial.
            (Gualano et al., 2011) Download
Creatine supplementation improves glucose tolerance in healthy subjects. PURPOSES: The aim was to investigate whether creatine supplementation has a beneficial effect on glycemic control of type 2 diabetic patients undergoing exercise training. METHODS: A 12-wk randomized, double-blind, placebo-controlled trial was performed. The patients were allocated to receive either creatine (CR) (5 g.d) or placebo (PL) and were enrolled in an exercise training program. The primary outcome was glycosylated hemoglobin (HbA1c). Secondary outcomes included the area under the curve of glucose, insulin, and C-peptide and insulin sensitivity indexes. Physical capacity, lipid profile, and GLUT-4 protein expression and translocation were also assessed. RESULTS: Twenty-five subjects were analyzed (CR: n=13; PL: n=12). HbA1c was significantly reduced in the creatine group when compared with the placebo group (CR: PRE=7.4 +/- 0.7, POST=6.4 +/- 0.4; PL: PRE=7.5 +/- 0.6, POST=7.6 +/- 0.7; P=0.004; difference=-1.1%, 95% confidence interval=-1.9% to -0.4%). The delta area under the curve of glucose concentration was significantly lower in the CR group than in the PL group (CR=-7790 +/- 4600, PL=2008 +/- 7614; P=0.05). The CR group also presented decreased glycemia at times 0, 30, and 60 min during a meal tolerance test and increased GLUT-4 translocation. Insulin and C-peptide concentrations, surrogates of insulin sensitivity, physical capacity, lipid profile, and adverse effects were comparable between the groups. CONCLUSIONS: Creatine supplementation combined with an exercise program improves glycemic control in type 2 diabetic patients. The underlying mechanism seems to be related to an increase in GLUT-4 recruitment to the sarcolemma.

Protective effects of oral creatine supplementation on spinal cord injury in rats.
            (Hausmann et al., 2002) Download
STUDY DESIGN: To evaluate a potential protective effect of increased creatine levels in spinal cord injury (SCI) in an animal model. OBJECTIVES: Acute SCI initiates a series of cellular and molecular events in the injured tissue leading to further damage in the surrounding area. This secondary damage is partly due to ischemia and a fatal intracellular loss of energy. Phospho-creatine in conjunction with the creatine kinase isoenzyme system acts as a potent intracellular energy buffer. Oral creatine supplementation has been shown to elevate the phospho-creatine content in brain and muscle tissue, leading to neuroprotective effects and increased muscle performance. SETTING: Zurich, Switzerland. METHODS: Twenty adult rats were fed for 4 weeks with or without creatine supplemented nutrition before undergoing a moderate spinal cord contusion. RESULTS: Following an initial complete hindlimb paralysis, rats of both groups substantially recovered within 1 week. However, creatine fed animals scored 2.8 points better than the controls in the BBB open field locomotor score (11.9 and 9.1 points respectively after 1 week; P=0.035, and 13 points compared to 11.4 after 2 weeks). The histological examination 2 weeks after SCI revealed that in all rats a cavity had developed which was comparable in size between the groups. In creatine fed rats, however, a significantly smaller amount of scar tissue surrounding the cavity was found. CONCLUSIONS: Thus creatine treatment seems to reduce the spread of secondary injury. Our results favour a pretreatment of patients with creatine for neuroprotection in cases of elective intramedullary spinal surgery. Further studies are needed to evaluate the benefit of immediate creatine administration in case of acute spinal cord or brain injury.

Effects of creatine supplementation on muscle power, endurance, and sprint performance.
            (Izquierdo et al., 2002) Download
PURPOSE: To determine the effects of creatine (Cr) supplementation (20 g x d(-1) during 5 d) on maximal strength, muscle power production during repetitive high-power-output exercise bouts (MRPB), repeated running sprints, and endurance in handball players. METHODS: Nineteen trained male handball players were randomly assigned in a double-blind fashion to either creatine (N = 9) or placebo (N = 10) group. Before and after supplementation, subjects performed one-repetition maximum half-squat (1RM(HS) and bench press (1RM(BP)), 2 sets of MRPB consisting of one set of 10 continuous repetitions (R10) followed by 1 set until exhaustion (R(max)), with exactly 2-min rest periods between each set, during bench-press and half-squat protocols with a resistance equal to 60 and 70% of the subjects' 1RM, respectively. In addition, a countermovement jumping test (CMJ) interspersed before and after the MRPB half-squat exercise bouts and a repeated sprint running test and a maximal multistage discontinuous incremental running test (MDRT) were performed. RESULTS: Cr supplementation significantly increased body mass (from 79.4 +/- 8 to 80 +/- 8 kg; P < 0.05), number of repetitions performed to fatigue, and total average power output values in the R(max) set of MRPB during bench press (21% and 17%, respectively) and half-squat (33% and 20%, respectively), the 1RM(HS) (11%), as well as the CMJ values after the MRPB half-squat (5%), and the average running times during the first 5 m of the six repeated 15-m sprints (3%). No changes were observed in the strength, running velocity, or body mass measures in the placebo group during the experimental period. CONCLUSION: Short-term Cr supplementation leads to significant improvements in lower-body maximal strength, maximal repetitive upper- and lower-body high-power exercise bouts, and total repetitions performed to fatigue in the R(max) set of MRPB, as well as enhanced repeated sprint performance and attenuated decline in jumping ability after MRPB in highly trained handball players. Cr supplementation did not result in any improvement in upper-body maximal strength and in endurance running performance.
Effects of creatine supplementation on exercise performance and muscular strength in amyotrophic lateral sclerosis: preliminary results.
            (Mazzini et al., 2001) Download
Creatine supplementation in humans has been reported to enhance power and strength both in normal subjects and in patients with various neuromuscular diseases. The purpose of this study was to examine the effects of supplementation on exercise performance and maximal voluntary isometric muscular contraction (MVIC) in Amyotrophic Lateral Sclerosis (ALS) patients. We report the results obtained in 28 patients with probable/definite ALS. In each patient we acquired the dynamometric measurement of MVIC in 10 muscle groups of upper and lower limbs and a measure of fatigue by means of an high-intensity intermittent protocol in elbow flexors and knee extensors muscles. All patients completed the protocols at the baseline and after supplementation of 20 g per day for 7 days and after supplementation of 3 g per day for 3 and 6 months. MVIC increased after 7 days of supplementation in 20 patients (70%) in knee extensors and in 15 (53%) of them also in elbow flexors. A statistically significant difference between pre and post-treatment mean values of MVIC was found both in elbow flexors (P<0.05) and knee extensors (p<0.04). The analysis of the slopes of fatigue test showed a statistically significant improvement after 7 days of supplementation in 11 patients (39%) in elbow flexors and in 9 patients (32%) also in knee extensors muscles. During the 6-month follow-up period all the examined parameters showed a linear progressive decline. In conclusion, our preliminary results have demonstrated that supplementation temporary increases maximal isometric power in ALS patients so it may be of potential benefit in situations such as high intensity activity and it can be proposed as a symptomatic treatment.

Creatine supplementation and cognitive performance in elderly individuals.
            (McMorris et al., 2007b) Download
The purpose of this study was to examine the effect of creatine supplementation on the cognitive performance of elderly people. Participants were divided into two groups, which were tested on random number generation, forward and backward number and spatial recall, and long-term memory tasks to establish a baseline level. Group 1 (n = 15) were given 5 g four times a day of placebo for 1 week, followed by the same dosage of creatine for the second week. Group 2 (n = 17) were given placebo both weeks. Participants were retested at the end of each week. Results showed a significant effect of creatine supplementation on all tasks except backward number recall. It was concluded that creatine supplementation aids cognition in the elderly.


Creatine supplementation, sleep deprivation, cortisol, melatonin and behavior.
            (McMorris et al., 2007a) Download
The effect of creatine supplementation and sleep deprivation, with intermittent moderate-intensity exercise, on cognitive and psychomotor performance, mood state, effort and salivary concentrations of cortisol and melatonin were examined. Subjects were divided into a creatine supplementation group and a placebo group. They took 5 g of creatine monohydrate or a placebo, dependent on their group, four times a day for 7 days immediately prior to the experiment. They undertook tests examining central executive functioning, short-term memory, choice reaction time, balance, mood state and effort at baseline and following 18-, 24- and 36-h sleep deprivation, with moderate intermittent exercise. Saliva samples were taken prior to each set of tests. A group x time analysis of covariance, with baseline performance the covariate, showed that the creatine group performed significantly (p < 0.05) better than the placebo group on the central executive task but only at 36 h. The creatine group demonstrated a significant (p < 0.01) linear improvement in performance of the central executive task throughout the experiment, while the placebo group showed no significant effects. There were no significant differences between the groups for any of the other variables. A significant (p < 0.001) main effect of time was found for the balance test with a linear improvement being registered. Cortisol concentrations on Day 1 were significantly (p < 0.01) higher than on Day 2. Mood significantly (p < 0.001) deteriorated up to 24 h with no change from 24 to 36 h. Effort at baseline was significantly (p < 0.01) lower than in the other conditions. It was concluded that, during sleep deprivation with moderate-intensity exercise, creatine supplementation only affects performance of complex central executive tasks.

Creatine supplementation increases soleus muscle creatine content and lowers the insulinogenic index in an animal model of inherited type 2 diabetes.
            (Op't Eijnde et al., 2006) Download
Creatine supplementation may exert beneficial effects on muscle performance and facilitate peripheral glucose disposal in both rats and human subjects. The present study was undertaken to explore the effects of creatine supplementation on the ATP, creatine, phosphocreatine and glycogen content of white and red gastrocnemius and soleus muscles and on blood D-glucose and plasma insulin concentrations before and during an intravenous glucose tolerance test in Goto-Kakizaki rats, a current animal model of inherited type 2 diabetes mellitus. Creatine supplementation increased muscle creatine content, especially in the soleus muscle of young rats (+35.5-/+15.8%; d.f.=10; p<0.05), and lowered the insulinogenic index, i.e. the paired ratio between plasma insulin and blood D-glucose concentrations. The latter change was mainly attributable to a lowering of plasma insulin concentration. It is proposed, therefore, that creatine supplementation may improve the sensitivity to insulin in extrapancreatic sites in the present animal model of type 2 diabetes.

Oral creatine supplementation attenuates L-DOPA-induced dyskinesia in 6-hydroxydopamine-lesioned rats.
            (Valastro et al., 2009) Download
L-DOPA-induced dyskinesia (LID) is among the motor complications that arise in Parkinson patients after a prolonged treatment with levodopa (L-DOPA). Since previous transcriptome and proteomic studies performed in the rat model of LID suggested important changes in striatal energy-related components, we hypothesize that oral creatine supplementation could prevent or attenuate the occurrence of LID. In this study, 6-hydroxydopamine-lesioned rats received a 2% creatine-supplemented diet for 1 month prior to L-DOPA therapy. During the 21 days of L-DOPA treatment, significant reductions in abnormal involuntary movements (AIMs) have been observed in the creatine-supplemented group, without any worsening of parkinsonism. In situ hybridization histochemistry and immunohistochemistry analysis of the striatum also showed a reduction in the levels of prodynorphin mRNA and FosB/DeltaFosB-immunopositive cells in creatine-supplemented diet group, an effect that was dependant on the development of AIMs. Further investigation of the bioenergetics' status of the denervated striatum revealed significant changes in the levels of creatine both after L-DOPA alone and with the supplemented diet. In conclusion, we demonstrated that combining L-DOPA therapy with a diet enriched in creatine could attenuate LID, which may represent a new way to control the motor complications associated with L-DOPA therapy.

Effects of creatine on mental fatigue and cerebral hemoglobin oxygenation.
            (Watanabe et al., 2002) Download
While the role of creatine in preventing muscle (peripheral) fatigue for high performance athletes is well understood, its biochemical role in prevention of mental (central) fatigue is not. Creatine is abundant in muscles and the brain and after phosphorylation used as an energy source for adenosine triphosphate synthesis. Using double-blind placebo-controlled paradigm, we demonstrated that dietary supplement of creatine (8 g/day for 5 days) reduces mental fatigue when subjects repeatedly perform a simple mathematical calculation. After taking the creatine supplement, task-evoked increase of cerebral oxygenated hemoglobin in the brains of subjects measured by near infrared spectroscopy was significantly reduced, which is compatible with increased oxygen utilization in the brain.


Andres, RH, et al. (2005a), ‘Creatine supplementation improves dopaminergic cell survival and protects against MPP+ toxicity in an organotypic tissue culture system.’, Cell Transplant, 14 (8), 537-50. PubMedID: 16355565
Andres, RH, et al. (2005b), ‘Effects of creatine treatment on survival and differentiation of GABA-ergic neurons in cultured striatal tissue.’, J Neurochem, 95 (1), 33-45. PubMedID: 16045451
Andres, RH, et al. (2008), ‘Functions and effects of creatine in the central nervous system.’, Brain Res Bull, 76 (4), 329-43. PubMedID: 18502307
Bender, A, et al. (2006), ‘Creatine supplementation in Parkinson disease: a placebo-controlled randomized pilot trial.’, Neurology, 67 (7), 1262-64. PubMedID: 17030762
Bender, A, et al. (2008), ‘Creatine improves health and survival of mice.’, Neurobiol Aging, 29 (9), 1404-11. PubMedID: 17416441
Benton, D and R Donohoe (2011), ‘The influence of creatine supplementation on the cognitive functioning of vegetarians and omnivores.’, Br J Nutr, 105 (7), 1100-5. PubMedID: 21118604
Gotshalk, LA, et al. (2008), ‘Creatine supplementation improves muscular performance in older women.’, Eur J Appl Physiol, 102 (2), 223-31. PubMedID: 17943308
Gualano, B, et al. (2011), ‘Creatine in type 2 diabetes: a randomized, double-blind, placebo-controlled trial.’, Med Sci Sports Exerc, 43 (5), 770-78. PubMedID: 20881878
Hausmann, ON, et al. (2002), ‘Protective effects of oral creatine supplementation on spinal cord injury in rats.’, Spinal Cord, 40 (9), 449-56. PubMedID: 12185606
Izquierdo, M, et al. (2002), ‘Effects of creatine supplementation on muscle power, endurance, and sprint performance.’, Med Sci Sports Exerc, 34 (2), 332-43. PubMedID: 11828245
Mazzini, L, et al. (2001), ‘Effects of creatine supplementation on exercise performance and muscular strength in amyotrophic lateral sclerosis: preliminary results.’, J Neurol Sci, 191 (1-2), 139-44. PubMedID: 11677005
McMorris, T, et al. (2007a), ‘Creatine supplementation, sleep deprivation, cortisol, melatonin and behavior.’, Physiol Behav, 90 (1), 21-28. PubMedID: 17046034
McMorris, T, et al. (2007b), ‘Creatine supplementation and cognitive performance in elderly individuals.’, Neuropsychol Dev Cogn B Aging Neuropsychol Cogn, 14 (5), 517-28. PubMedID: 17828627
Op’t Eijnde, B, et al. (2006), ‘Creatine supplementation increases soleus muscle creatine content and lowers the insulinogenic index in an animal model of inherited type 2 diabetes.’, Int J Mol Med, 17 (6), 1077-84. PubMedID: 16685419
Valastro, B, et al. (2009), ‘Oral creatine supplementation attenuates L-DOPA-induced dyskinesia in 6-hydroxydopamine-lesioned rats.’, Behav Brain Res, 197 (1), 90-96. PubMedID: 18762218
Watanabe, A, N Kato, and T Kato (2002), ‘Effects of creatine on mental fatigue and cerebral hemoglobin oxygenation.’, Neurosci Res, 42 (4), 279-85. PubMedID: 11985880