LE Magazine March 2003
Creatine
Creatine monohydrate in muscular
dystrophies: A double-blind, placebo-controlled clinical
study.
The authors assessed the safety and efficacy of creatine
monohydrate (Cr) in various types of muscular dystrophies in a
double-blind, crossover trial. Thirty-six patients (12
patients with facioscapulohumeral dystrophy, 10 patients with
Becker dystrophy, eight patients with Duchenne dystrophy and
six patients with sarcoglycan-deficient limb girdle muscular
dystrophy) were randomized to receive Cr or placebo for eight
weeks. There was mild but significant improvement in muscle
strength and daily-life activities by Medical Research Council
scales and the Neuromuscular Symptom Score. Cr was well
tolerated throughout the study period.
Neurology 2000 May
9;54(9):1848-50
Creatine monohydrate increases
strength in patients with neuromuscular disease.
Creatine monohydrate has been shown to increase strength in
studies of young healthy subjects and in a few studies with
patients. Creatine monohydrate (10 g daily for five days to 5
g daily for five days) was administered to patients with
neuromuscular disease in a pilot study (Study 1; n = 81),
followed by a single-blinded study (Study 2; n = 21). Body
weight, handgrip, dorsiflexion, and knee extensor strength
were measured before and after treatment. Creatine
administration increased all measured indices in both studies.
Short-term creatine monohydrate increased high-intensity
strength significantly in patients with neuromuscular
disease.
Neurology 1999 Mar 10;52(4):854-7
Neuroprotective effects of creatine
administration against NMDA and malonate toxicity.
We examined whether creatine administration could exert
neuroprotective effects against excitotoxicity mediated by
N-methyl-D-aspartate (NMDA),
alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid
(AMPA) and kainic acid. Oral administration of 1% creatine
significantly attenuated striatal excitotoxic lesions produced
by NMDA, but had no effect on lesions produced by AMPA or
kainic acid. Both creatine and nicotinamide can exert
significant protective effects against malonate-induced
striatal lesions. We, therefore, examined whether nicotinamide
could exert additive neuroprotective effects with creatine
against malonate-induced lesions. Nicotinamide with creatine
produced significantly better neuroprotection than creatine
alone against malonate-induced lesions. Creatine can,
therefore, produce significant neuroprotective effects against
NMDA mediated excitotoxic lesions in vivo and the combination
of nicotinamide with creatine exerts additive neuroprotective
effects.
Brain Res 2000 Mar
31;860(1-2):195-8
Creatine and cyclocreatine attenuate
MPTP neurotoxicity.
Systemic administration of 1-methyl-4-phenyl-1,2,3,
6-tetrahydropyridine (MPTP) produces parkinsonism in
experimental animals by a mechanism involving impaired energy
production. MPTP is converted by monoamine oxidase B to
1-methyl-4-phenylpyridinium (MPP+), which blocks complex I of
the electron transport chain. Oral supplementation with
creatine or cyclocreatine, which are substrates for creatine
kinase, may increase phosphocreatine (PCr) or
cyclophosphocreatine (PCCr) and buffer against ATP depletion
and thereby exert neuroprotective effects. In the present
study we found that oral supplementation with either creatine
or cyclocreatine produced significant protection against
MPTP-induced dopamine depletions in mice. Creatine protected
against MPTP-induced loss of Nissl (grandular endoplasmic
reticulum and ribosomes) and tyrosine hydroxylase
immunostained neurons in the substantia nigra. Creatine and
cyclocreatine had no effects on the conversion of MPTP to MPP+
in vivo. These results further implicate metabolic dysfunction
in MPTP neurotoxicity and suggest a novel therapeutic
approach, which may have applicability for Parkinson's
disease.
Exp Neurol 1999 May;157(1):142-9
Role of creatine and phosphocreatine
in neuronal protection from anoxic and ischemic damage.
Phosphocreatine can to some extent compensate for the lack
of ATP (Adenosine Triphosphate) synthesis that is caused in
the brain by deprivation of oxygen or glucose. Treatment of in
vitro rat hippocampal slices with creatine increases the
neuronal store of phosphocreatine. In this way it increases
the resistance of the tissue to anoxic or ischemic damage. In
vitro brain slices pretreatment with creatine delays anoxic
depolarization (AD) and prevents the irreversible loss of
evoked potentials that is caused by transient anoxia, although
it seems so far not to be active against milder, not
AD-mediated, damage. Although creatine crosses the blood-brain
barrier poorly, its administration in vivo at high doses
through the intracerebroventricular or the intraperitoneal way
causes an increase of cerebral phosphocreatine that has been
shown to be of therapeutic value in vitro. Accordingly,
preliminary data show that creatine pretreatment decreases
ischemic damage in vivo.
Amino Acids 2002;23(1-3):221-9
Neuroprotective effects of creatine
and cyclocreatine in animal models of Huntington's
disease.
The gene defect in Huntington's disease (HD) may result in
an impairment of energy metabolism. Malonate and
3-nitropropionic acid (3-NP) are inhibitors of succinate
dehydrogenase that produce energy depletion and lesions that
closely resemble those of HD. Oral supplementation with
creatine or cyclocreatine, which are substrates for the enzyme
creatine kinase, may increase phosphocreatine (PCr) or
phosphocyclocreatine (PCCr) levels and ATP generation and
thereby may exert neuroprotective effects. We found that oral
supplementation with either creatine or cyclocreatine produced
significant protection against malonate lesions, and that
creatine but not cyclocreatine supplementation significantly
protected against 3-NP neurotoxicity. Creatine and
cyclocreatine increased brain concentrations of PCr and PCCr,
respectively, and creatine protected against depletions of PCr
and ATP produced by 3-NP. Creatine supplementation protected
against 3-NP induced increases in striatal lactate
concentrations in vivo as assessed by 1H magnetic resonance
spectroscopy. Creatine and cyclocreatine protected against
malonate-induced increases in the conversion of salicylate to
2,3- and 2,5-dihydroxybenzoic acid, biochemical markers of
hydroxyl radical generation. Creatine administration protected
against 3-NP-induced increases in 3-nitrotyrosine
concentrations, a marker of peroxynitrite-mediated oxidative
injury. Oral supplementation with creatine or cyclocreatine
results in neuroprotective effects in vivo, which may
represent a novel therapeutic strategy for HD and other
neurodegenerative diseases.
J Neurosci 1998 Jan
1;18(1):156-63
Neuroprotective effects of creatine in
a transgenic mouse model of Huntington's disease.
Huntington's disease (HD) is a progressive
neurodegenerative illness for which there is no effective
therapy. We examined whether creatine, which may exert
neuroprotective effects by increasing phosphocreatine levels
or by stabilizing the mitochondrial permeability transition,
has beneficial effects in a transgenic mouse model of HD (line
6/2). Dietary creatine supplementation significantly improved
survival, slowed the development of brain atrophy, and delayed
atrophy of striatal neurons and the formation of
huntingtin-positive aggregates in R6/2 mice. Body weight and
motor performance on the rotarod test were significantly
improved in creatine-supplemented R6/2 mice, whereas the onset
of diabetes was markedly delayed. Nuclear magnetic resonance
spectroscopy showed that creatine supplementation
significantly increased brain creatine concentrations and
delayed decreases in N-acetylaspartate concentrations. These
results support a role of metabolic dysfunction in a
transgenic mouse model of HD and suggest a novel therapeutic
strategy to slow the pathological process.
J Neurosci 2000 Jun
15;20(12):4389-97
Neuroprotective effects of creatine in
a transgenic animal model of amyotrophic lateral
sclerosis.
Mitochondria are particularly vulnerable to oxidative
stress, and mitochondrial swelling and vacuolization are among
the earliest pathologic features found in two strains of
transgenic amyotrophic lateral sclerosis (ALS) mice with SOD1
mutations. Mice with the G93A human SOD1 mutation have altered
electron transport enzymes, and expression of the mutant
enzyme in vitro results in a loss of mitochondrial membrane
potential and elevated cytosolic calcium concentration.
Mitochondrial dysfunction may lead to ATP depletion, which may
contribute to cell death. If this is true, then buffering
intracellular energy levels could exert neuroprotective
effects. Creatine kinase and its substrates creatine and
phosphocreatine constitute an intricate cellular energy
buffering and transport system connecting sites of energy
production (mitochondria) with sites of energy consumption,
and creatine administration stabilizes the mitochondrial
creatine kinase and inhibits opening of the mitochondrial
transition pore. We found that oral administration of creatine
produced a dose-dependent improvement in motor performance and
extended survival in G93A transgenic mice, and it protected
mice from loss of both motor neurons and substantia nigra
neurons at 120 days of age. Creatine administration protected
G93A transgenic mice from increases in biochemical indices of
oxidative damage. Therefore, creatine administration may be a
new therapeutic strategy for ALS.
Nat Med 1999 Mar;5(3):347-50
Creatine supplementation in
chronic heart failure increases skeletal muscle creatine
phosphate and muscle performance.
BACKGROUND: Cardiac creatine levels are depressed in
chronic heart failure. Oral supplementation of creatine to
healthy volunteers has been shown to increase physical
performance. AIM: To evaluate the effects of creatine
supplementation on ejection fraction, symptom-limited physical
endurance and skeletal muscle strength in patients with
chronic heart failure. METHODS: With a double-blind,
placebo-controlled design 17 patients (age 43 to 70 years,
ejection fraction < 40) were supplemented with creatine 20
g daily for 10 days. Before and on the last day of
supplementation ejection fraction was determined by
radionuclide angiography as was symptom-limited 1-legged knee
extensor and 2-legged exercise performance on the cycle
ergometer. Muscle strength as unilateral concentric knee
extensor performance (peak torque, Nm at 180 degrees/s) was
also evaluated. Skeletal muscle biopsies were taken for the
determination of energy-rich phosphagens. RESULTS: Ejection
fraction at rest and at work did not change. Performance
before creatine supplementation did not differ between placebo
and creatine groups. While no change was seen in the placebo
group compared to baseline, creatine supplementation increased
skeletal muscle total creatine and creatine phosphate by 17
+/- 4% (P < 0.05) and 12 +/- 4% (P < 0.05),
respectively. Increments were seen only in patients with <
140 mmol total creatine/kg d.w. (P < 0.05). One-legged
performance (21%, P < 0.05), 2-legged performance (10%, P
< 0.05), and peak torque, Nm (5%, P < 0.05) increased.
Both peak torque and 1-legged performance increased linearly
with increased skeletal muscle phosphocreatine (P < 0.05).
The increments in 1-legged, 2-legged and peak torque were
significant compared to the placebo group, (P < 0.05).
CONCLUSIONS: One week of creatine supplementation to patients
with chronic heart failure did not increase ejection fraction
but increased skeletal muscle energy-rich phosphagens and
performance as regards both strength and endurance. This new
therapeutic approach merits further attention.
Cardiovasc Res 1995
Sep;30(3):413-8
The effect of dietary creatine
supplementation on skeletal muscle metabolism in congestive
heart failure.
AIMS: To assess the effects of dietary creatine
supplementation on skeletal muscle metabolism and endurance in
patients with chronic heart failure. METHODS: A forearm model
of muscle metabolism was used, with a cannula inserted
retrogradely into an antecubital vein of the dominant forearm.
Maximum voluntary contraction was measured using handgrip
dynanometry. Subjects performed handgrip exercise, 5-s
contraction followed by 5-s rest for five min at 25%, 50%, and
75% of maximum voluntary contraction or until exhaustion.
Blood was taken at rest and zero and two minutes after
exercise for measurement of lactate and ammonia. After 30
minutes the procedure was repeated with fixed workloads of 7
kg, 14 kg and 21 kg. Patients were assigned to creatine 20 g
daily or matching placebo for five days and returned after six
days for repeat study. RESULTS: Contractions (median (25th,
75th interquartiles)) until exhaustion at 75% of maximum
voluntary contraction increased after creatine treatment (8
(6, 14) vs 14 (8, 17), P = 0.025) with no significant placebo
effect. Ammonia per contraction at 75% maximum voluntary
contraction (11.6 mumol/l/contraction (8.3, 15.7) vs 8.9
mumol/l/contraction (5.9, 10.8), P = 0.037) and lactate per
contraction at 75% maximum voluntary contraction (0.32
mmol/l/contraction (0.28, 0.61) vs 0.27 mmol/l/contraction
(0.19, 0.49), P = 0.07) fell after creatine but not after
placebo. CONCLUSIONS: Creatine supplementation in chronic
heart failure augments skeletal muscle endurance and
attenuates the abnormal skeletal muscle metabolic response to
exercise.
Eur Heart J 1998 Apr;19(4):617-22
Nutritional assessment and muscle
energy metabolism in severe chronic congestive heart
failure-effects of long-term dietary supplementation.
In order to investigate nutritional status in relation to
the metabolic state of skeletal muscle in patients with severe
congestive heart failure, and to explore the influence of
long-term dietary supplementation, 22 patients were randomized
in a double-blind study to receive either a placebo (n = 13)
or high caloric fluid (n = 9). Before treatment, the muscle
content of adenosine triphosphate (ATP), creatine and glycogen
was lower than in healthy individuals, and muscle biopsies
revealed an excess of water. Two patients were found to be
malnourished according to nutritional assessment criteria.
Following study treatment, no significant changes occurred,
either within or between the two subgroups. Thus, patients
with severe congestive heart failure displayed metabolic
derangement in skeletal muscle which did not seem to be
explained by malnutrition.
Eur Heart J 1994
Dec;15(12):1641-50
Use of P-31 magnetic resonance
spectroscopy to detect metabolic abnormalities in muscles of
patients with fibromyalgia.
OBJECTIVE: To investigate the metabolic and functional
status of muscles of fibromyalgia (FM) patients, using P-31
magnetic resonance spectroscopy (MRS). METHODS: Twelve
patients with FM and 11 healthy subjects were studied.
Clinical status was assessed by questionnaire. Biochemical
status of muscle was evaluated with P-31 MRS by determining
concentrations of inorganic phosphate (Pi), phosphocreatine
(PCr), ATP, and phosphodiesters during rest and exercise.
Functional status was evaluated from the PCr/Pi ratio,
phosphorylation potential (PP), and total oxidative capacity
(Vmax). RESULTS: Patients with FM reported greater difficulty
in performing activities of daily living as well as increased
pain, fatigue, and weakness compared with controls. MRS
measurements showed that patients had significantly lower than
normal PCr and ATP levels (P < 0.004) and PCr/Pi ratios (P
< 0.04) in the quadriceps muscles during rest. Values for
PP and Vmax also were significantly reduced during rest and
exercise. CONCLUSION: P-31 MRS provides objective evidence for
metabolic abnormalities consistent with weakness and fatigue
in patients with FM. Noninvasive P-31 MRS may be useful in
assessing clinical status and evaluating the effectiveness of
treatment regimens in FM.
Arthritis Rheum 1998
Mar;41(3):406-13
High-performance capillary
electrophoresis-pure creatine monohydrate reduces blood lipids
in men and women.
1. A randomized, double-blind, placebo-controlled trial
utilizing creatine as a potential lipid-lowering agent was
conducted to determine plasma lipid, lipoprotein, glucose,
urea nitrogen and creatinine profiles in men and women ranging
in age from 32 to 70 years. 2. Thirty-four subjects (18 men
and 16 women) with total cholesterol concentrations exceeding
200 mg/dl received either a creatine supplement (5 g of
creatine plus 1 g of glucose) or a glucose placebo (6 g of
glucose) for 56 days. Creatine and placebo were taken orally
four times a day for five days and then twice a day for 51
days. Plasma analyses were measured at baseline, four and
eight weeks of treatment, and at four weeks after cessation of
treatment (week 12). 3. Significant reductions in plasma total
cholesterol, triacylglycerols and very-low-density
lipoprotein-C occurred within the creatine monohydrate group.
Minor reductions in plasma total cholesterol from baseline
(233 +/- 9 mg/dl) of 6% and 5% occurred at weeks four and
eight, respectively, before returning to baseline at week 12.
Baseline triacylglycerols (194 +/- 21 mg/dl) and
very-low-density lipoprotein-C (39 +/- 4 mg/dl) were reduced
by 23% and 22% at weeks four and eight, respectively, and
remained attenuated by 26% at week 12. These results remained
consistent when data were separated and analysed by gender.
Finally, a small, but statistically significant increase in
urea nitrogen was observed in women between baseline (11.8 +/-
0.7 mg/dl) and week eight (13.8 +/- 0.7 mg/dl, P < 0.05).
No significant differences were noted for low-density
lipoprotein-C, high-density lipoprotein-C, total
cholesterol/high-density lipoprotein ratio, glucose,
creatinine, body mass, body mass index or physical activity
within or between the experimental and placebo groups.
However, a trend towards reduced blood glucose levels was
present in males given creatine monohydrate (P = 0.051). 4.
These preliminary data suggest that creatine monohydrate may
modulate lipid metabolism in certain individuals. These
observations may demonstrate practical efficacy to the
hyperlipidemic patient as well as providing possible new
mechanistic insights into the cellular regulation of blood
lipid concentrations.
Clin Sci (Lond) 1996
Jul;91(1):113-8
Effect of oral creatine
supplementation on muscle [PCr] and short-term maximum power
output.
Our purpose was to determine the effect of creatine
supplementation on power output during a 30-s maximal cycling
(Wingate) test. Nine males underwent three randomly ordered
tests following ingestion of a creatine supplementation (CRE),
placebo (PLA), and control (CON). CRE was ingested as creatine
monohydrate (CrH2O) dissolved in a flavored drink (20g.d-1 for
3 d), while PLA consisted of the drink only. Tests were
performed 14 d apart on a Monarch ergometer modified for
immediate resistance loading. Needle biopsies were taken from
the vastus lateralis at the end of each treatment period and
before the exercise test. No difference was found between
conditions for peak, mean 10-s, and mean 30-s power output,
percent fatigue, or post-exercise blood lactate concentration.
Similarly, no difference between conditions was observed for
ATP, phosphocreatine (PCr), or total creatine (TCr); however,
the TCr/ATP was higher in the CRE condition (P < 0.05) than
in the CON and PLA conditions. Findings suggest that 3 d of
oral Cr supplementation does not increase resting muscle PCr
concentration and has no effect on performance during a single
short-term maximal cycling task.
Med Sci Sports Exerc 1997
Feb;29(2):216-9
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