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Modifi cation of fatigue indicators using citrulline malate for high performance endurance athletes

Authors:
  • Universidad del fútbol y deporte

Abstract

High intensity physical exercise favors accumulation of lactate in muscles and bloodstream, leading to impaired muscle func-tion and exercise performance. This study evaluated the effect of citrulline malate (CM) on blood lactate concentration and perception of fatigue after muscular effort in high performance athletes. Seventy-two high-performance athletes who gave written informed consent were randomly assigned to CM 3 g/day, CM 6 g/day or placebo for 13 days. Blood lactate mea-surements were performed every training day. Fatigue was as-sessed through an auto-administered questionnaire at baseline and after 6 and 13 days. Main criterion was the percentage of blood lactate recovery 30 minutes after training. The mean percentage of lactate recovery 30 minutes after training was 89.3 ± 1.1% in the CM3 and 97.9 ± 1.3% in the CM6 group, becoming significantly greater than placebo at day 5 with CM3 and at day 3 with CM6. Lactate variations were stable or de-creased in the 2 active groups, whereas they increased in the placebo group. At day 13, there was no fatigue perceived in 87.8% (CM6), 71.3% (CM3) and 15.9% (placebo) athletes. Citrulline malate enhances lactate and fatigue recovery of high performance endurance athletes, allowing a faster recovery and training adaptation without deletarious effects.
Rev Latinoamer Patol Clin, Vol. 59, Núm. 4, pp 194-201 • Octubre - Diciembre, 2012
194
www.medigraphic.org.mx
Key words: Citrulline malate, high exercise,
endurance training, sport, fatigue, lactate.
Palabras clave: Malato de citrulina,
ejercicio intensidad alta, entrenamiento de
resistencia, deporte, fatiga, lactato.
Recibido: 25/05/2012
Aceptado: 07/06/2012
Este artículo puede ser consultado en versión
completa en: http://www.medigraphic.com/
patologiaclinica
JA López-Cabral,* A Rivera-Cisneros,** H Rodríguez-Camacho,* JM
Sánchez-González,*** I Serna-Sánchez,* M Trejo-Trejo**
* Centro de Medicina y Ciencias Aplicadas al Deporte CODE Jalisco.
** División Ciencias de la Salud, Universidad de Guanajuato.
*** Academia Mexicana de Cirugía.
Corresponding author:
JA López-Cabral
George Santayana 4963. Jardines Universidad 45110. Zapopan, Jalisco,
México. E-mail: cabral_lopez@hotmail.com
Modi cation of fatigue indicators
using citrulline malate for high
performance endurance athletes
Abstract
High intensity physical exercise favors accumulation of lactate
in muscles and bloodstream, leading to impaired muscle func-
tion and exercise performance. This study evaluated the effect
of citrulline malate (CM) on blood lactate concentration and
perception of fatigue after muscular effort in high performance
athletes. Seventy-two high-performance athletes who gave
written informed consent were randomly assigned to CM 3
g/day, CM 6 g/day or placebo for 13 days. Blood lactate mea-
surements were performed every training day. Fatigue was as-
sessed through an auto-administered questionnaire at baseline
and after 6 and 13 days. Main criterion was the percentage of
blood lactate recovery 30 minutes after training. The mean
percentage of lactate recovery 30 minutes after training was
89.3 ± 1.1% in the CM3 and 97.9 ± 1.3% in the CM6 group,
becoming significantly greater than placebo at day 5 with CM3
and at day 3 with CM6. Lactate variations were stable or de-
creased in the 2 active groups, whereas they increased in the
placebo group. At day 13, there was no fatigue perceived in
87.8% (CM6), 71.3% (CM3) and 15.9% (placebo) athletes.
Citrulline malate enhances lactate and fatigue recovery of high
performance endurance athletes, allowing a faster recovery
and training adaptation without deletarious effects.
Resumen
Hacer ejercicio físico con una intensidad alta favorece la acu-
mulación de lactato en los músculos y circulación sanguínea, lo
cual afecta a la función muscular y el rendimiento deportivo.
Este estudio evaluó el efecto del malato de citrulina (MC) en
la concentración de lactato en sangre y la percepción de la
fatiga después de un esfuerzo muscular en deportistas de alto
rendimiento. A 72 deportistas de alto rendimiento que dieron
su consentimiento informado por escrito se les asignó al azar
a 3 g/día de MC, 6 g/día de MC o placebo durante 13 días. Las
mediciones de lactato en sangre se llevaron a cabo todos los días
de entrenamiento. La fatiga se evaluó mediante un cuestionario
autoadministrado al inicio del estudio y después de seis y 13 días.
El criterio principal fue el porcentaje de recuperación de lactato
en sangre 30 minutos después del entrenamiento. El porcen-
taje medio de recuperación de lactato 30 minutos después del
entrenamiento fue 89.3 ± 1.1% en el grupo MC3 y 97.9 ±
1.3% en el grupo MC6, llegando a ser significativamente mayor
que el placebo en el día 5 con MC3 y en el día 3 con MC6. Las
variaciones de lactato se mantuvieron estables o disminuyeron
en los dos grupos activos, mientras que aumentaron en el grupo
de placebo. En el día 13, no se percibió fatiga en 87.8% (MC6),
71.3% (MC3) ni en 15.9% (placebo) de los deportistas. El
malato de citrulina mejora la recuperación de lactato y la fatiga
de los deportistas con un entrenamiento de alta resistencia, lo
que permite una recuperación más rápida y una adaptación al
entrenamiento sin efectos nocivos.
www.medigraphic.org.mx
Rev Latinoamer Patol Clin, Vol. 59, Núm. 4, pp 194-201 • Octubre - Diciembre, 2012
195
López-Cabral JA y cols. Modification of fatigue with citrulline malate
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Introduction
O
vertraining syndrome frequently occurs in
athletes who train beyond the body’s ability
to recover. Without adequate rest and recovery,
long and hard training regimens can backfire, and
actually decrease physical performance. During
physical exercise, when the demand of energy is
higher than the maximum aerobic capacity, the an-
aerobic metabolism compensates leading to lactic
acid production. Once formed, lactic acid quickly
dissociates and diffuses in the blood stream as lac-
tate. As the intensity of physical exercise increases
and the anaerobic cellular reactions become pre-
dominant, changes occur in specific metabolites
associated to the muscle contractile machinery
(H+, ATP, ADP and inorganic phosphate). These
changes together with decrease in the sarcoplasmic
reticulum Ca
2+
release definitely culminate in the
inhibition of skeletal muscles contractility and re-
duction of performance known as fatigue.
1,2
In these
conditions, the lactate production is faster than its
clearance and the large amount of lactate produced
accumulates in the muscles and blood stream. Even
if the importance of removing the accumulated
lactate is under continuing debate, it has been rec-
ognized that elevated levels of skeletal muscle and
blood lactate are associated with impaired muscle
function and exercise performance.
3-5
During high intensity exercise, blood concen-
tration of ammonia, another metabolite, also in-
creases. Ammonia is produced during the reactions
of ATP re-synthesis and is eliminated through the
cycle of urea, responsible of ammonia detoxifica-
tion to urea in the liver. High blood concentrations
of ammonia are associated to muscle exhaustion.
Ammonia, in fact, facilitates the production of lac-
tate by activating the phosphofructokynase enzyme
and prevents the oxidative metabolism of pyruvate
hindering the supply of ATP to skeletal muscle.
6
Citrulline malate (CM - Reactimol
®
CONCOR-
DIA/BIOCODEX) is a mixture of citrulline, one of
non-essential amino acids, which is involved in the
urea cycle, and malate, a tricarboxylic acid cycle
(TCA) intermediate. It is usually prescribed in the
treatment of asthenia, at a daily dose of 3 g. Several
body of evidence in humans and rats has indicated
that CM treatment significantly reduces the sensa-
tion of fatigue and improves aerobic muscle func-
tion in subjects suffering from asthenia.
7
Perez-Guisado et al
8
demonstrated that a single
dose of CM conferred a benefit in pain control and
performance to athletes engaged in high-intensity
anaerobic exercises which increase lactate, am-
monia, and acidosis.
The present study aimed to evaluate the effect
of 3 and 6 g/day CM on blood lactate concentration
recovery and the perception of fatigue after muscu-
lar effort in high performance athletes (pentathlon,
athletics and speed skating).
Materials and methods
Subjects and study design. The trial was de-
signed as a randomized, double-blind, placebo-
controlled, parallel-groups study and took place at
CODE Jalisco, Guadalajara (Mexico) in April 2011.
Eligible subjects were healthy volunteer athletes
of both genders, aged 13 to 20 years. They had to
belong to Jalisco CODE teams (pentathlon, ath-
letics and speed skating) with a minimum of two
years of high performance training. Pregnancy or
breast feeding, declared allergy to CM or use of
CM or other anti-asthenic products within 1 month
before the study were exclusion criteria. The study
was approved by the Jalisco Health Department
Ethics Committee, and written informed consent
was obtained from all participants and their family
before study initiation. Subjects were randomly
assigned to receive CM 3 g/day, CM 6 g/day or
placebo for 13 days. Randomization was stratified
by sport. Commercially available CM was diluted in
1L of commercial lemon-flavour beverage used for
hydration of athletes. Subjects assigned to placebo
received the beverage only. Beverages containing
CM were indistinguishable from those without CM,
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López-Cabral JA y cols. Modification of fatigue with citrulline malate
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nor colour, nor smell, nor taste. The drinks were
prepared by a staff not involved in the study con-
duct. The study lasted two weeks (13 days), with
a 1-hour training session every day except the last
day of first week (Day 7) considered a rest day.
The study criteria included blood lactate levels,
an auto-administered fatigue questionnaire, body
weight and heart rate, and adverse event. Blood
lactate measurements were performed every
training day before training (Baseline Level – BL),
immediately after training (LES), then 5 minutes
(LES
5
) and 30 minutes (LES
30
) after training, us-
ing a commercial digital lactate analyzer (Lactate
Scout
®
, EKF Diagnostic). The questionnaire used
to define the subjective level of muscle fatigue
as perceived by athletes was a variant of the
26-points questionnaire described by Brun et al.
9
The number of questions was reduced to 12 in or-
der to reduce the time of athlete’s application and
maintain their attention focused. Athletes filled
the questionnaire at the end of the training week
before study initiation (Day 0), Day 6 and Day 13
of the study, in the interval of time LES
5
– LES
30
,
answering at each question with no (absence of
muscle fatigue); occasionally (occasional tired-
ness); always (presence of muscle fatigue); results
were expressed as a percentage of each type of
answer over the 12 questions. Body weight and
heart rate were measured before and immediately
after training at baseline and Day 13.
The primary efficacy criterion was the percent-
age of blood lactate recovery 30 minutes after
training, defined as (LES – LES
30
) / (LES – BL) x 100,
where LES, LES
30
and BL represent the maximum
level of blood lactate registered at the end of the
training, the level of blood lactate at 30 minutes
after the training phase and at baseline (before
training), respectively. Secondary criteria were
the percentage of responders determined as sub-
jects achieving an 80% or higher level of recovery
of blood lactate level 30 minutes after training,
changes over time in lactate levels, changes in rates
of subjective fatigue levels, and safety.
Statistical methods. Sample size was deter-
mined using a relevant difference of 20% between
placebo and CM in blood lactate recovery, with
a mean effect size of 11.8%, a variance of 23.5,
an alpha risk of 0.05, and a power of 0.80. The
homogeneity on the basal blood lactate level in
the three groups of study was assessed using an
analysis of variance. The percentage of recovery
was determined each day of the trial (except the
resting day) and results expressed as mean ± stan-
dard error of the mean (SEM) for each study group.
Percentages of recovery, changes in lactate levels
over time and changes in fatigue were compared
between groups using an analysis of variance for
repeated measurements model. The percentage of
responders was compared between groups using a
χ
2
test. The primary efficacy criterion analysis was
planned on the Intention-to-Treat (ITT) population,
i.e., subjects allocated to treatment, and on the Per
Protocol analysis (PP) i.e., subjects who completed
the study without major deviations to the protocol
Minitab
®
Statistical Software, version 15.0 (Minitab
Inc. Pennsylvania) was used for analyses.
Results
Seventy-two subjects were enrolled. All completed
the study without major deviations to the protocol
and were included in the ITT population, which was
identical to the PP population. Twenty-five athletes
were allocated to receive CM 3 g/day, 24 to CM 6
g/day and 23 to placebo. Demographics, baseline
characteristics and baseline levels of lactate were
evenly distributed between the 3 groups (table I).
The mean level of lactate at baseline was over the
accepted normal range (0.5 – 2.2 mmol/L).
Percentage of recovery of blood lactate level 30
minutes after a training session (figure 1). The over-
all mean percentage of recovery of blood lactate
level 30 minutes after training was 89.5 ± 1.4%
in the placebo group, 89.3 ± 1.1% in the CM 3 g
group and 97.9 ± 1.3% in the CM 6 g. The differ-
ence in blood lactate recovery for subjects treated
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López-Cabral JA y cols. Modification of fatigue with citrulline malate
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with CM 6 g and placebo started to be statistically
significant since the 1st day and confirmed from
the 3
rd
day up to the end of the treatment period.
In the CM 3 g group, the difference from placebo
became significant at Day 5.
Percentage of responders to CM therapy
(figure 2). During the first week of study, the
percentage of responders in the placebo group
progressively dropped from 82.6% to 63.6% dur-
ing the first three days of training, then stabilized to
about 70%. In the group of athletes treated with
CM 6 g, 100% of subjects reached a percentage
of recovery higher than 80% and this value sta-
tistically differed from that observed in placebo
group starting from Day 2. In the CM 3 g group,
the percentage of responders exceeded 80% and
became statistically different from the placebo
group at Day 4. On Day 3, in the placebo as in the
Table I. Demographics and baseline characteristics.
Citrulline Malate Citrulline Malate
3 g/day 6 g/day Placebo
n = 25 n = 24 n = 23
Age (years)* 16.9 ± 2.2 17.3 ± 2.3 17.2 ± 2.2
Male n (%) 17 (68.0) 14 (58.3) 15 (65.2)
Sport n (%)
Pentathlon 8 (32,00) 8 (33,33) 7 (30,43)
Athletics (Coach A) 7 (28,00) 7 (29,17) 7 (30,43)
Athletics (Coach B) 7 (28,00) 6 (25,00) 7 (30,43)
Speed-skating 3 (12,00) 3 (12,50) 2 (8,70)
Lactate level (mmol/L)** 2.6 ± 0.1 2.8 ± 0.1 2.8 ± 0.1
* Mean ± standard deviation. ** Mean ± standard error of the mean.
110
105
100
95
90
85
80
75
70
0 1 2 3 4 5 6 8 9 10 11 12 13
% of recovery in the lactate levels
from peak to 30 min after ending
training session as compared to basal
Placebo
CM 3 g/d
CM 6 g/d
*,**
*,**
*
*
*
*
*
**
*
*
*
*
* p<0.05 vs placebo
** p<0.05 vs CM 3 g
Days of the beginning of therapy
Figure 1. Percentage of recovery of lactate levels 30 minutes
after the end of training compared to basal levels over time.
Percentage of recovery of blood lactate 30 minutes after
training is defined as (LES – LES
30
) / (LES – BL) x 100, where
LES represents the maximum level of blood lactate registered
at the end of the training, LES
30
the level of blood lactate 30
minutes after the training phase and BL the lactate baseline
level (before training).
Data are shown as mean ± standard error of the mean (SEM).
CM = Citrulline malate.
* p < 0.05 compared to the placebo.
** p < 0.05 versus the lower dose of citrulline malate 3 g.
Placebo
CM 3 g/d
CM 6 g/d
* p<0.05 vs placebo
** p<0.05 vs CM 3 g
0 1 2 3 4 5 6 7 8 9 10 11 12 13
Days of the beginning of therapy
120
100
80
60
0
% responders (subjects with lactate
levels recovery higher to 80%)
* *,**
*
*
*
**
*
*
*
Figure 2. Frequency of subjects reaching at least 80% recov-
ery. During the 2nd week, D8 to D13, the 2 citrulline malate
curves are superimposed.
Data are shown as the percentage of each group. CM =
Citrulline malate.
* p < 0.05 compared to the placebo.
** p < 0.05 versus the lower dose of citrulline malate 3 g.
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198
López-Cabral JA y cols. Modification of fatigue with citrulline malate
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CM 3 g groups the percentage of responders had a
negative peak which was consistent with the largest
training load of the week. In the second week of
study, the percentage of responders in the placebo
group increased and remained stable to about 90%,
except at Day 10 in which training intensity was
again maximal. In the same week, the totality of
athletes treated with CM reported a percentage
of lactate recovery higher than 80%, so responded
to therapy, without differences between the two
dose groups.
Changes over time in lactate levels at base-
line, at peak at the end of training, and dur-
ing the recovery phase (figure 3). Basal lactate
levels in CM 6 g were statistically different from
those in placebo group since Day 2 up to the end
of the treatment. In the CM 3 g group, significant
differences appeared from Day 8 (figure 3A). At the
end of the training, when the peak of blood lactate
concentration was reached (LES), lactate levels
were statistically different from those observed in
the placebo group starting from Day 2 in the CM 6 g
group and Day 4 in the CM 3 g group (figure 3B).
At Day 8, after the resting day, the difference was
statistically significant from placebo for the CM 6 g
group. At baseline as well as at LES, lactate blood
concentrations tended to slightly increase over time
or remain stable in placebo group, whereas athletes
treated with CM showed a lactate recovery trend
during the first week and mostly during the second
week of study.
Five minutes after the end of training (LES
5
), the
values of lactate concentrations and the general
trend of curves in the three groups of study were
Placebo
CM 3 g/d
CM 6 g/d
Placebo
CM 3 g/d
CM 6 g/d
Placebo
CM 3 g/d
CM 6 g/d
Placebo
CM 3 g/d
CM 6 g/d
Basal blood lactate level (mmol/L)
0 1 2 3 4 5 6 8 9 10 11 12 13
6
5
4
3
2
1
0
* p<0.05 vs placebo
*
*
*
*
*
*
*
*
*
*
*
*
**
*
*
*
Basal blood lactate level at les
5
(mmol/L)
0 1 2 3 4 5 6 8 9 10 11 12 13
9
8
7
6
5
4
3
2
* p<0.05 vs placebo
*
*
*
*
*
*
*
*
Days from beginning of treatment
Days from beginning of treatment
*
*
*
*
*
*
*
*
*
*
*
*
Basal blood lactate level at les (mmol/L)
0 1 2 3 4 5 6 8 9 10 11 12 13
14
13
12
11
10
9
8
Days from beginning of treatment
0 1 2 3 4 5 6 8 9 10 11 12 13
* p<0.05 vs placebo
Days from beginning of treatment
* p<0.05 vs placebo
*
*
*
*
*
*
*
*
*
***
*
*
***
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
Basal blood lactate level at les
5
(mmol/L)
8
7
6
5
4
3
2
1
0
Figure 3. Changes over time in blood lactate levels during the 4 phases of monitoring: A) basal, B) end of training; C) recovery 5
min after training, and D) recovery 30 min after training.
Data are shown as mean ± standard error of the mean (SEM). CM = Citrulline malate.
* p < 0.05 compared to the placebo.
AB
CD
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199
López-Cabral JA y cols. Modification of fatigue with citrulline malate
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very similar to those reported at LES (figure 3C).
The LES
30
differed significantly between the 2 CM
groups and the placebo, with differences starting
from the 1st day for the CM 6 g group and from
the 4th day for the CM 3 g (figure 3D). These dif-
ferences persisted until the end of the study and
also after washout resting day (Day 7).
Fatigue level assessed by questionnaire (fig-
ure 4). At baseline, the 3 groups had a similar level
of perceived fatigue. After one week of treatment,
the perceived fatigue decreased in the 2 active
groups whereas it remained stable in the placebo
group. Both doses of CM reduced the perception
of fatigue during treatment. This effect appears to
be dose dependent in the first week and be similar
in the second week.
100
90
80
70
60
50
40
35
30
20
10
0
Frequency of answer (%)
Placebo
CM 3 g/d
CM 6 g/d
Muscle fatigue
(Possible answer to subjective questionnaire)
«No» «Occasionally» «Always»
Day 1 (Baseline)
23.1
26.0
23.6
59.6
54.0
54.9
17.3
20.0
21.5
100
90
80
70
60
50
40
35
30
20
10
0
Frequency of answer (%)
Placebo
CM 3 g/d
CM 6 g/d
Muscle fatigue
(Possible answer to subjective questionnaire)
«No» «Occasionally» «Always»
Week 1
21.3
*
59.3
59.6
19.1
9.7
*
,
**
84.0
*
31.0
*
,
**
16.0
*
0.0
100
90
80
70
60
50
40
35
30
20
10
0
Frequency of answer (%)
Placebo
CM 3 g/d
CM 6 g/d
Muscle fatigue
(Possible answer to subjective questionnaire)
«No» «Occasionally» «Always»
Week 2 (final)
15.9
*
71.3
58.3
25.7
*
,
**
87.8
*
26.7
*
,
**
12.2
*
0.0
*
2.0
Figure 4. Temporal evolution of the
frequency of responses to the subjective
questionnaire on the perception of fatigue
during treatment. The answer «No» means
no fatigue, while the answer «always» means
that the athlete perceives fatigue, according
to the questions used. The answer «Occa-
sionally» describes possible fatigue.
Data are shown as mean ± standard error
of the mean (SEM). CM = Citrulline malate.
* p < 0.05 compared to the placebo.
** p < 0.05 versus the lower dose of citrul-
line malate 3 g.
Safety. No adverse event was reported during
the study. No dehydration occurred. Monitoring of
weight and heart rate throughout the study showed
no changes.
Discussion
The present study shows that CM allows a greater
recovery of blood lactate and of fatigue after
muscular effort in high performance athletes.
The methodology used for the trial (randomised,
double-blind, placebo-controlled) is adequate
to warrant the validity of statistical results. The
stratification scheme prevents analyse results with
sport as cofactor. The study population, teenag-
ers, represents the majority of high-level athletes,
Rev Latinoamer Patol Clin, Vol. 59, Núm. 4, pp 194-201 • Octubre - Diciembre, 2012
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López-Cabral JA y cols. Modification of fatigue with citrulline malate
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Este documento es elaborado por Medigraphic
which allows extrapolate the observed results to
any endurance sportsman.
The mean basal levels of blood lactate concen-
tration were similar in the three study groups and
were higher than the normal range. This may be
due to the high training to which athletes were
submitted during the two weeks preceding the
study; this intensive training aimed to guarantee
blood lactate levels high enough to well appreciate
potential CM effects. The blood lactate concen-
tration has been chosen as evaluation criterion
because it represents one of the most often mea-
sured parameters during clinical exercise testing
and a rise in its value is considered an indicator of
intense muscular activity.
10
CM demonstrated its efficacy on the main study
efficacy criterion, blood lactate recovery 30 min
after training. This was supported also by the effects
obtained on the percentages of responders and
perceived fatigue. The study allowed also showing
that the expected results are obtained quicker with
6 g daily, although the 2 dosages have the same
efficacy after 2 weeks.
Athletes treated with placebo showed a lactate
recovery rate from peak and a percentage of re-
sponders in the second week of treatment slightly
higher than those reported in the first week. This
has been considered physiological and interpreted
as a consequence of the metabolic adaptation
which occurs during intense muscle exercise.
11-13
The same difference in values between the first
and the second week of study is less obvious in the
two CM treated groups where the effects of CM
are dominant over the physiological adaptation.
Lactate concentration variations from base-
line to peak and during recovery phase, in the
two weeks of study, showed that CM is efficient
in holding lactate concentration stable or even
decreasing, whereas in the placebo group blood
lactate accumulates over time. The CM efficiency
is evident at any monitoring point (baseline, LES,
LES
5
and LES
30
). Overall, if comparing the results
obtained in the two weeks, the CM effect on lac-
tate recovery at baseline as well as at peak is less
variable and more pronounced during the second
week. This is due to the mechanism of adaptation
in the metabolic response of the working muscles
during the first week training. The beneficial effects
exerted by muscular activity on removal of lactate
overproduction during endurance training are gath-
ered from blood lactate levels as measured at Day
8 of peak. This is the day following the resting day
and the corresponding values of lactate concentra-
tions are higher than those registered on Day 6,
confirming that physical exercise also contributes
to stimulate lactate recovery. The physiological
mechanisms underlying the CM effect on lactate
recovery observed in this study could be hypoth-
esized on the basis of results coming from previous
investigations. CM administrated in association with
physical exercises resulted in a significant reduc-
tion in the sensation of fatigue and increase in the
rate of oxidative ATP production during exercise.
7
These effects have been ascribed to malate, a TCA
intermediate, which could affect aerobic ATP pro-
duction through anaplerotic reactions. In another
study, CM administration has been associated to an
increased rate of ammonia clearance.
14
Citrulline is
involved in the urea cycle and allows detoxification
of ammonia, which concentration increases during
intense physical exercises with potential risks due
to its cellular toxicity.
CM, whereas given at recommended dosage or
higher dosage, has also shown to be well tolerated,
without adverse effects in this teenager population.
Conclusions
This randomized, double-blind, placebo-controlled
trial demonstrates that a supplementation of citrul-
line malate enhances lactate clearance and fatigue
recovery of high performance endurance athletes.
It becomes relevant to design strategies that clears
blood lactate after high intensity exercise bouts, as
this enables a faster recovery of the subject and may
support subsequent high-intensity exercise, leading
Rev Latinoamer Patol Clin, Vol. 59, Núm. 4, pp 194-201 • Octubre - Diciembre, 2012
201
López-Cabral JA y cols. Modification of fatigue with citrulline malate
www.medigraphic.org.mx
to greater overload and consequently enhanced
training adaptation, without deleterious effect.
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... The applicant identified a total of 35 references as being pertinent to the health claim. These included 19 human studies (Colin, 1972;Creff, 1972Creff, , 1982Vallat, 1972;Commandré, 1973;Mande, 1978;Dauverchain, 1982;Fornaris et al., 1984;Taillade, 1984;Vanuxem et al., 1990;Callis et al., 1991;Bendahan et al., 1997Bendahan et al., , 2001Bendahan et al., , 2002Moinard et al., 2008;Sureda et al., 2009Sureda et al., , 2010Pérez-Guisado and Jakeman, 2010;López-Cabral et al., 2012;López-Cabral, 2013, unpublished study report), six animal studies (Callis et al., 1991;Verley et al., 1995;Osowska et al., 2006;Giannesini et al., 2009;Giannesini et al., 2011;Takeda et al., 2011), seven in vitro studies (Briand et al., 1986(Briand et al., , 1992Thuillier-Brustion et al., 1990Goubel et al., 1995aGoubel et al., , b, 1997, and four reviews (Vanuxem et al., 1986;Rabier and Kamoun, 1995;Gibala et al., 1997;Curis et al., 2005). One of these references (Callis et al., 1991) reported on outcomes in humans and animals. ...
... All the references above except for one human study (López-Cabral et al., 2012;López-Cabral, 2013, unpublished study report) and one animal study (Takeda et al., 2011) were submitted by the applicant in a previous application for the same food and the same claim, which was assessed by the Panel with an unfavourable outcome as there were no human studies from which conclusions could be drawn for the scientific substantiation of the claim (EFSA NDA Panel, 2012a). ...
... The human study (López-Cabral et al., 2012;López-Cabral, 2013, unpublished study report) was a double-blind, randomised, placebo-controlled, parallel study in 72 athletes (age range 13-20 years) who were randomised to receive 3 g citrulline-malate (n = 25), 6 g citrulline-malate (n = 24) or a placebo (n = 23) for 13 days. The primary outcome of the study was percent changes in blood lactate concentrations within 30 minutes after exercise. ...
Article
Following an application from Biocodex, submitted for authorisation of a health claim pursuant to Article 13(5) of Regulation (EC) No 1924/2006 via the Competent Authority of Belgium, the EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA) was asked to deliver an opinion on the scientific substantiation of a health claim related to citrulline-malate and faster recovery from muscle fatigue after exercise. The Panel considers that citrulline-malate is sufficiently characterised. The claimed effect proposed by the applicant is “improved recovery from muscle fatigue”. Faster recovery from muscle fatigue by contributing to the restoration of muscle function after exercise is a beneficial physiological effect. The applicant identified, as being pertinent to the health claim, a total of 35 references, all of which, except for one human study and one animal study, were submitted by the applicant in a previous application for the same food and the same claim. No conclusions could be drawn from the animal study, which was carried out with citrulline only and not with citrulline-malate. The human study was concerned with blood lactate concentrations after exercise and did not assess muscle function. The evidence provided by the applicant did not establish that a faster reduction of blood lactate concentrations through a dietary intervention leads to faster recovery from muscle fatigue by contributing to the restoration of muscle function after exercise. No conclusions could be drawn from the human study for the scientific substantiation of the claim. A health claim on citrulline-malate and faster recovery from muscle fatigue after exercise has already been assessed by the Panel with an unfavourable outcome. The additional information submitted by the applicant did not provide evidence that could be used for the scientific substantiation of the claim.
... Amonia akan mengaktifkan fosfofruktokinase dan memfasilitasi produksi asam laktat 10,15 . Penelitian membuktikan bahwa olahraga dengan intensitas tinggi meningkatkan kadar asam laktat di dalam tubuh 15,25,[29][30][31][32] Asam laktat sebenarnya bermanfaat dalam meningkatkan produksi hemoglobin untuk kerja otot dan meningkatkan aliran darah 9 . Di sisi lain, asam laktat yang tinggi menyebabkan kelelahan dan gangguan fungsi otot serta performa olahraga 29,33 . ...
... Penelitian membuktikan bahwa olahraga dengan intensitas tinggi meningkatkan kadar asam laktat di dalam tubuh 15,25,[29][30][31][32] Asam laktat sebenarnya bermanfaat dalam meningkatkan produksi hemoglobin untuk kerja otot dan meningkatkan aliran darah 9 . Di sisi lain, asam laktat yang tinggi menyebabkan kelelahan dan gangguan fungsi otot serta performa olahraga 29,33 . Asam laktat yang berlebihan melepaskan ion proton H + dan meninggalkan produk akhir berupa garam asam laktat 34 . ...
... Sitrulin akan mendetoksifikasi amonia 16 sehingga produksi asam laktat dapat dikontrol 16 dan didaur ulang menjadi energi (glukoneogenesis) melalui siklus cori 38 . Studi lain menyatakan bahwa konsumsi sitrulin 3 g per hari dapat menurunkan kadar asam laktat dalam darah 29,32 . ...
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... Amonia akan mengaktifkan fosfofruktokinase yang membantu produksi laktat. Karena kadar amonia meningkat maka kadar laktat juga akan mengalami peningkatan sehingga terjadi kelelahan [13]. Selain Sitrulin, senyawa fenolik seperti karotenoid (Likopen dan Beta Karoten) yang berfungsi sebagai antioksidan dan antiinflamasi juga ditemukan pada semangka. ...
... Memberi Citrulline sebelum berolahraga dapat menunda kelelahan anaerob yang dialami atlet karena Citrulline mampu mengurangi akumulasi atau akumulasi asam laktat yang merupakan produk sampingan dari glikolisis anaerob. Citrulline mempercepat penguraian laktat di otot sehingga laktat dapat dimetabolisme kembali di hati dan ginjal untuk membentuk energi melalui siklus cory [13]. ...
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The relationship between changes in muscle metabolites and the contraction capacity was investigated in humans. Subjects (n = 13) contracted (knee extension) at a target force of 66% of the maximal voluntary contraction force (MVC) to fatigue, and the recovery in MVC and endurance (time to fatigue) were measured. Force recovered rapidly [half-time (t 1/2) less than 15 s] and after 2 min of recovery was not significantly different (P greater than 0.05) from the precontraction value. Endurance recovered more slowly (t 1/2 approximately 1.2 min) and was still significantly depressed after 2 and 4 min of recovery (P less than 0.05). In separate experiments (n = 10) muscle biopsy specimens were taken from the quadriceps femoris muscle before and after two successive contractions to fatigue at 66% of MVC with a recovery period of 2 or 4 min in between. The muscle content of high-energy phosphates and lactate was similar at fatigue after both contractions, whereas glucose 6-phosphate was lower after the second contraction (P less than 0.05). During recovery, muscle lactate decreased and was 74 and 43% of the value at fatigue after an elapsed period of 2 and 4 min, respectively. The decline in H+ due to lactate disappearance is balanced, however, by a release of H+ due to resynthesis of phosphocreatine, and after 2 min of recovery calculated muscle pH was found to remain at a low level similar to that at fatigue.(ABSTRACT TRUNCATED AT 250 WORDS)
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Muscle performance declines during prolonged and intense activity; important components are a reduction in force production and shortening velocity and a prolongation of relaxation. In this review we consider how the changes in metabolites (particularly H+, inorganic phosphate (Pi), ATP and ADP) and changes in sarcoplasmic reticulum Ca2+ release lead to the observed changes in force, shortening velocity and relaxation. The reduced force is caused by a combination of reduced maximum force-generating capacity, reduced myofibrillar Ca2+ sensitivity and reduced Ca2+ release. The reduced maximum force and Ca2+ sensitivity are largely explained by the effects of H+ and Pi that have been observed in skinned fibres. At least three different forms of reduced Ca2+ release can be recognized but the mechanisms involved are incompletely understood. The reduced shortening velocity can be partly explained by the effects of H+ that have been observed in skinned fibres. In addition it is proposed that ADP, which depresses shortening velocity, increases during contractions to a level that is considerably higher than existing measurements suggest. Changes in Ca2+ release are probably unimportant for the reduced shortening velocity. The prolongation of relaxation can arise both from slowing of the rate of decline of myoplasmic calcium concentration and from slowing of cross-bridge detachment rates. A method of analysis which separates these components is described. The increase in H+ and the other metabolite changes during fatigue can independently affect both components. Finally we show that reduced force, shortening velocity and slowed relaxation all contribute to the decline in muscle performance during a working cycle in which the muscle first shortens actively and then is stretched passively by an antagonist muscle.