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For decades, glycogen has been recognized as a storage form of glucose within the liver and muscles. Only recently has a greater role for glycogen as a regulator of metabolic signalling been suggested. Glycogen either directly or indirectly regulates a number of signalling proteins, including the adenosine-5′-phosphate- (AMP-) activated protein kinase (AMPK) and p38 mitogen-activated protein kinase (MAPK). AMPK and p38 MAPK play a significant role in controlling the expression and activity of the peroxisome proliferator activated receptor γ coactivators (PGCs), respectively. The PGCs can directly increase muscle mitochondrial mass and endurance exercise performance. As low muscle glycogen is generally associated with greater activation of these pathways, the concept of training with low glycogen to maximize the physiological adaptations to endurance exercise is gaining acceptance in the scientific community. In this review, we evaluate the scientific basis for this philosophy and propose some practical applications of this philosophy for the general population as well as elite endurance athletes.
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REVIEW ARTICLE
Optimizing training adaptations by manipulating glycogen
KEITH BAAR
1
* & SEAN MCGEE
2
1
Division of Molecular Physiology, University of Dundee, Dundee, UK, and
2
Department of Physiology, University of
Melbourne, Melbourne, VIC, Australia
Abstract
For decades, glycogen has been recognized as a storage form of glucose within the liver and muscles. Only recently has a
greater role for glycogen as a regulator of metabolic signalling been suggested. Glycogen either directly or indirectly
regulates a number of signalling proteins, including the adenosine-5?-phosphate- (AMP-) activated protein kinase (AMPK)
and p38 mitogen-activated protein kinase (MAPK). AMPK and p38 MAPK play a significant role in controlling the
expression and activity of the peroxisome proliferator activated receptor g coactivators (PGCs), respectively. The PGCs can
directly increase muscle mitochondrial mass and endurance exercise performance. As low muscle glycogen is generally
associated with greater activation of these pathways, the concept of training with low glycogen to maximize the physiological
adaptations to endurance exercise is gaining acceptance in the scientific community. In this review, we evaluate the scientific
basis for this philosophy and propose some practical applications of this philosophy for the general population as well as elite
endurance athletes.
Keywords: Exercise, AMP kinase, mitochondrial biogenesis, PGC-1
Introduction
Over the last few years, it has become increasingly
clear that the classical overload principle ! that
training adaptations occur as a result of systematic
and progressive exercise of sufficient frequency,
intensity, and duration ! is no longer adequate.
With our increasing understanding of the role of
nutrition in training, the modern version of the
principle must be: training adaptations occur in the
presence of optimal nutrition as a result of systematic
and progressive exercise of sufficient frequency,
intensity, and duration. This minor change to a
principle that is over 100 year s old signifies our
increasing understanding of the importance of nutri-
tion in facilitating the physiological adaptations
required for optimal performance.
Glycogen is the primary storage form of glucose
within the liver and muscles of mammals. Because of
the close relationship between glycogen concentra-
tions and fatigue, athletes and coaches have made
having high glycogen on race day a priority. How-
ever, glycogen plays a very important role in the
physiological adaptations that occur well before an
athlete steps to the starting line. As a result, many
scientists are proposing a ‘train low/compete high’
theory for glycogen. This method would have
athletes train in a glycogen-depleted state to max-
imize the physiological adaptations to endurance
exercise, and then glycogen load before race day to
maximize performance. This review evaluates the
scientific basis for the ‘train low/race high’ training
philosophy, and concludes that it might be an
effective strategy during the base phase of training,
but not later in the season when the focus turns to
performance.
Endurance exercise
Traditionally, exercise has been divided into three
general groups: enduranc e, resistance, and patterned
movements. Patterned movement exercises require a
precise motor program that results in the same
movement time after time. Examples of this type of
exercise are a golf swing or a jump shot in basketball.
Resistance exercises are those performed against a
*Correspondence: K. Baar, Division of Molecular Physiology, University of Dundee, CIR Complex, Dundee DD1 5EH, UK. E-mail:
k.baar@dundee.ac.uk
European Journal of Sport Science, Ma rch 2008; 8(2): 97!106
ISSN 1746-1391 print/ISSN 1536-7290 online # 2008 European College of Sport Science
DOI: 10.1080/17461390801919094
Downloaded By: [Baar, Keith] At: 16:54 24 April 2008
great external load such as weight lifting, a rugby
scrum, or line play in American football. Endurance
exercises are continuous submaximal efforts per-
formed for a long duration such as long-distance
running.
Although the above categories are generally ade-
quate, the muscular demands of endurance exercises
vary widely, pro mpting more specific classifications.
The classic endurance activity, long-distance r un-
ning , has very different demands than other endur-
ance exercises such as cycling, rowing, and
swimming. Running is what can be called a ‘strut’
endurance exercise, while cycling, rowing, and
swimming could be called motor or strength endur-
ance activities. These distinctions are based on the
role of the muscles acting as the primary movers in
the various exercises (Dickinson et al., 2000). In
running, the lower leg muscles function as struts,
contracting isometrically to allow the tendons to
store and return energy and decrea se the metabolic
cost of the exercise (Roberts, Marsh, Weyand, &
Taylor, 1997). In contrast, cycling requires the
quadriceps and hamstrings to serve as motors,
undergoing successive shortening contractions to
push and then pull the crank, passing power to the
bike. The same is true in rowing, where the boat is
propelled by very strong shortening contractions
from muscles in the back, buttocks, and thighs.
Similarly, in swimming athletes propel themselves
using shor tening contractions of the shoulders and
upper back.
The need for either isometric or shortening
contractions has major implications for the meta-
bolic and functional demands of the sport. This
results in the widely varied phenotypes of elite
athletes from each of these sports. Elite distance
runners have very small muscle mass in their legs,
whereas cyclists have disproportionately large thighs,
rowers have large backs and legs, and swimmers are
characterized by their large latissimus dorsi. In fact,
in long-distance running, performance is negatively
correlated with the volume of the lower leg (Holden,
2004), whereas performance in rowing correlates
positively with body weight (Bourgois et al., 2000).
Therefore, in motor endurance activities ther e is a
premium placed on maintaining muscle mass while
developing endurance, whereas fewer benefits of a
greater muscle mass exist in strut endurance events.
As a res ult of these fundamental differences, the type
and timing of nutrition required for optimal perfor-
mance will vary.
Training for optimal performance
To attain optimal performance, athletes need to train
consistently at a very high intensity. As a result,
recovery between training bouts plays an important
role in the maximal performance that can be
obtained. Therefore, to improve performance, nutri-
tional interventions must promote recovery, promote
a physiological adaptation, or both. If an interven-
tion improves the physiological adaptation but
doesn’t allow the athlete to maintain his or her
training intensity, it may not result in improved
performance.
A high maximal oxygen uptake (VO
2max
) is a
prerequisite for elite endurance athlete s, but differ-
ences in VO
2max
alone are not a definitive indicator of
performance. For elite athletes, the lactate threshold
and movement economy also play important roles in
performance. These parameters, considered together
as the power/velocity at the lactate threshold, con-
stitute one of the best determinants of endurance
performance (Coyle, 1999; Jones, 1998). The lactate
threshold is defined as the point at which lactate
accumulation in the blood accelerates as a result of
increasing lactate production and decreasing lactate
removal (Miller et al., 2002). Lactate is produced
when the energetic requirement of a muscle exceeds
its mitochondrial mass and lactate is transported out
of the active muscle into the blood through the
monocarboxylate transporter (MCT) 4 (Wilson
et al., 1998). From the blood, lactate can be taken
up via MCT1 and oxidized by muscles with a greater
mitochondria mass, or can be taken up by other
organs such as the liver and kidneys where it can be
reconverted to glucose via the Cori cycle (Brooks,
2000). As the intensity of exercise increases, there is
an increase in the mass of muscle recruited and an
increase in sympathetic nervous system (SNS) activ-
ity (Romijn et al., 1993). Increas ing the active muscle
mass recruits fibres with fewer mitochondria, result-
ing in an increase in lactate production. The increase
in SNS activity activates muscle phosphorylase,
increasing muscle glycogen breakdown and lactate
production. Higher SNS activ ity also shunts blood
away from the liver and kidneys, decreasing lactate
consumption and leading to the accumulation of
lactate in the blood. The larger the muscle mass that
can be recruited before the lactate threshol d is
reached (i.e. the bigger the mitochondria-rich muscle
mass), the greater the power/velocity at the lactate
threshold. Therefore, increasing the mitochondrial
mass within a large muscle mass, increasing MCT1
content and lactate consumption by muscle, and
decreasing sympathetic nervous system activation/
sensitivity are key to incre asing power at the lactate
threshold and therefore endurance performance.
Carbohydrate supplementation and modulation of
glycogen concentrations can affect SNS activity and
the signals that are thought to lead to mitochondrial
biogenesis (see below). However, its role in regulat-
ing lactate uptake into skeletal muscle has yet to be
deter mined.
98 K. Baar & S. McGee
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Signalling events that increase power at the
lactate threshold
The most well understood aspect of regulating
power at the lactate threshold is the control of
mitochondrial mass. All of the mitochondrial pro-
teins studied to date ! the insulin- and contr action-
stimulated glucose transpo rter GLUT4, as well as
the monocarboxylate transporters (MCTs) ! are
increased by exercise training (Coles, Litt, Hatta, &
Bonen, 2004; Holloszy, Kohrt, & Hansen, 1998).
The coordinated increase in mitochondrial mass,
GLUT4, and MCTs may be the result of the
increase in intracellular calcium, perturbations in
cellular energy balance, hormonal factors, metabo-
lites, and/or metabolic intermediates associated with
prolonged exercise (Hood, Irrcher, Ljubi cic, &
Joseph, 2006). With the increased utilization of
biochemical and molecular biology techniques, ex-
ercise physiologists are beginning to under stand how
these stimuli increase mitochondrial mass. In most
cases, they activate intracellular signalling pathways
that regulate the expression of an array of genes that
form the molecular basis for skeletal muscle adapta-
tion.
One family of transcriptional regulators in parti-
cular, the peroxisome proliferator-activated receptor
g coactivator family (PGCs: PGC-1a, PGC-1b), and
the PGC-1 related coactivator (PRC), are important
in driving mitochondrial biogenesis (Scarpulla,
2002). The PGCs are transcriptional coactivators
that recruit histone acetyl transferase (HAT) en-
zymes to a number of DNA binding transcription
factors, such as the myocyte enhancer factor 2
(MEF2; Handschin, Rhee, Lin, Tarr, & Spiegelman,
2003) and the nuclear respiratory factor 1 (NRF-1;
Wu et al., 1999). The recruitment of HAT enzymes
to specific DNA regions modifies the chromosome
structure to one that favours transcriptional activa-
tion. The activity as well as the expression of PGCs
is rapidly increased following a single bout of
endurance exercise. PGC mRNA increases 1.5- to
10-fold following a single bout of exercise in all
animals tested to date, including mice an d humans
(Baar et al., 2002; Pilegaard, Saltin, & Neufer, 2003;
Terada et al., 2002; Terada, Kawanaka, Goto,
Shimokawa, & Tabata, 2005; Wright et al., 2007).
The PGCs can also be activated in cell culture
models by chronic electrical stimulation (Irrcher,
Adhihetty, Sheehan, Joseph, & Hood, 2003), in-
creasing intracellular calcium (Ojuka, Jones, Han,
Chen, & Holloszy, 2003), activating AMP kinase
with AICAR (Lee et al., 2006), or activating the p38
MAP kinase pathway (Akimoto et al., 2005), all
models designed to mimic one aspect of endurance
exercise. Furthermore, high-intensity exercise in-
creases PGC activation more than low-intensity
exercise (Terada et al., 2005). Together, these data
suggest that high-intensity training increases PGC
signalling in skeletal muscle.
The effect of increasing PGCs has been studied
directly in genetically engineered mice. The over-
expression of either PGC-1 a or PGC-1b produces
mice with a dramatic increase in the oxidative
capacity of muscle (Arany et al., 2007; Lin et al.,
2002). Not only do mice over-expressing PGC-1a or
PGC-1b have greater expression of mitochondrial
enzymes, they also show an increase in performance.
Muscles from PGC-1a mice have a 3-fold increase in
time to fatigue when electrically stimulated (Lin et
al., 2002), while mice over-expressing PGC-1b are
able to run 35% further than wild-type mice during
run-to-exhaustion tests (Arany et al., 2007). To-
gether, these data demonstrate that PGCs increase
endurance performance and therefore the goal of
endurance athletes and coaches should be to max-
imize the activation of PGC signalling pathways in
skeletal muscle.
There are two ways to increase PGC signalling:
increase its activity or increase its expression. The
importance of PGC activity was recently highlighted
in a study demonstrating that increases in mitochon-
drial enzyme expression occur before an increase in
PGC protein (Wright et al., 2007). This suggests
that exercise acutely activates PGCs, allowing very
rapid changes in muscle metabolism. PGC-1a activ-
ity is controlled by association with a repressor
protein termed p160myb, which can powerfully
inhibit PGC function by blocking its association
with transcription factors (Fan et al., 2004). Phos-
phorylation of PGC-1a disrupts this association,
resulting in increased recruitment of PGC-1a to
transcription factors and increased PGC-1a tran-
scriptional activity. The p38 mitogen-activated pro-
tein kinase (MAPK) pathway is responsible for
phosphorylation of PGC-1a and disr uption of its
interaction with p160myb (Fan et al., 2004). p38
MAPK is activated by a number of different cellular
stresses including exercise (Widegren et al., 1998).
In humans, 60 min of cycling at 70% VO
2peak
increased PGC-1a association with MEF2, a mea-
sure of PGC-1a activation (McGee & Hargreaves,
2004). The increase in PGC-1a activity was asso-
ciated with increased p38 activation in the nucleus
supporting the hypothesis that p38-mediated phos-
phorylation of PGC-1a increases its activity and that
this increase in PGC activity could be important in
increasing mitochondrial mass following exercise.
Further support for this hypothesis comes from
mice, in which p38 MAPK has been constitutively
activated in fast muscle, resulting in enhanced
mitochondrial enzyme expression (Akimoto et al.,
2005). These data suggest that increasing the
activation of p38 MAPK leads to increased PGC
Optimizing training adaptations by manipulating glycogen 99
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activity, mitochondrial biogenesis, and increased
endurance. Therefore, training techniques that max-
imize the activity of p38 MAPK might have a
positive effect on endurance performance.
The other way to increase PGC effects is to
increase the amount of the protein within muscle.
Elegant work from the Yan laboratory has demon-
strated that the increase in PGC protein is the result
of increased transcription of the PGC gene, and that
this transcription is controlled by two primar y
inputs: pro teins binding to either the MEF2 or the
cyclic AMP responsive elements (CRE) within its
promoter (Figure 1). Mutation of either the MEF2
or the CRE sites within the PGC-1a promoter
eliminates the activation of PGC-1a transcription
following exercise (Akimoto, Sorg, & Yan, 2004).
That implies that both MEF2 and CRE binding
proteins are required to make more PGC. Proteins
binding to the cyclic AMP responsive elements are
regulated by SNS activity and will be examined
below, while the regulation of the MEF2 site will be
explored here. As stated above, PGCs coactivate
MEF2 (Handschin et al., 2003). As a result, the
MEF2 binding regions within the PGC-1 promoter
allow the establishment of a positive feedback loop
regulating PGC expression, which, if left unchecked,
could result in excess PGC within muscle. There-
fore, in addition to coactivation by PGCs, MEF2
transcriptional activity is repressed by the transcrip-
tional inhibitor histone deacetylase 5 (HDAC5;
Figure 2). HDAC5 modifies the local chromosome
structure to one that silences transcription (McKin-
sey, Zhang, & Olson, 2001). Phosphorylation of
HDAC5 at Ser259 and Ser498 disrupts the interac-
tion between MEF2 and HDAC5 (McKinsey,
Zhang , & Olson, 2000), leads to the removal of
HDAC5 from the nucleus by the chaperone protein
14-3-3, and results in chromatin remodelling and
enhanced MEF2 transcriptional activity (McKinsey
et al., 2001). Through interactions with MEF2,
HDAC5 has been identified as a key regulator of
PGC-1a expression (Czubryt, McAnally, Fishman, &
Olson, 2003). In the heart, mutation of ser259 and
ser498 on HDAC4, the key residues regulating
HDAC function, results in sudden death due to
cardiac mitochondrial abnormalities secondary to
reduced expression of PGC-1a and many mitochon-
drial enzymes (Czubryt et al., 2003). This suggests
that HDACs likely regulate a number of other
exercise responsive genes in skeletal muscle and
that phosphorylation of ser259 and ser498 is vital
for this process. Several signalling pathways, includ-
ing protein kinase D (Chang, Bezprozvannaya, Li, &
Olson, 2005), calcium/calmodulin-dependent pro-
tein kinases (CaMK; McKinsey et al., 2000), and the
AMP-activated protein kinase (AMPK; S. L. McGee
et al., unpublished), can phosphorylate these sites,
suggesting that they may play a role in mitochondrial
biogenesis. Because of its primary role in mitochon-
drial biogenesis and its regulation by glycogen, this
review will focus on AMPK. For more information
on the role of the other HDAC kinases, excellent
reviews can be found in Chin (2004), Hood et al.
(2006), and Rozengurt, Rey, and Waldron (2005).
Muscle contraction is associated with an increase
in the demand for cellular adenosine triphosphate
(ATP), which subsequently increases the AMP/ATP
ratio. When AMP is high and ATP is low, AMP
dislodges ATP from the a-subunit of AMPK,
allosterically activating the kinase and making it a
better substrate for phosphorylation by AMPK
kinases (Scott, Ross, Liu, & Hardie, 2007). In
skeletal muscle, the major AMPK kinase appears
to be LKB1 (Sakamoto et al., 2005); however, the
CaMK kinases a and b (Hawley et al., 2005; Woods
et al., 2005) and the TGFb activating kinase (TAK-
1; Momcilovic, Hong, & Carlson, 2006) may also
phosphorylate AMPK. Winder and Hardie were the
Figure 1. The role of the MEF2 and CRE sites within the PGC-
1a promoter on the activation of PGC-1a expression as deter-
mined by luciferase activity. The tibialis anterior muscles of mice
were stimulated to contract for 2 h and luciferase activity was
measured using in vivo bioluminescence imaging (Akimoto, Ribar,
Williams, & Yan, 2004). Note that endogenous promoter activity
is increased 3-fold over the first 3 h after exercise. Neither the
CRE nor the MEF2 mutant promoters were activated by exercise,
showing that both regions are required for the effects of exercise.
Adapted from Akimoto et al. (2004).
100 K. Baar & S. McGee
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first to demonstrate that AMPK could be activated
by exercise. Their seminal article demonstrated that
when rats ran at a high intensity, AMPK activity
increased by 2.5-fold within the first 5 min and did
not increase any further by 30 min (Winder &
Hardie, 1996). In humans, 20 min of cycling at
70% VO
2max
increased the activity of the a2 AMPK
isoform, without altering a 1 AMPK activity (Fujii et
al., 2000). Interestingly, cycling at a lower intensity
(50% VO
2max
) for the sa me 20 min did not activate
either a1 or a2 AMPK. Together, these data suggest
that intense endurance exercise activates a2 AMPK.
To investigate the effects of AMPK on muscle
directly, several researchers have used 5-aminoimi-
dazole-4-carboxamide ribonucleoside (AICAR), a
cell permeable agent that m imics AMP and activates
AMPK. Treating everything from muscle cells to
mice with AICAR activates a2 AMPK (Bolster,
Crozier, Kimball, & Jefferson, 2002) and results in
enhanced expression of PGC-1 and metabolic genes
(Irrcher et al., 2003; Jorgensen et al., 2007), suggest-
ing that a2 AMPK increases mitochondrial mass and
may mediate the adaptation to endurance exercise.
Furthermore, mice expressing a dominant negative
AMPK do not increase mitochondria in response to
metabolic stress (Zong et al., 2002). Consequently, it
has been hypothesized that AMPK might mediate
the incre ase in PGCs in response to training. Indeed,
in humans, cycling at 70% VO
2peak
doubled the
amount of a2 AMPK in the nucleus of cells from the
lateral quadriceps (McGee et al., 2003) and AMPK
can phosphorylate and inactivate HDAC5 (S. L.
McGee et al., unpublished). These data put AMPK
directly upstream of PGCs, potentially governing the
Figure 2. A diagram showing the proposed mechanism underlying the activation of PGC-1a transcription. Note that protein kinase D
(PKD), calcium/calmodulin-dependent protein kinase (CaMK), and the AMP-activated protein kinase (AMPK) can phosphorylate
HDAC5. Phosphorylation of HDAC5 disrupts the interaction between MEF2 and HDAC5, leads to the removal of HDAC5 from the
nucleus by the chaperone 14-3-3, and allows MEF2 to bind to the PGC-1a promoter. The sympathetic nervous system also can increase
PGC1 through b-adrenergic receptors increasing cyclic AMP. This results in the activation of TORC2, its downstream target CREB, and
activation of PGC-1a transcription.
Optimizing training adaptations by manipulating glycogen 101
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level of PGCs and theref ore the metabolic state of
the m uscle. As a result, training that increases
AMPK activity would be beneficial for endurance
performance.
Together with the HDAC5 regulated control of
MEF2, regulation of the cyclic AMP responsive
elements also plays an important role in the ability
to increase PGCs after exercise (Akimoto et al.,
2004). Exercise can increase the activation state of
the cyclic AMP response element binding protein
(CREB) in both exercised muscle (Widegren et al.,
1998) and non-exercised tissues such as the brain
(Griesbach, Hovda, Molteni, Wu, & Gome z-Pinilla,
2004) and other muscles that were not recruited
during the exercise (Widegren et al., 1998). Most
interestingly, the activation of CREB is greater in the
non-exercised muscle than in exercised muscle,
suggesting that exercise blocks the activation of
CREB by the sympathetic nervous system. The
significance of this finding was made apparent
recently by Miura et al. (2007), who suggested that
the sympathetic nervous system, potentially through
CREB, plays a significant role in the activation of
PGC-1a. First, they showed that the b2 agonist
clenbuterol increased the expression of PGC-1a.
Next, blocking all b receptors using propranolol or
the b2 receptors using ICI 118,551, they prevented
69% and 71% of the exercise-induced increase in
PGC-1a mRNA, respectively. Lastly, they demon-
strated that the induction of PGC-1a following
exercise was lower in mice lacking b-receptors then
in wild-type mice. Together, these data suggest that
SNS activity through b-adrenergic receptors may
play a significant role in the activation of PGCs and
the subseq uent increase in mitochondria.
The effect of glycogen on these pathways
In recent years, the role of glycogen in metabolism
has evolved from one where glycogen was seen as a
simple structure that stores energy, to one that
proposes additional roles for glycogen as a regulator
of cellular signalling and func tion (Hargreaves,
2004). The discovery that many proteins contain
regions known as glycogen binding domains has
helped uncover a role for glycogen in regulating
signaling (Machovic & Janecek, 2006). These do-
mains are thought to have evolved from amylolytic
enzymes that break down various carbohydrates
(Machovic & Janecek, 2006) and are now found in
a number of proteins that mediate diverse cellular
functions. Through glycogen binding domains, the
activity, localization, structure, and function of
proteins can be directly regulated by glycogen.
Consequently, the constantly changing architecture
of glycogen structure might regulate the cellular
function of proteins containing glycogen binding
domains. Given that exercise results in dynamic
changes in skeletal muscle glycogen, with glycogen
being degraded during exercise and resynthesized
during recovery, it appears that skeletal muscle
glycogen coul d play a role in signal transduction,
and hence adaptations, during exercise.
Few studies have examined this in the context of
long-term training on skeletal muscle adaptations.
The only study to date to look at the effect of
glycogen content on training adaptations used a 1-h
protocol of continuous leg extensions at 75% of
maximal workload (Hansen et al., 2005). The first
bout of exercise using both legs was followed 2 h
later by a second 1-h bout of leg extensions (glyco-
gen-depleted leg), while the other leg rested. The
next day, the other leg was trained in a glycogen
replete state. The participants trained this way for 10
weeks and both performance and mitochondrial
enzymes were determined separately for the two
legs. The leg that underwent one day of training in a
glycogen-deplete d state had a significantly greater
increase in total work and time to exhaustion without
any loss in maximal power (Hansen et al., 2005).
Furthermore, the increase in the activity of fatty acid
oxidation citrate synthase and 3-hydroxyacyl-CoA
dehydrogenase tended to be greater in the leg that
trained with lower glycogen, reaching significance
for citrate synthase. One important caveat with this
study is that the workload was identical for the two
legs. Since the rate of perceived exertion is greater in
the glycogen-depleted state (Rauch, St. Clair Gib-
son, Lambert, & Noakes, 2005), this means that the
low glycogen leg trained at a higher relative intensity
than the high glycogen leg. Whether this difference
played a role in the improved adaptation in the low
glycogen state remains to be determined. Regardless,
these data suggest that training at the same absolute
intensity with low glycogen may pr ovide a greater
stimulus for skeletal muscle adaptation than training
with normal glycogen concentrations.
To explain this difference, a number of recent
studies have examined the effect of muscle glycogen
on AMPK signalling during exercise. In rat muscle,
where glycogen has been depleted by prolonged
swimming followed by a high-fat, low-carbohydrate
diet, the activation of AMPK following either con-
tractions or AICAR treatment was greater than when
animals were fed a high carbohydrate diet to super-
compensate muscle glycogen (Derave et al., 2000;
Wojtaszewski et al ., 2003). Furthermore, this rela-
tionship is maintained despite the f act that there is
no difference in high-energy phosphate nucleotide
concentration (i.e. no difference in the AMP/ATP
ratio) between the high and low glycogen state
(Wojtaszewski, Jorgensen, Hellsten, Hardie, & Rich-
ter, 2002), suggesting that glycogen can directly
regulate AMPK activity. Insights into this phenom-
102 K. Baar & S. McGee
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enon came with the identification of a glycogen
binding domain within the b subunit of AMPK
(Polekhina et al., 2003). Although the effect of
glycogen binding on AMPK activity in vivo is not
yet conclusively resolved, it is tempting to speculate
that the tethering of AMPK to glycogen might
influence its activity. Certainly, it appears that
glycogen has a profound affect on AMPK localiza-
tion. In a recent study, 60 min of cycling at 70%
VO
2peak
with low muscle glycogen was associated
with greater AMPK activity, less AMPK associated
with glycogen, and greater AMPK translocation to
the nucleus than when muscle glycogen was high
(Steinberg et al., 2006). Furthermore, AMPK-sensi-
tive gene expression, as assessed by determining the
expression of the GLUT4, was potentiated following
exercise with low muscle glycogen (Steinberg et al.,
2006). The effect of lowering muscle glycogen on
other AMPK-dependent genes was not assessed;
however, it appears likely that enhanced AMPK
signalling would result in augmentation of the
adaptive response mediated by AMPK (Figure 3).
Together, these data suggest that exercising when
muscle glycogen is low induces gr eater skeletal
muscle adaptation through AMPK signalling than
exercising when muscle glycogen is high.
While carbo hydrate ingestion during exercise does
not prevent glycogen depletion, it acutely improves
performance (Jeukendrup, 2004). The acute effect
of increasing performance may, however, have a
detrimental effect on the long-ter m adaptation to
endurance training. Recently, two studies have
looked at the activation of AMPK in response to
motor endurance exercise in humans either with or
without carbohydrate supplementation (Akerstrom
et al., 2006; Lee- Young et al., 2006). The results of
the two studies are equivocal. In one, 2 h of one-
legged knee-extensor exercise at a workload of 60%
of maximal workload while drinking a carbohydrate
solution resulted in less activation of AMPK than the
same exercise while drinking only water (Akerstrom
et al., 2006). In the other, 1 h of cycling at 70%
VO
2peak
with carbohydrate supplementation had no
effect on AMPK activity (Lee-Young et al., 2006).
The difference between the studies might be due to
the effect of the carbohydrate supplem entation on
muscle glycogen concentrations, since where glyco-
gen sparing occurred AMPK activity was decreased
(Akerstrom et al., 2006). In the modified kicking
experiments, carbohydrate supplementation resulted
in glycogen sparing, possibly as a result of the
relatively muscle-specific nature of the exercise.
Since the body is fully supported during the exercise,
the exercise specifically isolates the quadriceps
muscles. The result is very specific increases in
blood flow that might better target the carbohydrate
supplementation and spare glycogen. Interestingly,
neither study looked at the PGCs. Since PGCs are
regulated by SNS activity (Miura et al., 2007) and
carbohydrate supp lementation decreases SNS acti-
vation (Jeukendrup, 2004), PGCs and not AMPK
might be a better short-term output measure for
deter mining the effect of carbohydrate supplementa-
tion on muscle adaptation to endurance exercise.
Depleting muscle glycogen has other effec ts on
muscle as well. In low glycogen conditions, p38
MAPK activity in the nucleus increases and potenti-
ates the expression of interleukin 6 (IL-6), which is a
p38 MAPK-sensitive gene, during exercise (Chan,
McGee, Watt, Hargreaves, & Febbraio, 2004). The
mechanisms by which glycogen might influence
MAPK sign alling have not been fully explored,
although it should be noted that the localization of
p38 was not different in response to lowered glyco-
gen, suggestin g that p38 itself does no t interact with
glycogen. Furthermore, as the MAPKs are particu-
larly sensitive to cellular stress, it is also possible that
lower glycogen concentrations could activate the
MAPKs through perturbed homeostatic mainte-
nance and not through direct interaction with
glycogen (Figure 3). Nonetheless, these data suggest
that exercising with lower muscle glycogen could
have potentially beneficial effects on MAPK activa-
tion in human skeletal muscle and could mediate
greater skeletal muscle adaptive responses to exer-
cise.
Effects of glycogen depletion on endurance
adaptations and per formance
While a number of interesting studies have been
published in this area in the last few years, definitive
studies have yet to be pergormed. The difficulty is
that the experiments to conclusively test whether
Figure 3. A schematic diagram of the activation of PGCs and
their downstream effects. The dark coloured arrows denote
processes that are increased by glycogen depletion. The lighter
coloured arrows denote processes that are decreased by carbohy-
drate supplementation during exercise.
Optimizing training adaptations by manipulating glycogen 103
Downloaded By: [Baar, Keith] At: 16:54 24 April 2008
endurance performance is enhanced by manipulat-
ing glycogen are scientifically more complex. The
acute effects of low glycogen on matched exercise are
clear: an increase in the signals that lead to increased
skeletal muscle mitochondria . However, the per-
ceived exertion of an exercise bout with a matched
workload (i.e. the same speed or power) is much
greater in a glycogen-depleted state (Rauch et al.,
2005). What is not clear at the moment is whether
training at a self-selected ‘high’ intensity would
negate the beneficial effe cts of exercising in a glyco-
gen-depleted state. Put another way, if an athlete
with more glycogen can exercise for longer at a higher
intensity, will this offset the advantages for an athlete
with lower glycogen who is exhausted earlier? If this
is the case, then training in a glycogen-depleted state
is ideal for lay people who seek the greatest benefit
for the least work. However, for elite athle tes, the
higher intensity of training made possible by a
glycogen-loaded state may be necessary to maximize
training intensity and therefore performance.
While the beneficial effects of an acute bout of
exercise in a glycogen-depleted state seem clear, the
question of whether an athlete with lower glycogen
can recover sufficiently to maintain a high training
standard during subsequent training bouts remains.
The importance of this question can be seen in
analogy with the work of Ben Levine and James
Stray-Gundersen on training at altitude (Levine &
Stray-Gundersen, 1997). While living at altitude
promotes a number of physiological adaptations
that should benefit endurance performance, in their
classic paper, living at high altitude and train ing at
low altitude was found to be better than both living
and training at altitude. They explained this surpris-
ing result by indicating that the athletes who trained
at sea level were able to sustain a higher training
intensity than those who trained at high altitude,
resulting in better performance. By analogy, while
training with lower glycogen concentrations and
without carbohydrate supplementation in theory
should result in greater acute adaptations, it may
prevent athletes from maintaining the training in-
tensity necessary to convert increased physiological
adaptations into improved performance.
To complicate matters further, in a low glycogen
state there is increased circulating cortisol to
stimulate gluconeogenesis and resynthesize liver
glycogen stores. The protein substrate for gluco-
neogenesis largely comes from muscle. In strut
endurance activities, increasing the rate of muscle
breakdown may not have a detrimental effect on
performance. However, in motor endurance activ-
ities where muscle mass and power are important
deter minants of performance, the loss of muscle
might decrease power at the lactate threshold and
therefore performance.
Practical conclusions
Manipulating glycogen can be an effective tool for
strut endurance athletes during the development of
their aerobic bas e, early in the season. For these
athletes, a higher premium is placed on metabolic
capacity than muscle strength. Therefore, the nega-
tive effects of the altered hormonal environment on
muscle mass should have a minimal effect on their
long-term performance. As the compe titive season
approaches and training becomes more intense,
increased training intensity will require fuller glyco-
gen stores. Therefore, long-distance runners would
be best to intersperse periods of low glycogen
training early in their competitive year, shifting to a
carbohydrate-rich diet as training intensity increases.
For mot or endurance athletes, on the other hand,
the benefits of improved mitochondrial mass and
aerobic capacity need to be weighed against the
potential negative effects on muscle mass. The
increased cortisol and the increase in AMPK activity
may directly limit skeletal muscle hypertrophy (Baar,
2006; Hickson, 1980) and therefore power at the
lactate threshold. Supplementing the diet with
increased protein to provide a non-muscle substrate
for gluconeogenesis could potentially minimize this
risk, although each athlete needs to work very closely
with coaches and nutritionists to deter mine what will
have the greatest impact on their performance !
greater muscle strength or improved endurance.
Determining the optimal diet and integrating it
effectively within a sound training schedule will go
a long way towards defining a champion.
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... Les stratégies fréquemment utilisées sont les entraînements à jeun (avant le déjeuner lorsque les réserves de glycogène sont réduites d'environ 80 %) ou les entraînements avec des réserves de glycogène volontairement réduites (deux entraînements dans la même journée avec des apports réduits en glucides entre les entraînements) (tableau 5) (2). La périodisation de la prise de glucides permettrait d'accroître l'utilisation des lipides lors des efforts d'intensité faible à modérée (23). Des entraînements effectués avec des réserves de glycogène basses sont associés à une activation de différentes voies de si-gnalisation qui jouent un rôle important sur la performance dans les sports d'endurance ; une de ces voies est celle de l'AMPK(AMP-activated protein kinase) qui joue un rôle dans la biogenèse des mitochondries et dans la régulation des transporteurs de glucose (GLUT-4) et des transporteurs de monocarboxylate (23). ...
... La périodisation de la prise de glucides permettrait d'accroître l'utilisation des lipides lors des efforts d'intensité faible à modérée (23). Des entraînements effectués avec des réserves de glycogène basses sont associés à une activation de différentes voies de si-gnalisation qui jouent un rôle important sur la performance dans les sports d'endurance ; une de ces voies est celle de l'AMPK(AMP-activated protein kinase) qui joue un rôle dans la biogenèse des mitochondries et dans la régulation des transporteurs de glucose (GLUT-4) et des transporteurs de monocarboxylate (23). Avec la périodisation de la consommation de glucides, précisons qu'un apport adéquat en glucides doit être maintenu lors des entraînements clés, comme ceux par intervalles, qui nécessitent l'utilisation des glucides pour être efficaces. ...
... Les recommandations nutritionnelles actuelles pour les athlètes d'ultra-endurance prônent une alimentation riche en glucides lors des entraînements et des courses (2, 3). Toutefois, l'athlète et son équipe peuvent cibler les séances d'entraînement qui seront effectuées avec des réserves de glycogène basses, avec ou sans consommation de glucides, pour créer des adaptations métaboliques (23). Étant donné la nature individualisée de la périodisation de la consommation de glucides, il est impossible d'émettre des recommandations applicables à tous. ...
... This strategy has been argued to require a 'periodised' training schedule (Jeukendrup, 2017), in which selected training sessions are undertaken with low CHO availability, with a subsequent increase in CHO in order to support performance in high-intensity sessions, as well as during competition (Baar and McGee, 2008). Hence, also being termed as 'train low, compete high' (Hansen et al., 2005). ...
... Recent research shows that CHO is not only utilised as a source of fuel for cell energy production, but also as a key regulator of several intracellular signalling processes, thus, suggesting that CHO can exert a significant influence on the physiological adaptations experienced from exercise (Baar and McGee, 2008). Following this discovery, researchers have attempted to manipulate CHO feeding to elucidate the optimal level of CHO availability t o b r i n g a b o u t d e s i r e d a d a p t a t i o n s . ...
... 'Train low' can reduce exercise intensity due to substrate deficiency (Havemann et al., 2006) and reduce muscle contraction as a result of compromised calcium regulation (Gejl et al., 2014). Consequently, this may not induce a high enough overload to see various adaptations occur, and also significantly worsen technical and tactical training performance (Baar and McGee, 2008). This may explain the decline in training intensity seen in the 'train low' studies of Yeo et al. (2008) and Hulston et al. (2010). ...
Article
Full-text available
Due to the importance of glycogen for energy production, research has traditionally recommended sufficient carbohydrate (CHO) availability to maximise exercise performance. However, recent evidence has suggested that undertaking some training sessions with low CHO availability may bring about greater physiological adaptations. This strategy has commonly been termed as 'train low'. Although desirable adaptations in gene expression related to mitochondrial biogenesis and the activity of enzymes related to aerobic metabolism have been observed, research is conflicted towards the ergogenic impact this technique has on exercise performance. Additionally, this strategy may produce maladaptations such as reduced training intensity, immunosuppression, protein oxidation and reduced pyruvate dehydrogenase (PDH) activity. Therefore, if athletes are to adopt this strategy, it is suggested that they periodise 'train low' to solely low-intensity sessions which won't be impaired by a drop in work rate, but otherwise maintaining sufficient daily CHO intake. Also, athletes could negate potential maladaptations by using caffeine and/or CHO mouth rinse to maintain exercise intensity, and increasing protein ingestion to counteract increased protein oxidation. Future research should directly compare the effect of 'train low' between use in all sessions and solely low-intensity sessions within one comprehensive study to better understand the mechanisms behind the apparent superiority of the latter strategy.
... Nutrition is a critical component of the preparation phase and might influence the physiological adaptations to training via several means. Firstly, moderating carbohydrate (CHO) intake and aligning it with the flux in training volume and intensity may optimize endurance adaptations via the mediation of adenosine-5′-phosphate-(AMP-) activated protein kinase (AMPK) cell-signalling pathways [5]. Conversely, exercising while chronically glycogen-depleted increases circulating stress hormones (e.g., cortisol), and causes disturbances in several indices of immune function (e.g., circulating leukocytes) [6] thereby increasing susceptibility to overtraining. ...
... The notion of train-low, compete-high is based on insights from cellular biology suggesting that careful manipulation of glycogen via dietary CHO restriction can serve as a regulator of metabolic cell-signalling, which can optimize substrate efficiency and endurance adaptations [5]. This may be particularly beneficial in the early stages of a training regimen, thereby allowing sufficient time for adaptations to occur. ...
... Periodically training with low muscle glycogen is associated with the activation of signalling pathways, including AMPK, which play a crucial role in mitochondrial biogenesis. Importantly, this regulates key transporter proteins including glucose transporter-4 (GLUT-4) and the monocarboxylate transporters, both of which mediate endurance performance (for review, see [5]). Chronic training with lowered (but not depleted) glycogen stores can result in adaptations that, following glycogen resynthesis, increase total work and time to exhaustion during exercise [43]. ...
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In this Position Statement, the International Society of Sports Nutrition (ISSN) provides an objective and critical review of the literature pertinent to nutritional considerations for training and racing in single-stage ultra-marathon. Recommendations for Training. i) Ultra-marathon runners should aim to meet the caloric demands of training by following an individualized and periodized strategy, comprising a varied, food-first approach; ii) Athletes should plan and implement their nutrition strategy with sufficient time to permit adaptations that enhance fat oxidative capacity; iii) The evidence overwhelmingly supports the inclusion of a moderate-to-high carbohydrate diet (i.e., ~ 60% of energy intake, 5–8 g·kg− 1·d− 1) to mitigate the negative effects of chronic, training-induced glycogen depletion; iv) Limiting carbohydrate intake before selected low-intensity sessions, and/or moderating daily carbohydrate intake, may enhance mitochondrial function and fat oxidative capacity. Nevertheless, this approach may compromise performance during high-intensity efforts; v) Protein intakes of ~ 1.6 g·kg− 1·d− 1 are necessary to maintain lean mass and support recovery from training, but amounts up to 2.5 g.kg− 1·d− 1 may be warranted during demanding training when calorie requirements are greater; Recommendations for Racing. vi) To attenuate caloric deficits, runners should aim to consume 150–400 Kcal·h− 1 (carbohydrate, 30–50 g·h− 1; protein, 5–10 g·h− 1) from a variety of calorie-dense foods. Consideration must be given to food palatability, individual tolerance, and the increased preference for savory foods in longer races; vii) Fluid volumes of 450–750 mL·h− 1 (~ 150–250 mL every 20 min) are recommended during racing. To minimize the likelihood of hyponatraemia, electrolytes (mainly sodium) may be needed in concentrations greater than that provided by most commercial products (i.e., > 575 mg·L− 1 sodium). Fluid and electrolyte requirements will be elevated when running in hot and/or humid conditions; viii) Evidence supports progressive gut-training and/or low-FODMAP diets (fermentable oligosaccharide, disaccharide, monosaccharide and polyol) to alleviate symptoms of gastrointestinal distress during racing; ix) The evidence in support of ketogenic diets and/or ketone esters to improve ultra-marathon performance is lacking, with further research warranted; x) Evidence supports the strategic use of caffeine to sustain performance in the latter stages of racing, particularly when sleep deprivation may compromise athlete safety.
... For example, glycogen depletion has a direct negative effect on endurance performance [49]. However, training in a glycogen-depleted state can enhance activation of key cell-signaling kinase-transcription factors and transcriptional co-activators, resulting in a coordinated up-regulation of nuclear and mitochondrial genomes [50,51] (indirect positive effect). Therefore, whilst the direct effect of glycogen depletion is negative, its indirect effect by enhancing mitochondrial biogenesis can have a positive effect on endurance performance [50,51]. ...
... However, training in a glycogen-depleted state can enhance activation of key cell-signaling kinase-transcription factors and transcriptional co-activators, resulting in a coordinated up-regulation of nuclear and mitochondrial genomes [50,51] (indirect positive effect). Therefore, whilst the direct effect of glycogen depletion is negative, its indirect effect by enhancing mitochondrial biogenesis can have a positive effect on endurance performance [50,51]. ...
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A conceptual framework has a central role in the scientific process. Its purpose is to synthesize evidence, assist in understanding phenomena, inform future research and act as a reference operational guide in practical settings. We propose an updated conceptual framework intended to facilitate the validation and interpretation of physical training measures. This revised conceptual framework was constructed through a process of qualitative analysis involving a synthesis of the literature, analysis and integration with existing frameworks (Banister and PerPot models). We identified, expanded, and integrated four constructs that are important in the conceptualization of the process and outcomes of physical training. These are: (1) formal introduction of a new measurable component ‘training effects’, a higher-order construct resulting from the combined effect of four possible responses (acute and chronic, positive and negative); (2) explanation, clarification and examples of training effect measures such as performance, physiological, subjective and other measures (cognitive, biomechanical, etc.); (3) integration of the sport performance outcome continuum (from performance improvements to overtraining); (4) extension and definition of the network of linkages (uni and bidirectional) between individual and contextual factors and other constructs. Additionally, we provided constitutive and operational definitions, and examples of theoretical and practical applications of the framework. These include validation and conceptualization of constructs (e.g., performance readiness), and understanding of higher-order constructs, such as training tolerance, when monitoring training to adapt it to individual responses and effects. This proposed conceptual framework provides an overarching model that may help understand and guide the development, validation, implementation and interpretation of measures used for athlete monitoring.
... For example, glycogen depletion has a direct negative effect on endurance performance [43]. However, training in a glycogen depleted state can enhance activation of key cell signaling kinase transcription factors and transcriptional co-activators, resulting in a coordinated up-regulation of nuclear and mitochondrial genomes [44,45] (indirect positive effect). Therefore, whilst the direct effect of glycogen depletion is negative, its indirect effect via enhanced mitochondrial biogenesis can have a positive effect on endurance performance [44,45]. ...
... However, training in a glycogen depleted state can enhance activation of key cell signaling kinase transcription factors and transcriptional co-activators, resulting in a coordinated up-regulation of nuclear and mitochondrial genomes [44,45] (indirect positive effect). Therefore, whilst the direct effect of glycogen depletion is negative, its indirect effect via enhanced mitochondrial biogenesis can have a positive effect on endurance performance [44,45]. ...
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A conceptual framework has a central role in the scientific process. Its purpose is to synthesize evidence, assist in understanding phenomena, inform future research and act as a reference operational guide in practical settings. We propose an updated conceptual framework intended to facilitate the validation and interpretation of physical training measures. This revised conceptual framework was constructed through a process of qualitative analysis involving a synthesis of the literature, analysis and integration with existing frameworks (Banister and PerPot models). We identified, expanded and integrated four concepts that are important in the conceptualization of the process and outcomes of physical training. These were: 1) formal introduction of a new measurable component ‘training effects’, a higher order construct resulting from the combined effect of four possible responses (acute and chronic, positive and negative); 2) explanation, clarification and examples of training effect measures such as functional (performance-based), physiological, subjective and other measures (cognitive, biomechanical, etc.); 3) integration of the sport performance outcome continuum (from performance improvements to overtraining); 4) extension and definition of the network of linkages (uni and bidirectional) between individual and contextual factors and other constructs. Additionally, we provided examples of theoretical and practical applications of the conceptual framework such as validation and conceptualization of constructs (e.g. performance readiness), and understanding of higher order constructs, such as training tolerance when monitoring training to adapt to individual responses and effects. This conceptual framework provides an overarching model that may help understand and guide the development, validation, implementation, and interpretation of measures used for athlete monitoring.
... [1][2][3][4][5][6][7][8] While these responses are affected by the nature of the exercise (eg, the exercise intensity 2,9,10 ), there is evidence substrate availability is also a potent modulator of this response. [11][12][13][14] It has been hypothesized that initiating endurance exercise with low muscle glycogen stores (the so-called "train-low" approach) results in a greater increase in the content of nuclear proteins 15,16 and in the transcription of genes 17-20 associated with mitochondrial biogenesis. However, although the "train-low" strategy has been reported to potentiate skeletal muscle signaling responses related to mitochondrial biogenesis, 17,[21][22][23] there are also contrasting findings showing no effects 24,25 and a consensus is yet to be reached. ...
... There is continued debate about whether beginning exercise with low muscle glycogen stores potentiates the exerciseinduced increase in genes associated with mitochondrial biogenesis and metabolism. 11,12,[50][51][52][53][54] Some of this controversy may relate to the observation that some of the evidence supporting the "train-low" approach is based on performing the experimental exercise session a few hours after a glycogenlowering exercise session. [21][22][23][24][26][27][28] Thus, it is difficult to determine if any observed effects are due to performing the T A B L E 2 Plasma lactate, glucose, epinephrine and norepinephrine concentrations, and serum-free fatty acid and glycerol concentrations pre-, Significantly different from pre the high-intensity interval exercise for the same condition (P < .05). ...
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Endurance exercise begun with reduced muscle glycogen stores seems to potentiate skeletal muscle protein abundance and gene expression. However, it is unknown whether this greater signaling responses is due to performing two exercise sessions in close proximity-as a first exercise session is necessary to reduce the muscle glycogen stores. In the present study, we manipulated the recovery duration between a first muscle glycogen-depleting exercise and a second exercise session, such that the second exercise session started with reduced muscle glycogen in both approaches but was performed either 2 or 15 hours after the first exercise session (so-called "twice-a-day" and "once-daily" approaches, respectively). We found that exercise twice-a-day increased the nuclear abundance of transcription factor EB (TFEB) and nuclear factor of activated T cells (NFAT) and potentiated the transcription of peroxisome proliferator-activated receptor-ɣ coactivator 1-alpha (PGC-1α), peroxisome proliferator-activated receptor-alpha (PPARα), and peroxisome proliferator-activated receptor beta/delta (PPARβ/δ) genes, in comparison with the once-daily exercise. These results suggest that part of the elevated molecular signaling reported with previous "train-low" approaches might be attributed to performing two exercise sessions in close proximity. The twice-a-day approach might be an effective strategy to induce adaptations related to mitochondrial biogenesis and fat oxidation.
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Bu kitap bölümü karbonhidratın performansa etkisini ele almakta olup bu etki karbonhidratın tüketim zamanına, yapısına, formuna, glisemik indeks değerlerine ve farklı gıda takviyeleri ile etkileşimine göre incelenmiştir.
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