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Effective Nutritional Supplement Combinations
Mike Greenwood2008, Nutritional Supplements in Sports and Exercise
9
Effective Nutritional Supplement
Combinations
Matt Cooke and Paul J. Cribb
Abstract
Few supplement combinations that are marketed to athletes are supported by
scientific evidence of their effectiveness. Quite often, under the rigor of scientific
investigation, the patented combination fails to provide any greater benefit than
a group given the active (generic) ingredient. The focus of this chapter is supplement combinations and dosing strategies that are effective at promoting an acute
physiological response that may improve/enhance exercise performance or influence chronic adaptations desired from training. In recent years, there has been a
particular focus on two nutritional ergogenic aids—creatine monohydrate and
protein/amino acids—in combination with specific nutrients in an effort to
augment or add to their already established independent ergogenic effects.
These combinations and others are discussed in this chapter.
Key words
Acute Chronic Supplementation Aerobic Anaerobic Exercise
performance Resistance training Protein Amino acids Carbohydrate
Creatine monohydrate Protein balance Glycogen resynthesis Sodium
D-Pinotol HMb Sodium bicarbonate Caffeine Ephedrine
1. INTRODUCTION
The first documented use of ‘‘natural preparations’’ to enhance
athletic prowess were the ancient Greeks (300 BCE). It is probable
that ever since that time, athletes have been combining various
nutritional compounds in an effort to increase the ergogenic potential of the supplement and enhance performance. Whether it is
to outperform the competition or maximize personal potential,
athletes are competitive by nature. This drive to succeed and a
From: Nutritional Supplements in Sports and Exercise
Edited by: M. Greenwood, D. Kalman, J. Antonio,
DOI: 10.1007/978-1-59745-231-1_9, Humana Press Inc., Totowa, NJ
259
260
Cooke and Cribb
growing awareness that nutritional choices can influence athletic
performance has fueled an explosion in the interest of nutritional
combinations as ergogenic aids: dietary supplement formulations
that enhance athletic performance. In the sports supplement industry, companies often market various combinations to consumers
based on the assumption that the supplement blend (or stack) will
provide greater benefit than any single compound alone. However,
few supplement combinations that are marketed to athletes are
supported by scientific evidence of their effectiveness. Quite often,
under the rigor of scientific investigation, the patented product
blend in question is shown to be no more effective than one active
(generic) ingredient.
From both a scientific and practical perspective, the focus of this
chapter is on supplement combinations and dosing strategies that
are documented to be safe and effective at promoting an acute
physiological response that may improve/enhance exercise performance or influence the chronic adaptations desired from training.
Few studies have linked acute physiological responses to chronic
adaptations in the same trial. However, manipulation (type timing
and quantity) of some nutritional variables, such as the macronutrients, is shown to alter events that affect chronic adaptations.
Therefore, where applicable, well controlled longer-term studies
that document enhanced chronic adaptations by certain dietary
supplement combinations are featured.
2. SUPPLEMENT COMBINATIONS THAT MAY ENHANCE
THE PHOSPHAGEN SYSTEM
Exercise at high intensity is dependent on the maximum rate of
adenosine triphosphate (ATP) regeneration, which occurs via the
phosphagen [ATP, phosphocreatine-creatine (PCr-Cr)] and glycolysis/glycogenolysis systems. Whereas the ADP-ATP aspect of the
phosphogen system is considered a ‘‘cofactor’’ (albeit an essential
one), the PCr system (encompassing its site-specific CK isoenzymes)
plays a pivotal, multifaceted role in muscle energy metabolism
(Fig. 1). The availability of PCr is now generally accepted as
most critical to the continuation of muscle force production and
performance during repeated, short bouts of powerful activity (1,2)
Effective Nutritional Supplement Combinations
261
Fig. 1. Main functions of the creatine-phosphocreatine (Cr-PCr) system in a
muscle fiber. The first is that of a temporal energy buffer for the regeneration of
ATP via anaerobic degradation of PCr to Cr and rephosphorylation of ADP.
The second major function of this system is that of a spatial energy buffer or
transport system that serves as an intracellular energy carrier connecting sites
of energy production (mitochondrion) with sites of energy utilization, such as
the NaþKþ pump, myofibrils, and the sarcoplasmic reticulum.
as well as aerobic exercise at high intensity (3,4). Since the early
1990s, it has been established that ‘‘loading’’ with creatine monohydrate (CrM) (n-[aminoiminomethyl]-N-methylglycine) (4 5 g
servings day-1 for 5 days) elevates muscle Cr concentrations (by
15%–40%) (1,12) and may enhance athletic performance under
a variety of circumstances (13–19). Regular use also appears to
enhance chronic adaptations, particularly during strength training
(30,31) The ergogenic potential of CrM is thought to reside in
its ability to augment the phosphagen system (i.e., increased PCr
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Cooke and Cribb
availability) (2,9,47). Chronic use is popular among a variety of
athletes and other populations who perform resistance training
exercise (34–40). A large scientific body of literature continues
to document this supplement’s physiological (23–26) and performance enhancing (27–31) effects as well as dispel concerns of
adverse effects (32,33). For these reasons, there is a steadily increasing amount of interest in combining CrM with other compounds to
enhance its ergogenic potential.
Other forms of oral Cr have shown limited potential (20–22).
Additionally, the presence of phosphatase enzymes in the blood
and gut suggests that supplementation with other energy-yielding
components of the phosphagen system, such as ATP or PCr, is not a
viable option as these enzymes readily cleave the phosphate from the
molecule (41). Whereas the Cr portion of the monohydrate form
consists of up to 92% Cr, it forms only 50% of the PCr molecule
(20). Oral supplementation with CrM enters the circulation intact
where active uptake by tissues is facilitated by a Naþ-dependent
transporter against a concentration gradient (42). The capacity
of CrM to enhance the bioenergetics of the phosphagen system
by increasing PCr availability is thought to reside in the extent of
Cr accumulation in muscle (31,47,48). To exert a beneficial effect on
performance and metabolism, an increase in muscle total Cr (PCr þ
Cr) content by at least 20 mmolkg dm-1 appears to be required (43).
Although a loading phase is shown consistently to achieve this
(as well as increase total Cr concentrations in other tissues with low
baseline Cr content), it is also apparent that this response can be
highly variable among subjects (see sidebar: Multifaceted Role of the
Muscle PCr-Cr System in Exercise Metabolism).
For these reasons, a number of studies have assessed Cr uptake in
the presence of other compounds. For example, Cr accumulation in
muscle is enhanced by the presence of insulin (50) and possibly
triiodothyronine (51) but may be depressed by the presence of some
drugs (e.g., oubain, digoxin) (52) or vitamin E deficiency (53). The
findings from some investigations suggest that caffeine impairs the
advantages of Cr loading (54), whereas other studies have involved
administering CrM in caffeine-containing beverages (e.g., tea,
coffee) and report significant elevations in muscle Cr and improved
athletic performance (9,13,15). Other investigations have reported
that muscle Cr uptake is not affected by PCr, creatinine, or cellular
Effective Nutritional Supplement Combinations
263
concentrations of various amino acids such as glycine, glutamine,
alanine, arginine, leucine, and glycine or the sulfur-containing
amino acids methionine and cysteine (55,56).
Improved cellular retention of Cr has been attributed to a stimulatory effect of insulin on the Cr transporter protein (50). Carbohydrates
(CHO) with a high glycemic index (GI) (e.g., glucose, sucrose) generally
evoke a high insulin response (57). Once it had been demonstrated that
the presence of insulin (at supraphysiological levels) increased muscle Cr
accumulation in humans (43), other investigations that examined the
effects of combining CrM with high-GI CHO soon followed. Green
et al. were the first to demonstrate reduced urine Cr losses (58) and a
60% increase in muscle Cr accumulation (59) from combining a high
dose of glucose (93 g) with each 5 g dose of CrM (4 5 gday-1 for 2
days) compared to CrM alone. Robinson et al. (60) also showed that a
high-CHO diet combined with CrM (4 5 gday-1 for 5 days) after
exercise provided effective (p < 0.01) Cr accumulation in the exercised
limb. However, data from subsequent studies suggested that lower
doses of CHO (glucose) may also be effective. For instance, Greenwood
et al. (61) assessed whole-body Cr retention (via 24-hour urine
samples for 4 days) and reported that a 5 g dose of CrM combined
with an 18 g dose of glucose (4 day-1 for 3 days) resulted in
significantly greater Cr retention than an equivalent dose of CrM
alone or an effervescent Cr supplement (containing sodium and
potassium bicarbonate). Along this line, Preen et al. (62) examined
the effectiveness of three CrM loading procedures on total Cr accumulation in muscle. A group of 18 physically active males were
divided into three equal groups and provided one of three regimens:
1) CrM (4 5 gday-1 for 5 days); 2) the same dose of CrMþglucose
(1 gkg-1 twice a day for 5 days); or 3) CrM combined with 60
minutes of daily exercise (repeated sprints) (CrMþE) for 5 days.
Results showed that the combination CrMþglucose provided a 7%
to 9% greater (p < 0.05) elevation in total muscle Cr concentrations
than CrM alone or CrMþE (62).
Supplementation with high-GI CHO appears to be effective for
promoting Cr uptake, although combining CrM with a protein
(PRO) supplement may provide similar benefits. For example,
using a group of recreational weightlifters, one study directly
compared the effects of two CrM-containing supplements:
CrMþCHO (glucose) and CrMþPRO (whey protein isolate)
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Cooke and Cribb
(1.5 g of supplementkg-1 day-1) during 11 weeks of resistance
training (63). After the 11-week program, the two CrM-containing
supplements provided a similar increase in total muscle Cr concentrations (10%). Additionally, the CrMþCHO and CrMþPRO
groups demonstrated greater (p<0.05) strength improvements
and muscle hypertrophy than an equivalent dose of CHO or PRO
(63) (see sidebar: Creatine þ Protein or Creatine þ Carbohydrate
for Better Muscle Hypertrophy?) Other studies have reported similar benefits from combining CrM with whey protein (64)
or CHO (glucose) (18) during resistance training, but muscle Cr
concentrations were not assessed. Whereas these studies utilized
relatively large doses of PRO or CHO (70–100 g or more) in combination with CrM (63–65) and reported positive outcomes, the
results of a study by Stout et al. (66) suggested that a smaller dose of
CHO (35 g glucose) with each 5 g dose of CrM is also effective for
improving training adaptation. However, no other studies have
directly compared the effects of different CrM-containing PRO or
CHO supplements on Cr accumulation and training adaptations.
Combining PRO, CHO, and CrM may be the most effective mix
for promoting whole-body Cr accumulation, particularly if smaller
doses of the macronutrients are desired. Steenge et al. (43) reported
that ingestion of CrM along with a PROþCHO supplement (50 g
dairy milk protein, 50 g glucose) over 5 days resulted in similar
insulin responses and (whole-body) percentage Cr accumulation
values (25%) as the same CrM dose combined with 100 g of
glucose(43). Whole-body Cr accumulation is an indirect method
assessing CrM uptake by tissues. Percent whole-body Cr retention
can be calculated as Cr ingested (g)/urinary Cr excretion (g) 100)
(43). The results obtained by Steenge et al. (43) suggested that the
combination of PRO and CHO with CrM may be an effective way to
improve Cr accumulation, particularly when smaller doses of these
macronutrients are desired. This combination may also have important implications for populations where the consumption of large
amounts of high-GI CHO is undesirable, such as those with, or at
risk of, type 2 diabetes. This combination (PRO-CHO-CrM) has
also been used to demonstrate that the timing of supplementation
may be important for improving Cr accumulation in muscle and
adaptations from training (67) (see sidebar: Can Supplement
Timing Double Gains in Muscle Mass?). Other studies have shown
Effective Nutritional Supplement Combinations
265
that CrM supplementation close to exercise promotes muscle Cr
uptake (60) and increases the girth and thickness of the exercised
limb after resistance training (68). Therefore, the use of a CrMcontaining PRO-CHO supplement before and after resistance exercise may provide a higher degree of Cr accumulation and
muscle anabolism and therefore promote better gains in strength
and muscle mass.
To summarize the research in this particular area, co-ingestion of
CrM with CHO and/or PRO (i.e., glucose or whey proteins;
35–100 g) appears to enhance muscle Cr storage, which may result
in enhanced performance and better training adaptations. Greater
accumulation in muscle appears to be due to a stimulatory effect of
insulin on cell Cr transporter. In fact, combining CrM with a PRO
and/or CHO supplement seems to reduce the individual variations
in muscle Cr accumulation reported previously in studies involving
acute loading (15,43,49). Additionally, there is evidence to suggest
that the timing of the supplement dose is important. The use of this
supplement combination close to exercise (i.e., just before and/or
after) appears to promote better Cr accumulation in muscle and
influence training adaptations (60,67). Therefore, the use of a CrMcontaining PRO-CHO supplement close to the time of exercising
represents a simple but highly effective strategy that promotes effective Cr accumulation (to increase PCr availability in muscle) and
provides an ergogenic effect during training that results in greater
adaptations. Further examination of dose-response data along with
the extent of Cr accumulation and adaptations would help define a
clearer supplementation prescription.
Aside from the use of macronutrients such as PRO and CHO,
some studies have examined the effects of co-ingesting CrM with
other compounds that affect insulin secretion and/or tissue sensitivity. For instance, in a single blinded study, Greenwood et al.
(69) examined whether co-ingestion of D-pinitol (a plant extract
with insulin-sensitizing characteristics) (70) with CrM affected
whole-body Cr retention (determined by 24-hour urine samples
for 4 days). Results revealed that whole-body Cr retention (and
percentage Cr retention) over the 3-day loading phase was greater
(p < 0.05) in the two groups given CrM combined with a low dose of
D-pinitol (LP) group was given 4 5 g CrM þ 2 0.5 g D-pinitol;
PreP group was given D-pinitol 2 0.5 g 5 days prior to and during
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CrM (4 5 g) supplementation compared to an equivalent dose of
glucose (placebo) or CrM alone. However, another group given a
high dose D-pinitol (4 0.5 g) with the same dose of CrM showed no
greater Cr retention than in the group given CrM alone (69). Interestingly, the group predosing with D-pinitol (PreP) demonstrated the
same results as the LP group, suggesting that no further benefit seems
to be gained by taking D-pinitol prior to supplementation (69). The
authors concluded that ingesting Cr with D-pinitol may augment
whole-body Cr retention in a manner similar to that reported with
CHO or CHO þ PRO supplementation (43). However, this is the
only study that has examined the effects of D-pinitol combined with
CrM supplementation on Cr accumulation. Because of the conflicting
nature of the results regarding the high versus low doses of D-pinitol,
further research is necessary before a clear conclusion can be drawn.
Another compound that has shown potential to enhance
Cr uptake and accumulation in muscle is -lipoic acid (ALA).
Supplementation with ALA is shown to increase the expression of
glucose transporter proteins (GLUT4) and enhance glucose uptake
in muscle (71,72). In light of the fact that Cr uptake is influenced by
insulin and that ALA can increase glucose disposal, Burke et al.
(73) examined the effects of combining ALA with CrM on muscle
Cr accumulation. In this study, muscle biopsies were obtained to
determine total Cr concentration in16 male subjects before and after
the 5-day supplementation intervention. Results showed a greater
increase (P < 0.05) in PCr and total Cr in the group given ALA
combined with CrMþCHO (CrM 20 gd-1 þ sucrose 100 gd-1 þ
ALA 1000 mgd-1) compared with a group given the same dose of
CrMþCHO or CrM alone. The authors concluded that co-ingestion
of ALA with CrM (and a small amount of sucrose) can enhance
muscle Cr concentrations compared to an equivalent dose of
CrMþCHO or CHO alone (73). However, the authors also
acknowledged that a limitation of this study was the high baseline
muscle Cr concentrations exhibited by the participants; the groups
were 10% higher than starting values reported in other studies
(135 mmolkg–1 vs. 125 mmolkg–1). Initial muscle Cr content
is an important determinant of muscle Cr uptake (48). That is,
study participants with lower muscle Cr concentrations tend to
show the largest increases after supplementation; conversely, those
with higher muscle Cr concentrations show little or no increase.
Effective Nutritional Supplement Combinations
267
Burke et al. (73) suggested that the higher starting values of the
participants may have been the reason for the lack of increase in PCr
and total Cr experienced by two of the three groups in this study. As
is the case with D-pinitol, only one study has examined the effects of
ALA on Cr accumulation. The ability of D-pinitol or ALA to affect
muscle Cr accumulation during CrM supplementation needs to
be confirmed by other investigations. Other compounds such as
pyruvate, b-hydroxy-b-methylbutyrate (HMb), and b-alanine have
been examined in combination with CrM. However, these studies did
not assess muscle Cr concentrations in response to supplementation,
and therefore their results are discussed elsewhere in the chapter.
To summarize this section, supplement combinations that have
been shown to increase muscle Cr concentrations successfully are
presented in Table 1. The ergogenic potential of CrM and its capacity
to enhance the bioenergetics of the phosphagen system are thought to
depend on the extent of Cr accumulation in muscle. This has led to
increased interest in combining CrM with compounds to improve the
uptake and accumulation of Cr in muscle. However, when viewed
in comparison to the large body of literature that demonstrates
CrM’s widespread use, safety, and performance-enhancing effects, a
relatively undersized amount of work documents effective strategies
and supplement combinations that may improve muscle Cr accumulation in response to supplementation. Probably owing to an
insulin-stimulating effect on the cellular Cr transporter, combining
each dose of CrM with high-GI CHO and protein (50 g of each or a
total of 1 gkg-1) appears to be a most effective strategy for improving
Cr accumulation. The combination of PRO and CHO is particularly
effective when smaller doses of these macronutrients are desired.
Other compounds that affect insulin secretion and/or tissue sensitivity, such as D-pinotol and ALA, have shown potential to augment
muscle Cr accumulation but require further investigation before clear
conclusions can be made about their effectiveness.
3. SUPPLEMENT COMBINATIONS TO ENHANCE
MUSCLE GLYCOGEN
Along with the phosphagen system, glycolysis and glycogenolysis
are considered to be important energy contributors during high
intensity exercise. A relation between muscle glycogen concentration
Table 1
Supplement combinations shown to enhance muscle Cr accumulation
Reference
Experimental
comparison
CrMþCHO vs. CrM
only
Robinson
(60)
High-CHO diet with
CrM vs. high-CHO
diet without CrM
Greenwood
(61)
CrMþCHO vs. CrM
only and
effervescent Cr
268
Green (58)
Protocol
Supplementation
Change
Muscle [PCr and Cr]
before and after
supplementation;no
exercise
Muscle [PCr and Cr],
one-legged cycle
exercise to
exhaustion preceded
supplementation
Whole-body Cr
retention via 24-hr
urine samples for 4
days; 3-day
supplementation; no
exercise
5 g CrM or 5 g CrM þ
93 g CHO (glucose)
4day-1, 5 days
After 5 days, 60%
greater [PCr] from
CrMþCHO
(p < 0.01)
After 5 days, 23%
greater increase in
muscle [total Cr] in
exercised limb (p <
0.01)
After 4 days, greater
Cr retention from
CrMþCHO
compared to other
groups (p <0.05)
(0%, 60%, 80%, and
60% CrM retained
for P, CrM,
CrMþCHO, and
effervescent Cr,
respectively)
20 g CrMday-1 5 days
5 g CrM þ 18 g CHO
(glucose) 4day-1,
or equivalent dose of
CrM, 3 days
269
Preen (62)
CrMþCHO vs. CrM
only and CrM þ
exercise (E)
Muscle [PCr and Cr]
before and after
5-day intervention;
one group
performed exercise
CrM 20 gday-1
CrMþCHO
20 gday1 þ glucose
1 gkg-1, 2day-1
CrM þ E 20 gday-1
þ 60 min repeatedsprints daily
Derave
(111)
CrMþPRO compared
to CrM only and
placebo (P)
Muscle [PCr and Cr]
prior to and after 2week right-leg
immobilization
followed by 6 weeks
of right leg resistance
training
CrM: 15 gday-1
during
immobilization
followed by
2.5 gday-1 during
rehabilitation
CrMþPRO: CrM
dose þ 40 g protein
and 6 g AA during
training
After 5 days, 9%
greater increase in
[total Cr] from
CrMþCHO
(p < 0.05).(25% vs.
16% and 18% for
CrMþCHO vs. CrM
and CrMþE,
respectively)
After training, 30%
increase from
baseline in [total Cr]
(right leg) in both
CrM and
CrMþPRO vs. P
(p < 0.05)
(Continued )
Table 1
(Continued)
Reference
Protocol
Supplementation
Change
Steenge
(43)
CrMþCHO (low and
high dose) compared
to CrMþCHO þ
PRO
CrM (4 5 g)
þ5 g CHO
þ50 g CHO,
þ93 g CHO or
þPROþCHO (50 g
each)
Cribb (63)
Compared
CrMþCHO and
CrMþPRO to CHO
and PRO alone
Insulin and wholebody Cr retention
values (24 hr) before
and after each
supplement trial (all
participants
completed four
trials)
Muscle [PCr and Cr]
before and after 11
weeks of resistance
exercise
After 24 hr
PROþCHO
provided similar
insulin responses
and [total Cr]
accumulation values
(25%) as high-dose
CHO (p < 0.05)
After 11 weeks, 10%
increase from
baseline, [total Cr]
after 11 weeks in
both CrMþCHO
and CrMþPRO
groups (p < 0.05)
270
Experimental
comparison
All groups: 1.5 g of
supplementkgday-1
for 11 weeks
CrM groups:
0.3 gkgday-1 5 days
followed by
0.01 gkgday-1 for
10 weeks
271
Cribb (67)
Compared
supplement-timing;
CrMþPROþCHO
before and after
resistance exercise to
same supplement at
times not close to
training
Muscle [PCr and Cr]
assessed before and
after 10 weeks of
resistance exercise
Dose: 1 g
supplementkg-1
2day-1 (CrM
0.01 gkg -1) Taken
immediately before
and after workouts
or twice a day
5 hours outside
workouts, 10 weeks
Greenwood
(69)
Compared CrM þ
D-pinitol high-dose
(HP) and low-dose
(LP) as well as
predosing (PreP) to
CrM only and
placebo (P)
Whole-body Cr
retention via 24-hr
urine samples for 4
days, 3 days
supplementation, no
exercise
CrM 4 5 g
þ 2 0.5 g D-pinitol
(LP) þ 4 0.5 g
D-pinitol (HP)
D-pinitol 2 0.5 g
D-pinitol 5 days prior
to and during CrM
(PreP)
After 10 weeks, 14%
greater increase in
[PCr] and 18%
greater increase in
[total Cr] from
supplement timing
(PCr 16% vs. 2%;
total Cr 25% vs. 7%,
respectively)
(p < 0.05).
After 4 days, wholebody Cr retention
was greater in LP
and PreP compared
to HP, CrM-only,
and P (p < 0.05).
0%, 61% – 15%, 83%
– 5%, 61% – 22%,
and 78% – 9% CrM
(Continued )
Table 1
(Continued)
Reference
Burke (73)
Experimental
comparison
ALAþCrMþCHO vs.
CrMþCHO and
CrM-only
Protocol
Muscle [PCr and Cr]
assessed before and
after 5-day
intervention
Supplementation
272
CrM: 20 gd-1
þ100 gd-1 sucrose
(CrMþCHO)
þ1000 mgd-1 ALA
(ALAþCrMþCHO)
Change
retained for P, CM,
LP, HP, and Pre-P
groups, respectively)
After 5 days, greater
increase in [PCr] and
[total Cr] from
ALAþCrMþCHO
(p < 0.05) compared
to CrMþCHO and
CrM-only
(21%, 0%, and 0%
increase for
[PCr] and 13.8%,
2.0%, and 4.0%
[total Cr] for
ALAþCrMþCHO,
CrMþCHO, and
CrM, respectively)
(p < 0.05)
Effective Nutritional Supplement Combinations
273
and exercise performance is well established. That is, the reliance on
muscle glycogen during exercise increases with intensity, and a direct
relation between fatigue and depletion of muscle glycogen stores has
been described (74–78). Furthermore, the increase in endurance after
an aerobic training program is associated with increased muscle
glycogen storage capacity as well as its more efficient use (79,80).
Muscle glycogen is also an essential fuel source for the regeneration of
ATP during short-term, high intensity (anaerobic) exercise. For
example, during a set of 12 maximum-effort repetitions, just over
82% of ATP demands are estimated to be met by glycogenolysis (81).
A single bout of high-intensity resistance exercise characteristically
results in a significant (30%–40%) reduction in muscle glycogen
(82–84). Muscle glycogen synthesis is affected not only by the extent
of depletion but also by the type, duration, and intensity of the
preceding exercise (74–78,85). Nevertheless, the rapid restoration of
muscle glycogen stores is a critical issue for all athletes who undertake
training or competition sessions on the same or successive days. In
general, the faster muscle glycogen stores can be replenished after
exercise, the faster is the recovery process and the greater the return of
performance capacity (85).
Supplementation strategies that may increase the rate of muscle
glycogen synthesis have been the focus of extensive investigation.
For example, the importance of timing (86,87), frequency (88),
and amount (89,90) of CHO for postexercise muscle glycogen
restoration has been demonstrated. Regarding the effect of various
types of CHO that may optimize postexercise glycogen synthesis,
some well controlled studies have reported that rapid increases
occur during the first 24 hours of recovery with a combination of
high-GI CHOs in contrast to low-GI CHOs (91,92). The high-GI
sources included glucose and sucrose, and whole foods were also
on the list (i.e., white potatoes, rice, pasta). The activation of
glycogen synthase (the rate-limiting enzyme for glycogen synthesis)
by insulin is well documented (93,94). As high-GI CHOs generally
evoke greater blood glucose and insulin levels than low-GI sources,
this probably explains the more rapid synthesis of muscle glycogen
after exercise from the selection of high-GI CHO sources. [For further
reading on the GI of foods and meals, refer to Du et al. (95) and
Brand-Miller (57)]. Aside from the influence of the GI, other efforts
to further increase the rate of storage by increasing the amount and
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Cooke and Cribb
frequency of CHO intake or by changing the type and form of CHO
supplement used have proved unsuccessful (86,88,96,97).
Rather than focus on a single macronutrient to optimize muscle
glycogen stores, a combination would provide a more practical,
optimal approach to help meet the complex array of nutritional
demands of exercise training. Probably because of the synergistic
effect on insulin secretion, the impact of combining PRO with a
CHO supplement on muscle glycogen synthesis after exercise has
become a topic of interest (98–105). Zawadzki et al. (101) were the
first to report that the combination of PRO-CHO was more effective than CHO alone in the replenishment of muscle glycogen during the 4 hours immediately after exercise. These authors suggested
that the greater rate of muscle glycogen storage from PRO-CHO was
the result of a greater plasma insulin response. However, the enhancement of muscle glycogen storage observed by these researchers may
have been due to the larger amount of calories provided by the PROCHO treatment. Moreover, some evidence suggests that if adequate
CHO is provided the addition of PRO has no beneficial effect on
muscle glycogen recovery (106). To partially support this notion,
some (85,99,105) but definitely not all (98,103,104) investigations
have reported increased glycogen synthesis after the consumption of
a PRO-CHO supplement compared to CHO-only of an equivalent
dose or caloric content. However, only one study (85) has examined
the effects of PRO-CHO supplementation compared with CHO
supplementation of equal CHO content (LCHO) and equal caloric
content (HCHO) in the same trial. Unlike most studies that have
assessed glycogen resynthesis with repeated muscle biopsy, Ivy et al.
(85) utilized natural abundance 13C-nuclear magnetic resonance
(NMR) spectroscopy to measure muscle glycogen concentrations.
A limitation of repeated muscle biopsies is the number and frequency of measurements that can be obtained as well as the sampling of only a small volume in nonhomogeneous tissue. Because of
the noninvasive nature, the NMR technique is purported to provide
better time resolution (frequency), repeatability, and precision
(107). Using this method to assess muscle glycogen synthesis, Ivy
et al. (85) reported that the combination of PRO-CHO yielded
greater (< 0.05) muscle glycogen storage during the 4 hours immediately after intense exercise compared with both LCHO and
HCHO supplements. The percentages of glycogen restored during
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the 4-hour recovery period were 46.8%, 31.1%, and 28.0% for the
PRO-CHO, HCHO, and LCHO treatments, respectively. More
recently, Berardi et al. (105) utilized the NMR technique and
reported a similar result. That is, supplementation with PROCHO resulted in greater muscle glycogen resynthesis 6 hours after
exercise than an isocaloric dose of CHO (p < 0.05).
In general, it appears that the addition of PRO to a CHO supplement increases the rate of muscle glycogen storage during the hours
immediately after exercise, particularly if the supplement contains a
low to moderate amount of CHO. The mechanism by which protein
increases the efficiency of muscle glycogen storage is not known, but
there are several possibilities. In brief, the combination of PRO and
CHO may accelerate the rate of muscle glycogen storage possibly by
activating glycogen synthesis by two mechanisms. First, this combination may raise plasma insulin levels beyond that typical of CHO
alone, which may augment muscle glucose uptake and activate
glycogen synthase. Insulin stimulates glucose uptake, glycolysis,
and glycogen synthesis in muscle via the activation of the PI3–PKB(Akt)–GSK-3 signaling pathway (108). Second, the increase in
plasma amino acids that occur as a result of consuming PRO may
activate glycogen synthase through an insulin-independent pathway
that has not been clearly identified (85), thereby having an additive
effect on the activity of this enzyme. Whereas glucose, sucrose, and
glucose polymer supplements as well as high-GI whole-food sources
are effective means of replenishing muscle glycogen, the type of
protein (or amino acids) that may be best to combine with CHO
has received less attention. Studies that have reported a beneficial
impact on muscle glycogen stores from the addition of PRO to a
CHO supplement have utilized dairy proteins (85,101,102), such as
whey isolates (105). A hydrolyzed wheat protein supplement in
conjunction with insulin-promoting amino acids (AAs) such as
leucine and phenylalanine (99,100) has also been shown to have a
favorable effect on postexercise glycogen synthesis. In fact, studies
that have examined this area directly suggest that the insulin
response to PRO-CHO supplementation may be positively correlated with plasma concentrations of AAs such as leucine, phenylalanine, and tyrosine (100). Therefore, the concentration of certain
AAs in the supplement may underline its ability to stimulate insulin
and therefore muscle glycogen restoration.
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Indeed, Yaspelkis and Ivy (109) examined the effects of combining CHO with arginine on postexercise muscle glycogen storage
following muscle glycogen depletion. Well trained cyclists rode for
2 hours on two occasions to deplete their muscle glycogen stores. At
0, 1, 2, and 3 hours after each exercise bout, the subjects ingested
either a CHO supplement (1 g CHO/kg body weight) or a CHOarginine (CHO/AA) supplement (1 g CHO/kg and 0.08 g arginine
HCl/kg). No difference in the rate of glycogen storage was found
between the CHO/AA and CHO treatments, although significance
was approached. There were also no differences between treatments
in regard to plasma glucose, insulin, or blood lactate responses.
However, postexercise CHO oxidation during the CHO/AA treatment was significantly reduced compared to that with the CHO
treatment. These results suggest that the addition of arginine to a
CHO supplement reduces the rate of CHO oxidation after exercise
and therefore may increase the availability of glucose for muscle
glycogen storage during recovery (109).
As discussed earlier, supplementation with CrM promote an
ergogenic effect by enhancing PCr availability in muscle. However, another ergogenic effect of this supplement appears to be its
positive impact on muscle glycogen storage. Seven studies have
measured muscle glycogen levels in humans after CrM supplementation, and six have reported a stimulatory effect (60,67,110–113).
Robinson et al. (60) first showed that CrM supplementation in
conjunction with a high-CHO diet for 5 days (after a bout of
exhaustive exercise) resulted in a 23% greater increase in muscle
glycogen than that with a high-CHO diet without CrM. Nelson
et al. (110) reported that loading with CrM for 5 days enhanced a
subsequent 3-day muscle glycogen-loading protocol by 12%. Op ‘t
Eijnde et al. (111) demonstrated that supplementation with CrM
(20 g daily) had no effect on muscle glycogen stores during 2
weeks of leg immobilization. However, further administration
(15 g daily) did enhance muscle glycogen levels (by 46% more
than placebo) during 3 weeks of subsequent strength training. In
a follow-up study that involved a similar protocol (and a 6-week
training phase), these researchers reported that supplementation
with PRO (46 g) combined with CrM augmented posttraining
muscle glycogen by 35% more than placebo (but not CrM
alone) (112). Van Loon et al. (113) demonstrated that a 5-day
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CrM-loading phase augmented muscle glycogen by 14% compared
with no change in the placebo group. Furthermore, this study confirmed a significant correlation between changes in muscle Cr (mean
increase of 32%) and muscle glycogen during the loading phase.
This substantiates other work (110–112) suggesting that significant
increases in muscle Cr is a prerequisite for enhanced muscle glycogen storage (48). Supplementation with CrMþCHO or PRO during
exercise increases muscle GLUT-4 expression and glycogen storage
(111,112). Treatment with CrM has also been shown to increase
total body water including intracellular cell volume (114). Changes
in cell volume (cellular water content) have been shown to influence
glycogen levels (115). Therefore, the ability of CrM to influence
GLUT-4 biogenesis and/or regulate cell volume may explain its
beneficial impact on muscle glycogen storage. Overall, the findings
of these studies suggest that increasing muscle Cr (by 20%) via
supplementation ensures a beneficial impact on glycogen storage.
In summary, when considering all of the research that has been
completed on this topic, it appears that the addition of PRO to a
CHO supplement increases the rate of muscle glycogen storage
during the hours immediately after exercise, particularly if small
doses of these macronutrients are desired. However, more work is
needed that focuses on different types of protein and/or composition
of its amino acids (in combination with CHO) to ascertain what
combinations may provide the most beneficial effect on muscle
glycogen. Loading with CrM or the addition of CrM to a PROCHO supplement not only appears to augment Cr uptake, it is an
effective strategy for optimizing muscle glycogen stores. For some
athletes, however, careful consideration is needed when contemplating the addition of CrM. For example, loading with CrM characteristically results in a 1- to 3-kg gain in body weight (lean mass)
(13–16,18,19). This added mass may offset any potential ergogenic
benefit that might be achieved via boosting muscle gylcogen stores.
Therefore, in sports where any gain in body weight may disadvantage the athlete, the combination of PRO-CHO (without CrM)
maybe a more prudent choice to promote muscle glycogen. However, for all athletes, along with more efficient glycogen restoration,
another important advantage of PRO-CHO postexercise supplementation is this combinations’ well documented effect on protein
synthesis and muscle anabolism.
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4. SUPPLEMENT COMBINATIONS TO ENHANCE
MUSCLE ANABOLISM
Any adaptive change in muscle mass in response to exercise
training must involve alterations in protein turnover. That is, provided the exercise intensity is of sufficient magnitude, muscle protein
synthesis and breakdown are acutely stimulated (116). In the
absence of nutrient intake, muscle protein degradation exceeds
synthesis during the early stages of recovery from exercise, and the
net muscle protein balance remains negative (i.e., the muscle is in a
catabolic state) (117). Resistance exercise (RE) is incorporated into
nearly every athletes’ program in an effort to improve either
strength, muscle mass, body composition, or the power-to-weight
ratio. In addition to athletic populations, others such as older adults
and those living with clinical illnesses would benefit from these
adaptations. For these reasons, there has been a concentrated
focus in the exercise science communities on specific nutritional
strategies that affect the acute responses to RE (i.e., enhance muscle
protein synthesis, reduce breakdown) and promote a positive protein balance (anabolism). In particular, the stimulation of muscle
protein synthesis is thought to be the facilitating process that underlines gains in strength and muscle hypertrophy from training
(118–120). Probably for this reason, a number of acute response
studies have examined the effects of strategic nutrient supplementation close to RE on muscle protein synthesis in an attempt to
stimulate a higher rate and promote a positive net balance after
exercise.
The optimal composition of nutrients to maximize muscle protein
synthesis (and anabolism) after exercise is not known. However, the
acute stimulation of protein synthesis appears to be dependent on
the availability of the essential amino acids (EAAs). A positive net
protein balance is not achieved unless an exogenous source is provided after exercise (117). It is also clear that the combination of
protein and carbohydrate (PRO-CHO) at a time close to exercise
(i.e., the hours just before and/or afterward) yields a high anabolic
response by altering the acute hormonal and protein turnover
response patterns to create an environment that probably helps
optimize conditions for recovery. For example, the combination of
protein (or EAAs) and RE was initially shown to have a synergistic
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effect on (thigh) muscle protein synthesis that resulted in a positive
net balance (117,121). However, the addition of CHO (glucose 35 g)
to EAAs (6 g) at this time amplifies muscle anabolism to a greater
extent than when either macronutrient is provided separately after
exercise (122). In fact, when this combination was consumed 1 or
3 hours after RE, an increase in synthesis rates of up to 400% above
preexercise values was reported, which is the highest ever recorded
(123). The same supplement has been shown to promote a similar
anabolic effect in muscle when administered just before RE (124).
These investigations utilized AA solutions, whereas other studies
have confirmed that whole proteins (15–35 g), such as the dairy
proteins whey and casein, evoke an acute anabolic response that is
similar in magnitude to free-form AA (87,125–127). The finding
that doses of whole proteins (e.g., whey, casein) are just as efficient
as free-form AA at promoting muscle anabolism is important; in
general, whole protein supplements are more economical than freeform AAs and may also provide other health benefits (e.g., additional vitamins, minerals and/or enhanced antioxidant capacity).
It is clear that the strategic intake of nutrients (i.e., consumption
of PRO-CHO before and/or after intense exercise) not only augments muscle protein synthesis, most importantly it shifts the net
protein balance to a positive state (albeit transiently). This anabolic
response can be at least partly attributed to changes in the acute
hormonal response pattern. For instance, a novel study by Kraemer
et al. (128) examined the effects of a high calorie PRO-CHO supplement (total 7.9 kcalkg-1, 1.3 g glucose polymerkg-1, and 0.7 g dairy
proteinskg-1(day-1) consumed 2 hours before and just after resistance exercise for consecutive 3 days of training. Results showed
that compared to a low-calorie (non-insulin-stimulating) placebo,
the PRO-CHO supplement consistently provided higher blood insulin levels during the hour after exercise (128). This PRO-CHOinduced stimulation of insulin is important; it improves the anabolic
response by increasing AA uptake and decreases the rate of muscle
protein breakdown (129). Kraemer et al. (128) also reported that
nutrient timing with the PRO-CHO supplement enhanced acute
serum growth hormone (GH) responses for 30 minutes after exercise
(on the first day) compared to the noncaloric placebo. Although the
reason for this increase is not clear, Chandler et al. (130) also
reported an increase in serum GH in response to consumption of a
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similar PRO-CHO supplement immediately and 120 minutes after
resistance exercise. In contrast, Williams et al. (131) reported no
significant effect of PRO-CHO on the GH response to exercise. The
regulation of hepatic insulin-like growth fact-1 (IGF-1) is characteristic of GH (132). Kraemer et al. (128) also reported that the PROCHO supplement elevated serum IGF-1 levels for 30 minutes after
exercise on two of three training days. Another investigation
reported an increase in (resting) plasma IGF-1 after 6 months of
training in response to the daily consumption of a PRO-CHO
supplement (42 g PRO, 24 g CHO) in contrast to CHO (70 g) alone
(133). Furthermore, Willoughby et al. (134) reported that 10 weeks
of heavy resistance exercise combined with a similar dose of PROCHO before and after each workout was effective for increasing
serum IGF-1 and muscle IGF-1 mRNA expression. However, it is
important to note that although nutrient timing with PRO-CHO
close to RE may increase serum IGF-1 concentrations, the anabolic
action of this growth factor on tissue is thought to reside in alterations in its binding proteins (135). Separately, PRO-CHO meals
(136) and RE (137) appear to influence regulation of the IGF1-binding proteins. However, no studies have examined the impact
of combining supplementation and exercise on the IGF-1-binding
proteins and muscle anabolism.
Testosterone is an important anabolic hormone thought to augment the synthesis of muscle protein. The intake of a PRO-CHO
supplement before and after RE appears to be one of the few
strategies shown consistently to affect circulating testosterone levels
(118,127,129,138). The nutrient-timing study by Kraemer et al.
(128) also assessed acute testosterone responses, and these researchers reported an acute increase in circulating testosterone followed by
a sharp decrease (to levels that were significantly lower than baseline) with PRO-CHO supplementation. This response was consistently observed on each of the three training days assessed. Chandler
et al. (130) and Bloomer et al. (138) reported a similar response.
This rapid decrease in blood testosterone levels in response to supplementation close to exercise may be due to increased metabolic
clearance of this hormone, such as increased uptake by muscle. At
least one study supported this assumption. Chandler et al. (130)
showed that a decline in circulating testosterone in response to
nutrient timing after RE was not linked to a decrease in luteinizing
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hormone production. As mentioned previously, nutrient timing
with PRO-CHO provides a dramatic increase in muscle protein
synthesis in the hours after exercise (121,124). Therefore, the drop
in circulating testosterone could be due to increased uptake by
muscle to facilitate this process. To further support this contention,
Volek (119) reported that a postworkout PRO-CHO meal
decreased circulating testosterone that corresponded with an
increase in muscle androgen receptor content. Along this line, a
more recent study (that utilized resistance-trained participants)
reported that whereas a PRO-CHO meal after exercise up-regulated
androgen receptor content in muscle, the addition of L-carnitine
-1
L-tartrate (equivalent to 2 g of L-carnitine(day for 3 weeks) resulted
in an even greater response (139). Previous work by this research
group (140) showed that 3 weeks of L-carnitine L-tartrate reduced
the amount of exercise-induced muscle tissue damage by 7% to 10%
(assessed via magnetic resonance imaging scans of the thigh) as well
as increased IGF-1-binding protein (IGFBP-3) concentrations
before and up to 180 minutes after acute exercise. Therefore, the
addition of L-carnitine L-tartrate to a PRO-CHO postexercise supplementation regimen may improve testosterone uptake and the
overall anabolic response from resistance exercise.
At the molecular level, the synergistic effect of a supplement
containing PRO-CHO on muscle anabolism is probably due to the
activation of insulin-dependent but also insulin-independent pathways. For example, unlike exercise or insulin, amino acids do not
appear to stimulate muscle protein synthesis via phosphorylation
(activation) of the PI3 and PKB(Akt) signaling proteins (141,142).
Human studies (143) have confirmed in vitro (144) and in vivo
(145,146) work that has shown EAAs stimulate muscle protein
synthesis directly via the phosphorylation of downstream signaling
proteins such as the Raptor–mTOR complex (and its regulatory
proteins S6K1 and 4E-BP1) or the eIF–2B complex (the only one
of the three regulators of muscle protein synthesis that is not under
direct control of mTOR) (147). Additionally, some EAAs, such as the
branched-chain amino acids (BCAAs) (leucine, valine, isoleucine)
are particularly effective at enhancing muscle protein synthesis via
these pathways (148). Consequently, attention has shifted toward
examining the effects of combining certain AAs with whole proteins
and CHO on postexercise muscle anabolism (126,149). For
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example, Borsheim et al. (149) reported that the combination of
whey protein (17.5 g), free-form AAs (4.9 g), and CHO (77.4 g)
stimulated net muscle protein synthesis to a greater extent than an
isoenergetic CHO supplement after resistance exercise. The authors
also concluded that the addition of whole protein to the AA-CHO
supplement prolonged the anabolic response observed in previous
studies with AA-CHO mixtures.
The BCAA leucine is an established regulator of whole-body and
skeletal muscle protein metabolism (150). Supplementation with
leucine alone can stimulate muscle protein synthesis, independently
of insulin 146,151), and may also play a role in minimizing protein
breakdown (152). Koopman et al. (126) attempted to extend these
findings by investigating whether adding leucine to a PRO-CHO
supplement could further promote muscle protein anabolism. In this
study, eight healthy but untrained male subjects were randomly
assigned to three trials in which they consumed drinks containing
either CHO (0.3 gkg-1 h-1), CHOþPRO (0.3 g CHO þ 0.2 g whey
proteinkg-1 hr-1), or PRO-CHO and free leucine (0.1 gkg-1)
(CHOþPROþLeu) for 5 hours following 45 minutes of RE (126).
Whole-body protein turnover and the fractional synthesis rates in
muscle (incorporation of labeled phenylalanine) were assessed. The
results obtained suggested that the addition of the leucine significantly increased whole-body net protein balance and provided a
higher anabolic response in muscle (126). However, it is worth
noting that the total amounts of leucine in the two PRO-CHO
supplements were different. The leucine-enriched PRO-CHO supplement provided 9.6 ghr-1 for an 80 kg person, whereas the PROCHO supplement provided only 1.6 ghr-1 (for an individual of the
same weight) (126).
In summary, it is clear that supplementation with PRO-CHO
(with or without additional AAs) can alter the acute anabolic
response to resistance exercise. However, a more pertinent question
is whether repeated metabolic alterations provided by supplementation with PRO-CHO are of sufficient magnitude to alter long-term
adaptations to resistance training. As the following section demonstrates, a strong theoretical basis exists for expecting a beneficial
effect from supplementation during resistance training, but no
studies to date have systematically linked acute physiological
responses to chronic adaptations in the same study.
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5. COMBINATIONS THAT ENHANCE AEROBIC/
ANAEROBIC PERFORMANCE
Caffeine, a naturally occurring substance, is the most commonly
consumed stimulant drug in the world. It produces multiple physiological effects throughout the body including: increased catecholamine
release and fat metabolism, resulting in glycogen sparing; increased
intracellular Ca2þ release; inhibition of cyclic adenosine monophospate
(cAMP) phosphodiesterase, and antagonism of adenosine receptors
(153). Several studies have demonstrated improved exercise performance in submaximal endurance activities (153–155), but its potential
ergogenic effect in acute, high intensity exercise is less clear (154).
Ephedrine was used as a central nervous system (CNS) stimulant
in China for centuries before its introduction to Western medicine in
1924 (156). Ephedrine and its related alkaloids (mostly pseudoephedrine) are sympathomimetic agents that stimulate the sympathetic nervous system, increasing circulating catecholamines (157).
A number of studies have reported beneficial effects on exercise
performance using ephedrine as the supplement (158,159), whereas
few studies have reported benefit utilizing the related alkaloids such
as pseudoephedrine (160,161). This is most likely due to ephedrine’s
direct adrenoceptor stimulating actions (162), resulting in it being
approximately 2.5-fold more potent than pseudoephedrine (160).
Although both caffeine and ephedrine have demonstrated independent ergogenic effects on exercise performance, research published from Bell and Jacob’s laboratory at the Defense and Civil
Institute of Environmental Medicine in Canada has indicated that in
several instances caffeine–ephedrine mixtures confer a greater ergogenic benefit than either drug alone (163–167). In a series of studies
performed by Bell and Jacob (163–166), positive results were
observed during various exercise modalities: submaximal steadystate aerobic exercise (167); short- and long-distance running
(164,166); and maximal anaerobic cycling (163). The caffeine–ephedrine mixture was normally consumed 1.5 to 2.0 hours prior to exercise at a dosage range of 4 to 5 mg/kg for caffeine and 0.8 to1.0 mg/kg
for ephedrine (163–166). Higher dosages were shown to elicit negative side affects such as vomiting and nausea during the exercise
test; thus, Bell and colleagues recommended using the lower dosages
of 4 mg/kg for caffeine and 0.8 mg/kg for ephedrine. Importantly,
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the lower dosage provided an ergogenic effect similar in magnitude
to those reported previously using the higher doses (168).
Results from these associated studies showed that caffeine, ephedrine, and the caffeine–ephedrine supplements produced significant
effects on a variety of metabolic and cardiovascular responses such
as blood glucose, catecholamines, and heart rate during exercise
compared to the dietary fiber placebo (164,166,167,169). Despite
the independent effects of caffeine and ephedrine on metabolic and
cardiovascular responses during exercise, no ergogenic effects on
exercise performance was observed. However, when combined,
exercise performance was significantly enhanced in a variety of
exercise modalities. Researchers suggested that this is most likely
due to ephedrine’s effect on arousal (i.e., decreasing rating of perceived exertion during exercise) combined with caffeine’s ability to
enhance muscle metabolism (164,166,167,169).
Although it is clearly evident that the combination of caffeine and
ephedrine has a pronounced ergogenic effect on a variety of exercise
modalities compared to either supplement alone, it should be noted that
these beneficial effects have predominantly been observed in studies
involving the Canadian military. Hence, further research is needed to
examine the practical application in recreational athletes and untrained
individuals. A more important issue is that all dietary supplements
containing ephedrine alkaloids are illegal for marketing in the United
States (170). Therefore, until ephedrine and ephedrine alakaloids are
made legal again, the performance-enhancing effects of the caffeine–
ephedrine mixture can be utilized only under research conditions.
The benefits of creatine monohydrate (CrM) to athletes is clear
(see earlier). One proposed ergogenic benefit is the capacity of CrM
to help maintain normal muscle pH levels during high intensity
exercise by consuming excess hydrogen ions during ATP resynthesis
and thus possibly delaying fatigue (refer to Multifaceted Role of the
Muscle PCr-Cr System in Exercise Metabolism). The intake of
sodium bicarbonate (NaHCO3) has also been shown to prevent
exercise-induced perturbations in the acid-base balance, which has
resulted in enhanced performance (171–173).
Mero and colleagues (174) examined the buffering capacity of
sodium bicarbonate in combination with CrM on consecutive maximal
swims. In a double-blind crossover procedure, competitive male and
female swimmers completed, in a randomized order, two treatments
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(placebo and a combination of CrM þ sodium bicarbonate). There
was a 30-day washout period between treatments. Both treatments
consisted of placebo or CrM supplementation (20 g/day) for 6 days.
On the morning of the seventh day, a placebo or sodium bicarbonate
supplement (0.3 g/kg body weight) was taken 2 hours prior to the
warmup. Two maximal 100-m freestyle swims were performed with a
passive recovery of 10 minutes between them. The first swim performances for both treatment groups had similar times. However, the
increase in time for the second swim performances was significantly
less in the combination group compared to the placebo. Furthermore,
the mean blood pH was higher in the combination group compared to
the placebo group after supplementation on the test day. The data
indicated that simultaneous supplementation of CrM and sodium
bicarbonate enhances the buffering capacity of the body and hence
the anaerobic performance (174).
In summary, it is evident that when nutritional supplements with
complementary independent ergogenic effects are combined, additional benefits can be attained. Research has shown that both caffeine-ephedrine and CrM-sodium bicarbonate supplement mixtures
provide an acute physiological response that enhances anaerobic
and/or aerobic exercise. However, a number of limitations exist
with both supplements. As mentioned, further research is needed to
examine the practical application of the caffeine–ephedrine combination in recreational athletes and untrained individuals, as most of
the research has been performed in military soldiers. More importantly, however, because all dietary supplements containing ephedrine alkaloids are illegal for marketing in the United States, its use
as an ergogenic aid is limited in active individuals. Although sodium
bicarbonate is a legal supplement, limited studies have examined its
ergogenic effects on exercise performance when combined with CrM,
and so further investigation is needed to confirm such observations.
6. CHRONIC ADAPTATIONS: SUPPLEMENT
COMBINATIONS THAT PROMOTE MUSCLE
HYPERTROPHY AND STRENGTH
In most instances, supplement combination of CrM with protein (PRO) and/or carbohydrate (CHO) has been shown in longerterm trials (6–12 weeks) to enhance the chronic adaptations that
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are desired from resistance training (i.e., gains in strength and lean
body mass and/or improvements in body composition). Kreider
and his research group were among the first to examine the effects
of CrM-containing PRO and CHO supplements on the development of strength and lean body mass during structured resistance
training.
In a study involving 25 National Collegiate Athletic Association
(NCAA) division IA football players, Kreider et al. (18) demonstrated that 28 days of supplementation with CrM-CHO (containing
glucose 99 gday-1 and CrM 15.75 gday-1) resulted in greater (p < 0.05)
gains in dual energy x-ray absorptiometry (DEXA)- determined
body mass and lean (fat/bone-free) body mass (LBM) compared
to an equivalent dose of CHO. Treatment with CrM-CHO also
resulted in greater total bench press, squats, and power clean lifting
volume as well as sprint performance (18).
Using a group of experienced weightlifters, Burke et al. (64)
assessed strength and LBM changes after 6 weeks of resistance
exercise while ingesting a supplement containing CrM and PRO
(whey 1.2 gkgday-1 and CrM 0.1 gkgday-1 for 6 weeks) in comparison to a similar dose of PRO (whey) or CHO (maltodextrin)
(1.2 gkgday-1). LBM increased to a greater extent in the CrMPRO group than in the PRO- or CHO-alone groups. Bench press
strength also increased to a greater extent in the CrM-PRO group
than in the PRO- or CHO-only groups, but all other strength/power
measures increased to a similar extent (64).
Only one study has directly compared the effects of CrM-CHO
and CrM-PRO supplementation (supplement 1.5 gkgday-1) on
strength, body composition, and muscle hypertrophy during a resistance training program (63). In this study, four groups of matched,
recreational bodybuilders were assessed before and after an 11-week
program. The groups given the CrM-containing supplements
demonstrated greater (p < 0.05) strength improvements in all three
assessments (1RM bench press, squats, pulldown) and muscle fiber
hypertrophy compared to groups given an equivalent dose of CHO
or PRO (63). However, there were some subtle but significant
differences in body composition changes observed among the
groups, and these differences may have implications for different
populations (see sidebar: Creatine þ Protein or Creatine þ Carbohydrate for Better Muscle Hypertrophy?)
Effective Nutritional Supplement Combinations
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Kreider’s group were the first to demonstrate that a CrMcontaining PRO-CHO supplement (containing glucose 50 gd-1,
dairy protein 50 gd-1, CrM 15.75 gd-1) during resistance training
can provide greater (p < 0.05) gains in strength and LBM than an
equivalent dose of PRO-CHO (that does not contain CrM) (19).
The effectiveness of adding CrM to a PRO-CHO supplement
regarding the development of strength and muscle mass was confirmed some 10 years later in another trial (175). Like Kreider et al.
(19), this study utilized experienced lifters (recreational bodybuilders). However, in this trial the two groups were given the
exact same PRO-CHO supplement (50% whey isolate and 50%
glucose) (each 1.5 gkgday-1) in a double-blind manner with one
of the supplements containing a daily serving of CrM (0.1 gkgday-1).
A third group was provided with an equivalent dose of PRO only
(1.5 gkgday-1). Assessments completed the week before and after
the 10-week program included strength (1RM, barbell bench press,
squats, pulldown), body composition (determined by DEXA) and
vastus lateralis muscle biopsies for determination of muscle fiber
type (I, IIa, IIx), cross-sectional area (CSA), and contractile protein
content. The most important finding of this investigation was
that the CrM-containing PRO-CHO supplement provided greater
(p < 0.05) gains in 1RM strength (in all three assessments) and muscle
hypertrophy compared to supplementation with an equivalent dose
of PRO-CHO or PRO (175). Most importantly, a greater (p < 0.05)
muscle hypertrophic response from the combination of CrM-PROCHO was evident at three levels of physiology. That is, this group
demonstrated a greater gain in LBM, hypertrophy of the type IIa and
IIx fibers, and increased contractile protein (175). This research is
particularly relevant as few studies involving exercise and supplementation have confirmed improvements in body composition plus
hypertrophic responses at the cellular level (i.e., fiber-specific hypertrophy) and subcellular level (i.e., contractile protein content).
However, not all studies support the hypothesis that a CrMcontaining PRO-CHO supplement provides greater adaptations
than supplementation with a similar amount of nitrogen and energy.
A study by Tarnopolsky et al. (65) utilized previously inactive
participants and daily supplementation with either CrM (10 g) þ
CHO (75 g) (1252 KJ or 300 kcal) or protein (10 g) þ CHO (75 g)
(1420 KJ or 340 kcal) during 10 weeks of resistance training. Results
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indicated that CrM treatment provided no greater gains in strength,
LBM, or muscle fiber hypertrophy (65). One explanation for the
discrepancy between these results and those reported by Kreider
et al. (18,19) and Cribb et al. (63,176) may have been the populations used. Whereas Kreider et al. (18,19) and Cribb et al. (63,175)
utilized experienced (trained) participants, Tarnopolsky et al. (65)
recruited participants who had been inactive prior to the study.
Although the influence of training status on the effects of supplementation is unknown, it has been speculated that trained individuals might experience more efficient muscle Cr uptake, as exercise
training is associated with improved insulin sensitivity (30). Therefore, resistance-trained individuals may theoretically experience
greater adaptations from supplementation (30).
Aside form PRO and CHO, other compounds with purported
ergogenic potential have been examined in combination with CrM
during resistance training. However, in terms of absolute strength
and body composition changes, the benefit of the supplement combination has seldom exceeded the results achieved from CrM treatment alone. For example, when compared with CrM only
(0.22 gkgday-1), supplementation with a combination of pyruvate
and CrM during 5 weeks of resistance training provided no greater
benefit with regard to gains in body mass, LBM, 1RM strength,
power output, or force development (vertical jump test) (176). Likewise, studies that have examined the effects of combining CrM with
magnesium (154) or HMb (178,179) (a leucine metabolite) have
shown no greater ergogenic effect than treatment with CrM alone.
With regard to HMb, this is not surprising; research groups outside
those involved in the patent of this supplement have been unable to
show a consistent beneficial effect from its use. This includes not
only strength development but also body composition and a range
of symptoms associated with muscle damage (180–184).
One compound that may prove to be an exception is b-alanine.
Studies by Hill et al. (185) and Harris et al. (186) demonstrated that
28 days of b-alanine (4–6 gkgday-1) supplementation increased
intramuscular levels of carnosine by approximately 60%. Carnosine
appears to serve as a buffer and helps maintain skeletal muscle acidbase homeostasis when a large quantity of Hþ is produced during
high-intensity exercise (187). Harris et al. (188) also demonstrated
improvements in performance during a 4-minute maximal cycle
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ergometry test in men after supplementation with b-alanine
(3.2 gkgday-1) for 5 weeks. Others have shown that a similar
supplementation protocol can improve submaximal cycle ergometry
performance and time-to-exhaustion (189), delay the onset of neuromuscular fatigue during incremental cycle ergometry (190), or
increase the amount of work completed during high-intensity exercise (cycling to exhaustion at 110% of estimated power
maximum) (185).
The efficacy of combining CrM and b-alanine was examined in
regard to strength performance during resistance training. Hoffman
et al. completed a 6-week training/supplementation study involving
three groups: CrM, CrMþb-alanine, placebo. Both the CrM and
CrMþb-alanine groups demonstrated significantly better gains in
1RM strength and LBM than the placebo group, but no differences
were detected between the two CrM-treated groups (191). However, there were trends for better gains in LBM in the group given
CrMþb-alanine. Additionally, this group tended to show greater
(average) training volumes for the bench press and squat exercises. If
the study was of longer duration, it is possible that the greater
amount of work completed by this group may have had an affect
on strength development and lean tissue accruement.
The protein source acutely affects muscle amino acid uptake and
net protein balance following resistance exercise. This appears to be
related not only to amino acid composition but also to the pattern of
amino acid delivery to peripheral tissues. For example, dairy milk
proteins are shown to be more effective at supporting protein accretion than soy proteins (192). Whey protein is a collective term that
encompasses a range of soluble protein fractions found in dairy
milk. In supplement form, whey protein is considered a ‘‘fastabsorbing’’ protein based on studies that showing that consumption
(20–30 g) instigates a rapid but transient increase in blood amino
acids levels and stimulates a high rate of muscle protein synthesis
(193). On the other hand, casein (the other major dairy milk protein) is more slowly absorbed from the gut and manifests a lower but
sustained increase in blood amino acids for several hours (193).
These attributes suggest that the combination of whey and casein
may be most beneficial in supporting muscle protein anabolism and
increasing muscle mass during the course of an intense (highoverload) resistance training program.
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In young, healthy adults, a blend of whey and casein (30 g)
taken after exercise has been shown to result in greater hypertrophy of type I and II muscle fibers and improve muscle performance after 14 weeks of training (193). Kerksick et al. (194)
examined the effects of supplementation with a combination of
whey and casein (40 g and 8 g, respectively) or whey and amino
acids (whey 40 g þ BCAA 3 g þ glutamine 5 g) or a CHO placebo
(total 48 g) on performance and training adaptations during 10
weeks of resistance training. Although strength gains were similar
among the protein-supplemented groups, the group given the
whey-casein combination experienced the greatest (p<0.05)
increase in DEXA-determined LBM (194). The whey protein
supplements used in these investigations are generally isolates
(90% protein) and concentrates ( 80% protein). However, the
degree of hydrolysis of the material (be it casein or whey) can
affect the protein’s absorption/digestion kinetics (195).
Although the supplement combination of whey and casein
appears to be effective at promoting lean mass during resistance
training, no studies have examined what type or ratio is most
beneficial. Whether the addition of certain amino acids can optimize
the effects of the supplement blend also remains unclear. Nevertheless, a substantial body of evidence now suggests that supplementation with proteins and amino acid mixtures can influence
adaptations to training. However, a steadily increasing amount of
work suggests that the precise timing of the supplement may
enhance the response even further.
The acute response studies discussed earlier clearly demonstrate
that oral supplementation with whole proteins (e.g., whey, casein)
or essential amino acids immediately before and/or after resistance
exercise promotes a better anabolic response (i.e., higher stimulation of protein synthesis and a positive net protein balance) compared to placebo treatments. In young adults, the presence of
CHO (e.g., glucose) appears to enhance this response by increasing
blood insulin levels. Insulin receptor activation stimulates the
PI3K–Akt/PKB–mTOR signaling pathway, which is known to
have profound effects on the up-regulation of muscle-specific
gene expression and protein synthesis (196). Proteins that contain
a high dose of essential amino acids (leucine in particular) are
known to up-regulate the activity of mTOR and p70S6 kinase
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and hyperphosphorylate 4E-BP1 (198). This suggests that amino
acids and insulin signaling do not function in isolation but may
function cooperatively to optimize the anabolic response in skeletal
muscle. For these reasons, it has been suggested that the consumption of a supplement containing PRO and CHO immediately before
and after resistance exercise (i.e., supplement timing) may provide
the ideal anabolic conditions for muscle growth (195). Indeed, most
studies that have assessed chronic adaptations during resistance
training have reported greater muscle hypertrophy (193,199) or a
statistical trend for gains in LBM (200,201) from this strategy.
For example, Willoughby et al. (134) demonstrated that supplementation with a protein blend (whey 20 g, casein 8 g, and 12 g free
amino acids; total 40 g of protein) 1 hour before and immediately
after each workout (10 weeks) was more effective than 40 g of CHO
(placebo) at increasing muscle strength and mass. Additionally,
these researchers reported that the protein blend provided a significant increase in systemic (serum IGF) and local (muscle IGF-1,
MHC isoforms mRNA, myofibrillar protein) indicators suggestive
of skeletal muscle anabolism and hypertrophy (133). However,
there have been some important limitations to these insightful
investigations. First, the participants in most studies that have
examined the effects of supplement timing were not permitted to
consume any nutrients other than the designated supplement for up
to 3 hours before and after each workout. Therefore, the results can
be attributed to the presence (or absence) of macronutrients but not
the supplement per se.
To date, only one study has examined whether supplement timing
with PRO and CHO provides greater benefits in terms of muscle
hypertrophy or strength development compared to the consumption
of the same supplement at other times during the day. This study, by
Cribb and Hayes (67), examined the effects of supplement timing
with a CrM-containing PRO-CHO supplement during a 10-week
resistance exercise training program. The researchers reported that
when a CrM-PRO-CHO supplement was consumed immediately
before and after each workout this strategy resulted in greater
(p < 0.05) strength gains (two of three assessments), muscle hypertrophy of type II fibers, and better improvements in body composition (67) (see sidebar: Can Supplement Timing Double Gains in
Muscle Mass?).
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To summarize this section, chronic adaptations that are desired
from resistance training (i.e., strength, muscle hypertrophy, and/or
lean body mass) are enhanced by the combination of CrM with PRO
and/or CHO (up to 1–5 gkgday-1) appears to be effective. Whether
CrM is consumed in combination with PRO or CHO may depend
on individual requirements. That is, the additional CHO may be
useful to only some athletes. However, as the combination of CrM
and PRO appears to provide similar benefits, this combination may
be more suited to those in whom a high CHO intake (e.g., glucose) is
not desired. The consumption of a supplement containing PRO and
CHO before and after resistance exercise (i.e., supplement timing)
appears to provide the ideal anabolic conditions for muscle growth.
For instance, most studies that have assessed chronic adaptations
report significantly greater muscle hypertrophy from this strategy. If
smaller doses of these macronutrients are desired, supplement timing with a CrM-containing PRO-CHO supplement (1 gkgday-1
containing CrM 0.1 g-1kg-1day) has been shown to be a particularly
effective strategy for augmenting strength gains and muscle hypertrophy. The incorporation of b-alanine (3.2 gkgday-1) may provide a buffer to help maintain skeletal muscle acid-base homeostasis,
which may promote greater training volumes during the program.
Finally, when considering the protein source, because of their
unique digestion/absorption kinetics, the combination of whey
and casein proteins appears to be most suitable for promoting
muscle anabolism and lean mass during resistance training; however, no studies have examined what type or ratio is most beneficial.
Whether the addition of certain amino acids can optimize the effects
of this supplement blend also remains unclear.
7. COMBINATIONS SHOWN TO ENHANCE ANAEROBIC/
AEROBIC EXERCISE PERFORMANCE
As mentioned earlier, oral b-alanine supplementation has been
shown to improve submaximal cycle ergometry performance and
time-to-exhaustion (189), delay the onset of neuromuscular fatigue during incremental cycle ergometry (190), and/or increase
the amount of work completed during high-intensity exercise
(cycling to exhaustion at 110% of estimated power maximum)
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(185). Although carnosine, but more importantly b-alanine supplementation may be an important physiological factor in determining high intensity exercise performance, several studies
suggest that it could also potentially enhance the buffering capacity of CrM and thus provide additional ergogenic effects (185).
Recently, the potential synergistic effect of b-alanine and CrM
supplementation was examined on various indices of cardiorespiratory endurance in healthy males (202). Supplementation
groups included CrM only (5.25 g), b-alanine only (1.6 g),
CrMþb-alanine (CrM 5.25 g/b-alanine 1.6 g þ 34 g dextrose),
and dextrose placebo. Following 28 days of supplementation,
the CrM and b-alanine groups independently showed improvement in two (power output at ventilatory threshold, time to
exhaustion), and one (power output at lactate threshold) of the
physiological parameters measured, respectively. However when
combined, supplementation resulted in improvements in five of
the eight physiological parameters measured (including percent
VO2 peak associated with the lactate threshold and ventilatory
threshold) during the incremental cycle ergometry test. Although
it is important to reiterate that the improvements were not significant when compared among groups, it was evident by a significant time effect within groups that the combination of CrM
and b-alanine was greater at delaying the onset of the fatigue and
thus potentially enhancing endurance performance (202). However, with limited research examining the potential synergistic
effects of b-alanine and CrM supplementation, further studies
are clearly warranted to confirm the beneficial effects of b-alanine
and CrM supplementation during exercise performance.
Research has revealed that the combination of specific amino
acids (AAs)—particularly BCAAs (leucine, isoleucine, valine), arginine, and glutamine—improves indices of muscle function, damage,
and recovery both during and following exercise in college track
athletes (middle- and long-distance runners) (203,204) and rugby
players (205). The AA mixture (% of total protein in grams) used for
each study (203–205) consisted of L-glutamine (14%), L-arginine
(14%), L-leucine, L-isoleucine, L-valine (total BCAA 30%), L-threonine, L-lysine, L-proline, L-methionine, L-histidine, L-phenylalanine,
and L-tryptophan, with total protein varying from 2.2 to 7.2 g/day.
Ohtani and colleagues (204) examined the effects of a daily dose of
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an AA mixture (mentioned above) on middle- and long distance
runners engaging in sustained exercise for 2 to 3 hours/day, 5 days/
week for 6 months. During the 6-month period, subjects received three
1-month dosage treatments (2.2, 4.4, and 6.6 g/day), separated by a
washout month between each trial. The 2.2 g/day dose was administered as a single dose at dinner; the 4.4 g/day dose was administered
as two 2.2 g doses at breakfast and dinner; and the 6.6 g/day dose was
given as three 2.2 g doses, one at each daily meal. Results showed that
the AA mixture at the daily dose of 6.6 g had the greatest effect,
improving the self-assessment of the physical condition, reducing
muscle damage, and enhancing hematopoiesis measures, which suggests improved oxygen-handling capacity (204).
A similar study (205) examined the effects of the same AA
mixture but at a higher dosage (7.2 g/day), on rugby players for 3
months during a period of intensive physical training. Athletes
maintained a regular training schedule with their teammates before,
during, and after the 90-day trial period. The subjects were
instructed to take a 3.6 g dose of the AA mixture after morning
and evening meals each day for 90 days. Results from both studies
(204,205) suggest that long-term administration of the AA mixture
may increase the production of red blood cells, thereby perhaps
enhancing the capacity of the blood to carry oxygen. Furthermore,
these highly trained athletes reported that long-term intake of the
AA mixture produced a favorable effect on their physical fitness. In
contrast to trained athletes, another study (206) demonstrated
significant increases in treadmill time to exhaustion in healthy
untrained women following 6 weeks of essential AA supplementation. The essential AA composition per 10 g consisted of L-isoleucine
1.483 g, L-leucine 1.964 g, L-valine 1.657 g, L-lysine 1.429 g, L-methionine
0.699 g, L-phenylalanine 1.289 g, L-threonine 1.111 g, L-tryptophan
0.368 g. Subjects consumed, on average, 128 g of AAs per week, or
18.3 g daily. It is clear from the results of the current study, taken
together with the previous studies (203–205), that BCAAs when
combined with other essential or nonessential amino acids have a
beneficial effect during and after aerobic exercise performance.
Although these results are interesting and provide practical application to most athletes when training or competing, a limitation to
these studies is that the results were obtained in comparison to an
isocaloric sugar (dextrin) placebo and not an equivalent dose of
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other AAs or protein. Thus, further research is needed to determine
whether these specific AA combinations are more advantageous
than regular protein supplements at improving indices of muscle
function, damage, and recovery during and after exercise.
In summary, research has demonstrated that CrM/b-alanine
supplementation and the use of specific AA combinations influence
chronic adaptations that enhance exercise performance (predominantly aerobic exercise). However, similar to the combinations mentioned in the section Combinations That Enhance Aerobic/
Anaerobic Performance, there are a number of limitations that
exist for both these supplements. First, limited research has proven
the beneficial effects of CrM/b-alanine supplementation on exercise performance. Therefore, until further research is conducted,
we can only speculate as to whether combining CrM and b-alanine
provides benefit additional to that seen when each of the supplements is used alone. Second, although the combination of specific
AAs such as BCAAs (leucine, isoleucine, valine), arginine, and
glutamine has shown to improve exercise performance, further
research is needed to determine whether these specific AA combinations are more advantageous than regular protein supplements,
as the results obtained to date were in comparison to an isocalorie
sugar (dextrin) placebo, not an equivalent dose of other AAs or
protein.
8. CONCLUSION
The focus of this chapter was supplement combinations and
dosing strategies that are effective at promoting either an acute
physiological response that may improve/enhance exercise performance or influence chronic adaptations desired from training. The
main conclusions are as follows.
Few supplement combinations that are marketed to athletes are sup-
ported by scientific evidence of their effectiveness. Quite often, under
the rigor of scientific investigation, the patented combination fails to
provide any greater benefit than a group given the active (generic)
ingredient. One good example is creatine monohydrate (CrM).
The capacity of CrM to augment the phosphocreatine system and
provide an ergogenic benefit under a variety of conditions is well
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documented. However, the wide variability with regard to dose
responses and muscle uptake among individuals has led to increasing
interest in combinations that may improve muscle creatine accumulation in response to supplementation.
Probably due to an insulin-stimulating effect on the cellular creatine
transporter, combining each dose of CrM (5–10 g) with high-GI
CHO or dairy proteins (up to 1.5 gkg-1 day-1) appears to be a
highly effective strategy that promotes creatine accumulation. Taking each dose of CrM with PRO and CHO (total 100 g) close to the
time of the exercise may be most effective at promoting Cr
accumulation.
Other compounds that show the potential to enhance muscle accumulation and/or the ergogenic effect of CrM are D-pinotol, -linolic
acid, and b-alanine. However, each requires further investigation
before clear conclusions can be made regarding their effectiveness.
The addition of PRO (or amino acids) to a CHO supplement appears
to enhance the rate of muscle glycogen storage during the hours
following exercise. The combination of CrM, PRO, and CHO not
only appears to augment Cr uptake it may optimize muscle glycogen
stores as well. It is important to remember that characteristically CrM
increases lean mass; therefore, individual requirements should be
considered in sports where any gain in body weight may disadvantage
the athlete.
For all athletes, along more efficient glycogen restoration, an important advantage of combining PRO (or essential amino acids) with
CHO in a postexercise supplement is this combination’s well documented positive effect on protein synthesis and net protein balance,
which underlines efficient recovery.
Chronic adaptations that are desired from resistance training (i.e.,
increased strength, muscle hypertrophy, lean body mass) appear to be
enhanced by the combination of CrM with PRO or CHO (up to
1–5 gkgday-1). The combination utilized may depend on individual
requirements of the athlete. For instance, the additional CHO may be
useful to some with high-energy requirements. However, as PRO
appears to provide similar benefits, the combination of CrM and
PRO may be more suited when high CHO intake (e.g., glucose) is
not desired.
The consumption of a supplement containing PRO and CHO before
and after resistance exercise (i.e., supplement timing) appears to
provide the ideal anabolic conditions for muscle growth. That is,
most resistance training studies that have assessed chronic adaptations report significantly greater muscle hypertrophy from this
strategy.
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Additionally, supplement timing with a CrM-containing PRO-CHO
supplement [1 gkg-1 twice a day (CrM 0.1 g-1kg-1)] is shown to be a
particularly effective strategy for increasing muscle creatine stores and
enhancing muscle strength and hypertrophy during resistance
training.
Caffeine-ephedrine and CrM-sodium bicarbonate supplement
combinations provide an acute physiological response that enhances
anaerobic and/or aerobic exercise, whereas CrM/b-alanine supplementation and the use of specific amino acid combinations influence
chronic adaptations that predominantly enhance aerobic exercise
performance. However, as mentioned, a number of limitations exist
in the research methodology utilized and/or the supplement itself.
Thus, the practical application for athletes and recreationally active
individuals may require further investigation.
8.1. Multifaceted Role of the Muscle PCr-Cr System
in Exercise Metabolism
To appreciate fully the rationale behind the intense research focus
on supplements that may enhance the phosphocreatine-creatine
(PCr-Cr) system in muscle, one must understand its fundamental,
multifaceted roles in relation to exercise metabolism. The PCr-Cr
system as a whole integrates all the local pools (or compartments)
of adenine nucleotides (i.e., the transfer of energy from mitochondrial compartments to that in myofibrils and cellular membranes
as well as the feedback signal transmission from sites of energy
utilization to sites of energy production). The availability of PCr
is now generally accepted as most critical to the continuation of
muscle force production and performance during repeated, short
bouts of powerful activity (1,2) as well as aerobic exercise at high
intensity (3,4).
The main roles of the PCr-Cr system are illustrated in Figure 1.
The first is that of a temporal energy buffer for ATP regeneration
achieved via anaerobic degradation of PCr to Cr and rephosphorylation of ADP. This energy buffering function is most prominent in
the fast-twitch/glycolytic fibers; these fibers contain the largest pool
of PCr (5). The ATP required for high intensity exercise is met by
the simultaneous breakdown of PCr and anaerobic glycolysis, and
the PCr-Cr system provides up to one-third of the total energy
required (6). The second major function of the PCr-Cr system is
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that of a spatial energy buffer (or transport system). In this capacity,
the PCr-Cr system serves as an intracellular energy carrier connecting sites of energy production (mitochondria) with sites of energy
utilization (Naþ/Kþ pump, myofibrils, sarcoplasmic reticulum)
(Fig. 1). To describe the specificity of this system, this system has
been coined the creatine-phosphate (Cr-Pi) shuttle (7)—Cr literally shuttles energy from the mitochondrion to highly specific
sites via compartment-specific creatine kinase (CK) isoenzymes
located at each of the energy producing or utilizing sites that
transduce the PCr to ATP (8) and then returns to regenerate
energy exactly the equivalent to its consumption at those sites
(7). A third function of the PCr-Cr system is the prevention of a
rise in ADP, which would have an inhibitory effect on a variety of
ATP-dependent processes, such as cross-bridge cycling. A rise in
ADP production would also activate the kinase reactions that
ultimately result in the destruction of muscle adenine nucleotides
(2). Therefore, the removal of ADP via the CK reaction-induced
rephosphorylation serves to reduce the loss of adenine nucleotides
while maintaining a high intracellular ATP/ADP ratio at the sites
of high energy requirements (9).
The CK reaction during the resynthesis of ATP takes up protons
(8). Therefore, another function of this PCr-Cr system is the maintenance of pH in exercising muscle. In a reversible reaction (catalyzed by the site-specific CK), Cr and ATP form PCr and ADP
(Fig. 1). The formation of the polar PCr ‘‘locks’’ Cr within the
muscle and maintains the retention of Cr because the charge prevents partitioning through biological membranes (2). When pH
declines (i.e., during exercise when lactic acid accumulates), the
reaction favors the generation of ATP. Conversely, during recovery
periods (i.e., periods of rest between exercise sets), when ATP is
being generated aerobically, the reaction proceeds toward the right
and increases PCr levels. The notion that maintenance of PCr
availability is crucial to continued force production and performance during high intensity exercise is further supported by
research demonstrating that the rate of PCr utilization is extremely
high during the initial seconds of intense contraction—high anaerobic ATP regeneration rates result in a 60% to 80% fall in PCr (10).
Not only is the depletion of muscle PCr associated with fatigue (9),
the resynthesis of PCr and the restoration of peak performance
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are shown to proceed in direct proportion to one another despite low
muscle pH during recovery (10).
A loading phase with creatine monohydrate (CrM) (4 5 g
servingsday-1 for 5 days) is able to increase Cr concentrations in
muscle and other tissues with a low baseline Cr content, such as the
brain, liver, and kidney (4–46). Via its accumulation in the cell,
CrM enhances the cellular bioenergetics of the PCr-Cr system by
increasing PCr availability (2,9,47). The beneficial effect of oral
supplementation is thought to be dependent on the extent of Cr
accumulation (31,47,48). However, it is also apparent that this
response can be highly variable among subjects (49). Large variations in Cr accumulation (0–40 mmolkg dm-1) in response to supplementation can be partly accounted for by differences in
presupplementation muscle concentrations (48) and possibly in
muscle fiber type distribution (5), but it remains unclear as to why
muscle Cr accumulation can vary tremendously (up to sixfold)
among individuals with similar presupplementation concentrations
(15,43,49). This variability in muscle Cr uptake among some individuals combined with the significance of the PCr-Cr system and
CrM’s potential to augment this all-important pathway is the underlining rationale of studies that examine the effects of CrM supplementation in combination with other compounds.
8.2. Creatine þ Protein or Creatine þ Carbohydrate
for Better Muscle Hypertrophy?
8.2.1. PAUL J. CRIBB
The combination of creatine monohydrate (CrM) and carbohydrate (CHO) has been shown to provide greater improvements in
strength and body composition (i.e., increase lean mass with no
increase in fat mass) compared to CHO alone. CrM combined
with protein (PRO) (whey protein) has also been shown to augment
muscle strength and lean body mass (LBM) when compared to CHO
or PRO only. However, prior to this study, no one had compared
the effects of different CrM-containing PRO and CHO supplements
on muscle Cr accumulation or chronic adaptations during resistance
training.
The aim of this study was to examine the effects of combining
CrM with CHO and with PRO (whey protein isolate) during an
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11-week resistance training program in comparison to PRO and
CHO alone. In a double-blind, randomized protocol, resistancetrained males were matched for strength and placed into one of
four groups: creatine/carbohydrate (CrCHO), creatine/whey protein isolate (CrWP), WP only, or CHO only (CHO). All participants
consumed the supplement (1.5 g-1kg-1day-1) for the duration of the
resistance training program while maintaining their habitual daily
diet. The CrM-containing supplements (CrCHO, CrWP) protocol
included a 1-week loading phase (0.3 g-1kg-1day-1, or 24 g day-1, for
an 80 kg individual) that was followed by a maintenance phase
(0.1 g-1kg-1day-1 or 8 g day-1 for an 80 kg individual) for the duration
of the study. All assessments were completed the week before and
after the 11-week supervised resistance training program. Assessments included dietary analyses (before and during supplementation), strength (1RM, in the barbell squat, bench press, and cable
pulldown), body composition (via DEXA*), and vastus lateralis
muscle biopsies for histochemical determination of muscle fiber
type (I, IIa, IIx), cross-sectional area (CSA), muscle contractile
protein, and Cr content.
Results showed that although there were no differences between
the groups at the start of the study and each group consumed a
protein-rich diet, the two CrM-treated groups demonstrated greater
hypertrophy responses than the WP and CHO-only groups. However, the hypertrophy responses among all groups did vary at the
three levels of muscle physiology that were assessed (i.e., LBM,
fiber-specific hypertrophy, contractile protein content). For example, the CrCHO and CrWP groups each demonstrated larger gains
in LBM (5.5% and 5.0%, respectively) than the CHO (1.1%) and
WP (3.7%) groups (Fig. 2). The CrCHO and CrWP groups also
demonstrated the largest increases in hypertrophy in type I, IIa,
and IIx fibers; but again no difference between the two CrMtreated groups was detected. Additionally, the changes LBM
were reflected by the changes in contractile protein content. That
is, both CrCHO and CrWP groups demonstrated greater increases
in contractile protein content (milligrams per gram of muscle)
compared to the CHO and WP groups (Fig. 3). However, there
*
DEXA (dual x-ray absorptiometry) measures body density and composition via
x-rays. Bone, fat and muscle possess different densities and will therefore absorb
x-rays at different amounts. This allows researchers then to quantify body composition.
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6
5
kgs
4
3
2
1
0
change in lean body mass
Fig. 2. Change in lean body mass.
was no difference in contractile protein accretion between the two
CrM-treated groups. With regard to muscle Cr accumulation, both
the CrCHO and CrWP groups demonstrated similar elevations
(10%) in muscle Cr content after the 11-week training/supplementation program.
Based on previous findings of the anabolic effect of whey protein
on muscle, an additive effect due to combining CrM and WP on
muscle strength and hypertrophy was anticipated in this study.
However, no greater effect was observed from combining CrM
with whey protein when compared to the CrCHO group. One
explanation for this may have been the already high protein intake
by all groups (aside from supplementation). For instance, the
results of at least one longitudinal study suggested that once dietary protein requirements appear to be met it is the energy content
of the diet that has the largest effect on hypertrophy during resistance training (198). In other words, when CrM is consumed in
the presence of a high protein diet, the addition of CHO may be
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35
30
CHO
CrCHO
WP
CrWP
mg/g of muscle
25
20
15
10
5
0
change in contractile protein
Fig. 3. Change in contractile protein.
more beneficial than extra PRO. However, the results of our
study also suggest that the consumption of CrM with PRO provides benefits similar to those of CrM with CHO. This may have
important implications for people who cannot consume large
amounts of CHO (e.g., glucose) such as those with, or at risk of,
type 2 diabetes.
In conclusion, it does appear as though combining CrM with
CHO, or PRO can influence the magnitude of chronic adaptations
desired from resistance exercise to a greater extent than CHO or
PRO alone. The hypertrophic responses from these supplements
varied at the three levels assessed (i.e., changes in lean mass, fiberspecific hypertrophy, and contractile protein content). Currently,
this is the only study that has compared the effects of different CrMcontaining PRO and CHO supplements on muscle Cr accumulation
and chronic adaptations during resistance training. Therefore, this
topic should continue to receive attention from the scientific community as these results have important implications not only for
athletes but also an ageing population and others who have a
reduced capacity for exercise.
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8.3. Addition of Protein to a Carbohydrate Supplement
for Increased Efficiency of Muscle Glycogen Storage
8.3.1. JOHN L. IVY
An essential process in the recovery from exercise is replenishment of muscle glycogen stores. When time is limited between
exercise workouts or competitions, it is necessary to maximize the
rate of muscle glycogen resynthesis. Research suggests that adding
protein to a carbohydrate supplement increases the efficiency by
which carbohydrate is converted to muscle glycogen. The mechanism by which protein increases the efficiency of muscle glycogen
storage is not known, but there are several possibilities.
Insulin controls two important steps required for muscle glycogen synthesis. First, it activates the transport of glucose across the
plasma membrane of the muscle, and second it increases the activity
of glycogen synthase, the rate-limiting enzyme in glycogen synthesis.
When carbohydrate is consumed, insulin is released from the pancreas to maintain blood glucose homeostasis. Peptides and certain
amino acids also stimulate the release of insulin and when combined
with carbohydrate the insulin response can be synergistic. This
greater insulin response can result in a faster rate of muscle glucose
uptake and its conversion to glycogen. The stimulating effect of
protein on glycogen synthesis, however, has been observed without
a greater insulin response than is typically seen with carbohydrate
supplementation alone.
A second possibility is that the amino acids released from protein
digestion activate the glycogen synthesis process via a mechanism
that is insulin-independent, thus having an additive effect on this
process. Glycogen synthase activity is controlled, in part, by glycogen synthase kinase-3, which phosphorylates glycogen synthase,
resulting in its inactivation. Inhibition of glycogen synthase
kinase-3 results in the dephosphorylation of glycogen synthase and
its activation. Glycogen synthase kinase-3 can be inhibited by the
protein p70S6K, a downstream target of mTOR (mammalian target
of rapamycin), which is activated by essential amino acids. Therefore, an elevation of blood amino acids along with insulin following
a carbohydrate–protein supplement may function additively to activate glycogen synthase and increase the rate of glycogen synthesis.
Furthermore, certain amino acids, such as leucine, have been found
to increase the rate of skeletal muscle glucose transport. This raises
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the possibility that a rise in blood amino acid levels at the same time
blood insulin levels are increasing increases activation of both skeletal muscle glucose transport and glycogen synthase, resulting in an
enhanced rate of muscle glycogen synthesis.
8.4. Can Supplement Timing Double Gains in Muscle Mass?
8.4.1. ALAN HAYES
Some studies have reported greater muscle hypertrophy during
resistance exercise training from supplement timing (i.e., the strategic consumption of proteins/amino acids and carbohydrates before
and/or after each workout). However, prior to this study, no one
had examined whether this strategy provided greater muscle hypertrophy or strength development than supplementation at other
times during the day. The purpose of this study (67) was to examine
the effects of supplement timing versus supplementation in the
hours not close to the workout on muscle fiber hypertrophy,
strength, and body composition during a 10-week resistance exercise
program.
Resistance-trained males were matched for strength and randomly placed into one of two groups; group 1 (n = 8) consumed a
protein-carbohydrate (PRO-CHO) supplement (1 gkg-1 twice day)
immediately before and after every workout (4 days per week for 10
weeks). Group 2 (n=9) consumed the same dose of the same supplement in the morning and late in the evening. These times were at
least 5 hours outside of the workout. The two groups consumed the
exact same supplement [0.03 g creatine monophosphate (CrM) þ
0.5 g whey isolate þ 0.5 g glucose per kilogram body weight]
twice each training day, 4 times per week. The only difference
was the time of day the supplement doses were consumed. Assessments completed the week before and after the 10-week supervised
training program (Max-OT ) included strength (1RM, barbell
bench press, squats, dead lifts), body composition (DEXA—see
footnote to sidebar Creatine þ Protein or Creatine þ Carbohydrate for Better Muscle Hypertrophy?), and vastus lateralis muscle
biopsies for determination of muscle fiber type (I, IIa, IIx), crosssectional area (size), contractile protein, and creatine and glycogen
content.
Results showed that although both groups demonstrated significant improvements in strength and gains in lean mass, the
TM
305
Effective Nutritional Supplement Combinations
supplement-timing group showed higher (p < 0.05) resting muscle
Cr and glycogen concentrations after the training program, greater
strength gains (two of three assessments), hypertrophy of type IIa
and IIx fibers, and synthesis of contractile protein. Additionally,
this group demonstrated a gain in lean body mass that was almost
double that of the group that supplemented at times not close to
training (2.72 vs 1.45 kg, respectively) (Fig. 4).
There were several aspects of this study that made it unique
compared to others that have examined the effects of supplementation close to the time of resistance exercise. First, the changes in
body composition were confirmed with hypertrophic responses at
the cellular level (i.e., fiber-specific hypertrophy) and the subcellular
level (i.e., contractile protein content). Second, this study utilized
experienced bodybuilders who characteristically followed regimented eating patterns, and the effects of supplementation were examined in the presence of the participants’ normal eating patterns.
3.5
3
group-1 (supplement-timing)
*
group-2 (supplement taken 5 hours
before & after exercise)
2.5
2
kgs
1.5
1
*
0.5
0
12
3
–0.5
–1
–1.5
–2
LBM
fat mass
body fat %
Fig. 4. Body composition changes after 10 weeks of training. *Greater change
than that in the group that did not follow supplement timing (p < 0.05). From
Cribb and Hayes (67), with permission.
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Cooke and Cribb
Although these results are important, it is the design of this study
that makes the findings particularly relevant to a wide sector of the
population. Supplement timing with the combination of CrM-PROCHO represents a simple but effective strategy that may enhance
strength and muscle mass gains during resistance training in healthy
adults. However, this protocol may also have important implications for populations that require improvements in strength
and body composition but have a reduced capacity for exercise,
such as the frail elderly, cardiac rehabilitation patients, and others
living with conditions that compromise health such as human
immunodeficiency virus infection, cancer, and the various muscular
dystrophies.
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