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389
International Journal of Sport Nutrition and Exercise Metabolism, 2008, 18, 389-398
© 2008 Human Kinetics, Inc.
Burke is with the Dept. of Human Kinetics, St. Francis Xavier University, Antigonish, NS, Canada.
Candow is with the Faculty of Kinesiology and Health Studies, University of Regina, Regina, SK, Canada
S4S 0A2. Chilibeck is with the College of Kinesiology, University of Saskatchewan, Saskatoon, SK,
Canada S7N 5B2. MacNeil is with the Dept. of Kinesiology, and Tarnopolsky, the Dept. of Pediatrics
and Medicine, McMaster University, Hamilton, ON, Canada. Roy is with the Dept. of Physical Education
and Kinesiology, Brock University, St. Catharines, ON, Canada. Ziegenfuss is with the Ohio Research
Group, Wadsworth Medical Center, Wadsworth, OH.
Effect of Creatine Supplementation and
Resistance-Exercise Training on Muscle
Insulin-Like Growth Factor in Young Adults
Darren G. Burke, Darren G. Candow, Philip D. Chilibeck,
Lauren G. MacNeil, Brian D. Roy, Mark A. Tarnopolsky,
and Tim Ziegenfuss
The purpose of this study was to compare changes in muscle insulin-like growth
factor-I (IGF-I) content resulting from resistance-exercise training (RET) and
creatine supplementation (CR). Male (n = 24) and female (n = 18) participants with
minimal resistance-exercise-training experience (≥1 year) who were participating
in at least 30 min of structured physical activity (i.e., walking, jogging, cycling)
3–5 ×/wk volunteered for the study. Participants were randomly assigned in blocks
(gender) to supplement with creatine (CR: 0.25 g/kg lean-tissue mass for 7 days;
0.06 g/kg lean-tissue mass for 49 days; n = 22, 12 males, 10 female) or isocaloric
placebo (PL: n = 20, 12 male, 8 female) and engage in a whole-body RET program
for 8 wk. Eighteen participants were classified as vegetarian (lacto-ovo or vegan;
CR: 5 male, 5 female; PL: 3 male, 5 female). Muscle biopsies (vastus lateralis)
were taken before and after the intervention and analyzed for IGF-I using standard
immunohistochemical procedures. Stained muscle cross-sections were examined
microscopically and IGF-I content quantified using image-analysis software.
Results showed that RET increased intramuscular IGF-I content by 67%, with
greater accumulation from CR (+78%) than PL (+54%; p = .06). There were no
differences in IGF-I between vegetarians and nonvegetarians. These findings
indicate that creatine supplementation during resistance-exercise training increases
intramuscular IGF-I concentration in healthy men and women, independent of
habitual dietary routine.
Keywords: peptide hormone, muscle biopsy, sport nutrition, vegetarians
390 Burke et al.
The combination of creatine supplementation and resistance training has been
shown to increase lean-tissue mass (Brose, Parise, & Tarnopolsky, 2003; Burke et
al., 2000, 2003; Chrusch, Chilibeck, Chad, Davison, & Burke, 2001) and muscle-
fiber size (Burke et al., 2003, Volek et al., 1999). The underlying mechanisms
explaining the increase in muscle mass from creatine supplementation remain to
be determined; however, potential mechanisms include an increase in high-energy
phosphate concentration (total creatine [TCr], phosphocreatine [PCr], and creatine
[Cr]; Burke et al., 2003) and PCr resynthesis after exercise (Greenhaff, Bodin,
Soderland, & Hultman, 1994), cellular hydration status (Hultman, Soderland, Tim-
mons, Cederblad, & Greenhaff, 1996), satellite-cell activity (Dangott, Schultz, &
Mozdziak, 2000; Olsen et al., 2006; Vierck, Icenoggle, Bucci, & Dodson, 2003), and
myofibrillar protein kinetics (Willoughby & Rosene, 2003; Parise, Mihic, MacLen-
nan, Yarasheski, & Tarnopolsky, 2001). Theoretically, creatine supplementation
might enhance the metabolic adaptations from regular resistance-exercise-training
sessions, leading to greater production of insulin-like growth factor-I (IGF-I) over
time (Deldicque et al., 2005). This might help explain the increase in lean-tissue
mass found in many creatine and resistance-exercise-training studies (Brose et al.;
Burke et al., 2000, 2003; Chrusch et al.).
Most IGF-I production occurs in the liver in response to changes in growth-
hormone concentrations and acts as an endocrine hormone, regulating tissue-specific
growth and differentiation (Czerwinski, Martin, & Bechtel, 1994; Hameed, Har-
ridge, & Goldspink, 2002). The IGF-I produced in skeletal muscle through the
process of overload is an isoform of systemic IGF-I (Hameed et al.; MacGregor
& Parkhouse, 1996) and controls local tissue repair and remodeling (Goldspink,
1999). Borst et al. (2001) demonstrated that resistance-exercise training resulted
in a 20% increase in blood IGF-I after 13 and 25 weeks of training in young men
and women, and Singh et al. (1999) reported a 500% increase in muscle stained
for IGF-I in older participants after 10 weeks of resistance-exercise training. In
two recent reports it was found that creatine supplementation, independent of
exercise, augmented IGF-I mRNA in cultured myotubes (Louis, Van Beneden,
Dehoux, Thissen, & Francaux, 2004) and in human skeletal muscle (Deldicque
et al., 2005), possibly by enhancing the anabolic status of the cell involving IGF.
There have been several suggestions for the possible link between muscle IGF-I
activation and muscle overloading, including activation of the PI3K-Akt/PKB-
mTOR-signaling pathways (Deldicque et al.) and stretch tension on the basement
membrane (Goldspink) causing damage to sarcolemma and myofibrillar proteins
(Bamman et al., 2001).
Creatine supplementation results in an increase in intramuscular creatine
concentrations (Green, Hultman, Macdonald, Sewell, & Greenhaff, 1996; Harris,
Soderland, & Hultman, 1992). Large interindividual differences, however, in base-
line resting creatine concentrations and responsiveness to creatine supplementation
are evident (Casey & Greenhaff, 2000; Vandenberghe et al., 1997). Participants
with initially low resting creatine concentrations (i.e., vegetarians) experience the
greatest increase from creatine supplementation (Casey, Constantin-Teodosiu,
Howell, Hultman, & Greenhaff, 1996; Greenhaff et al., 1994; Harris et al., 1992),
leading to exercise improvements (Shomrat, Weinstein, & Katz, 2000). We have
previously shown that creatine supplementation during 8 weeks of whole-body
resistance-exercise training increased TCr, PCr, Type II fiber area of the vastus
Creatine and IGF-I 391
lateralis, bench-press strength, and isokinetic knee-flexion and -extension work
over placebo (Burke et al., 2003). Vegetarians who supplemented with creatine
experienced a greater increase in TCr and PCr concentration and total isokinetic
work performance over nonvegetarians (Burke et al., 2003), possibly because of
lower initial resting creatine concentrations leading to accelerated intramuscular
creatine uptake from exogenous supplementation.
The purpose of this study was to determine the effects of creatine supplemen-
tation (8 weeks) combined with heavy resistance-exercise training (>70% 1-RM)
on muscle IGF-I concentration in vegetarian and nonvegetarian participants as
previously described (Burke et al., 2003). Based on our previous findings of
greater adaptations from creatine supplementation, we hypothesized that creatine
supplementation during resistance training would increase IGF-I over placebo, and
vegetarians on creatine would experience greater gains than nonvegetarians.
Methods
Participants
Male (n = 24) and female (n = 18) participants with minimal resistance-training
experience (≥1year) who were participating in at least 30 min of structured physical
activity (i.e., walking, jogging, cycling) 3–5 times a week volunteered for the study.
Eighteen participants were classified as vegetarian (lacto-ovo or vegan). Participants
were self-described as vegetarian, whether they were lacto-ovo or vegan, and had
to have been vegetarian for a minimum of 3 years. Participant exclusion criteria
included a history of creatine supplementation for 6 weeks before the start of the
study or any disease or medical condition that would have prevented participation
in resistance training. Participants were randomly assigned (double-blind) to receive
creatine or placebo in stratified blocks based on gender. All participants completed
a Physical Activity Readiness Questionnaire (PAR-Q), which screens for health
problems that might present a risk with physical activity. Participants who indi-
cated a health problem were required to have medical approval before participating
in the study. The study was approved by the University of Saskatchewan ethics
review board for research in human participants. The participants were informed
of the risks and purposes of the study before their written consent was obtained.
Participant characteristics are presented in Table 1.
Supplementation
Participants were randomized (double-blind) to supplement with creatine (load-
ing phase: 0.25 g · kg lean-tissue mass–1 · day–1 for 7 days; maintenance phase:
Table 1 Characteristics of Participants Taking Either Creatine or
Placebo, M ± SE
Group
n,
M/F Age Height (cm) Weight (kg) %
Fat
Creatine 12/10 31 ± 2.6 170.3 ± 2.9 68.6 ± 4.0 20.5 ± 2.6
Placebo 12/8 37 ± 6.8 170.2 ± 2.9 69.3 ± 4.3 22.0 ± 2.6
392 Burke et al.
0.06 g · kg lean-tissue mass–1 · day–1 for an additional 49 days; n = 22; 12 male [5
vegetarians], 10 female [5 vegetarians]) or placebo (maltodextrin; n = 20; 12 male
[3 vegetarians], 8 female [5 vegetarians]) during 8 weeks of resistance-exercise
training. The creatine loading was divided into four equal servings (~0.06 g · kg
lean-tissue mass–1 · day–1) consumed in the morning, in the afternoon or before the
resistance-exercise-training session, in the evening or after the resistance-exercise
training session, and before going to bed. The creatine maintenance dose of 0.06 g/
kg was chosen because it has been shown to be effective for increasing muscle mass
and strength (Chrusch et al., 2001). Participants were instructed to supplement with
creatine immediately after each resistance-exercise-training session because creatine
supplementation postexercise leads to significant muscle hypertrophy (Chilibeck,
Stride, Farthing, & Burke, 2004). On nontraining days, participants were instructed
to consume creatine (or placebo) in the morning or before going to bed. The average
absolute daily doses of creatine for participants during loading and maintenance
were 16.8 ± 0.7 and 4.2 ± 0.2 g/day, respectively. Participants mixed each supple-
ment with ~300 ml of a fruit-flavored drink. The creatine and placebo supplements
were identical in taste, texture, and appearance. Supplementation compliance was
indirectly monitored by verbal communication and having participants return empty
supplement bags when picking up additional supplements.
Muscle Biopsy, Histochemical Staining, and Image Analysis
Percutaneous needle biopsies were obtained from the distal third of the vastus
lateralis muscle using a 5-mm Stille needle (Micrins, New York, NY) under local
anesthetic with 1% lidocaine (Smith-Kline Beecham, Toronto, ON) and with suc-
tion applied via a 60-cc syringe. Participant muscle biopsies were performed 24 hr
before the first training session. Target biopsy time after their last exercise session
was 24 hr, with biopsies actually occurring 18–30 hr postexercise.
Preparation of staining started with fixation of the frozen section with 100%
acetone at 4 °C for 10 min. The tissue was then washed in a bath with 10 mM of
phosphate-buffered saline, pH 7.5, for 10 min. One hundred microliters of pri-
mary antibody (IGF-I: H-70, Santa Cruz Biotechnology, CA) was applied to each
section and incubated for 30 min. The section was then washed with 10 mM of
phosphate-buffer saline, pH 7.5. Then, 100 µL of biotinylated secondary antibody
(Rabbit ImmunoCruz Staining System, Santa Cruz Biotechnology) was applied and
incubated for 10 min, then removed and washed well with 10 mM of phosphate-
buffer saline, pH 7.5. One hundred microliters of HRP-streptavidin conjugate
was then added and incubated for 10 min, which was followed by the addition of
concentrated DAB chromogenic substrate and an incubation of 5 min. Then, 100
µl of hematoxylin was applied and left to sit for 2 min, which was followed by
dehydration with alcohol and mounting. Six to eight samples were done at a time
and always included pretraining and posttraining samples for each participant.
After immunoperoxidase staining, sections were mounted, and the area positively
stained was analyzed using Scion Image Version Beta 4.0.2 software (Scion
Corp., Frederick, MD). First, each slide was viewed under 100× magnification
(Olympus BX60, Tokyo, Japan). Then, three or four pictures were taken per slide
(Spot Diagnostic Instruments Inc., Sterling Heights, MI) and immediately saved
Creatine and IGF-I 393
as JPEG files on a Dell Dimension XPS R450 (Dell Computer Co., Austin, TX).
Approximately 100–150 muscle fibers were used to determine the area positively
stained for IGF-I content (Figure 2).
Exercise Program
All participants followed the same high-volume, heavy-load (>70% 1RM)
resistance-exercise-training program for 8 weeks. The program was a 4-day split
routine involving whole-body musculature that was previously found to increase
lean-tissue mass and strength (Burke et al., 2003; Candow, Chilibeck, Burke, Davi-
son, & Smith-Palmer, 2001). Briefly, chest and triceps muscles were trained on
Day 1 with the following exercises in order: flat bench press, incline bench press,
flat dumbbell flies, incline dumbbell flies, cable triceps extensions, rope reverse
triceps extensions, and French curls. On Day 2, participants trained back and biceps
muscles: chin-ups, low row, lat-pull downs, alternate dumbbell row, standing EZ-
curls, preacher curls, and alternate dumbbell curls. Day 3 was for legs, shoulder,
and abdominal muscles and included the following exercises in order: vertical leg
press, leg extension, hamstring curl, standing calf raises, seated dumbbell press,
upright rows, shrugs, lateral raises, and abdominal crunches. Day 4 was a day of
rest. These 4 days were considered one cycle, and the cycle was repeated continu-
ously throughout the duration of the study. Participants performed seven cycles of
3–5 sets of 4–12 repetitions to muscle failure for each set. During Cycles 1 and 7,
participants performed three sets of 10–12 repetitions, with 1-min rests between
sets. For Cycles 2 and 6, participants performed three sets of 8–10 repetitions, with
1.5-min rests between sets. During Cycles 3 and 5, participants performed four
sets of 6–8 repetitions, with 2-min rests between sets. For Cycle 4, participants
performed five sets of 4–6 repetitions, with 3-min rests between sets. Training logs
detailing the weight used and number of sets and repetitions performed for each
exercise were completed for every workout. Training volume was calculated (kg
× reps) for the entire resistance-exercise-training program.
Diet
Dietary intake was recorded before and after the study to assess whether there
were differences in total energy and macronutrient composition between creatine
and placebo. Participants were given instruction about proper portion sizes and
how to accurately record all food or beverages consumed. They used a 3-day food
booklet to record what they ate for 2 weekdays and 1 weekend day. Fuel Nutrition
software 2.1a (LogiForm International Inc., Saint-Foy, Quebec) was used to analyze
the food records for total calories and the amount of energy from carbohydrate,
fat, and protein.
Statistical Analysis
A 2 (creatine vs. placebo) × 2 (vegetarian vs. nonvegetarian) × 2 (pre vs. post)
ANOVA with repeated measures on the third factor was used to determine differ-
ences between the creatine and placebo groups and vegetarians and nonvegetarians
394 Burke et al.
over time. Tukey’s post hoc tests were used to determine differences between group
means. All results are expressed as M ± SE. Statistical analyses were carried out
using SPSS version 10.02 for Microsoft Windows. Statistical significance was set
at p < .05.
Results
There were no differences in total training volume between creatine and placebo
over the 8 weeks of training. Creatine supplementation, however, resulted in greater
training volumes at Weeks 2 and 7 (p < .05). Dietary analyses indicated that veg-
etarians consumed fewer total calories (vegetarian: pre 2,159 ± 71 kcal, post 2,213
± 78 kcal; nonvegetarian: pre 2,638 ± 67 kcal, post 2,629 ± 61 kcal; p < .05) and
protein (vegetarian: pre 78 ± 2 g/day, post 80 ± 2 g/day; nonvegetarian: 139 ± 2 g/
day, post 138 ± 3 g/day; p < .05) over time, with no other differences.
At baseline the mean muscle-fiber area positively stained for IGF-I content
was 4.42% (range 1.37–12.10%), and there were no significant differences between
groups at baseline (CR 4.44%, PL 4.38%). The resistance-exercise-training program
resulted in a significant increase of 67% in IGF-I, however, and the participants
who supplemented with creatine experienced an increase of 78% in IGF-I, com-
pared with a 55% increase exhibited by the participants who were on placebo (p
= .06; Figure 1).
As previously reported (Burke et al., 2003), there were no significant dif-
ferences between groups for body weight or lean-tissue mass at baseline. Par-
ticipants supplementing with creatine, however, experienced a greater increase in
body mass and lean-tissue mass than those on placebo (body mass: CR 2.2 kg or
3.2%, PL 0.6 kg or 0.9%; lean-tissue mass: CR 2.5 kg or 6%, PL 1.9 kg or 2%;
p < .05). Vegetarians on creatine experienced an increase of 2.4 kg in lean-tissue
mass, compared with an increase of 1.9 kg for nonvegetarians on creatine (p =
.06). Vegetarians supplementing with creatine experienced a greater increase in
Figure 1 — Change in area positively stained for insulin-like growth factor-I (IGF-I) from
before to after training and supplementation, M ± SE (p = .06). Area is expressed in µm2
Creatine and IGF-I 395
high-energy phosphate content than nonvegetarians on creatine (TCr: vegetarians
25%, nonvegetarians 7%; PCr: vegetarians 37%, nonvegetarians 11%; p < .05).
There were no changes in TCr, PCr, or free Cr for placebo participants. Creatine
supplementation increased Type II fiber area of the vastus lateralis by 28% (p <
.05), compared with a 5% increase for placebo. The change in lean-tissue mass
was significantly correlated to the change in intramuscular TCr content (r = .61, p
< .05), and the change in intramuscular IGF-I content was significantly correlated
to the change in intramuscular TCr content (r = .82, p < .05; Figure 2).
Discussion
The primary purpose of this study was to determine the effects of creatine supple-
mentation and resistance-exercise training on muscle IGF-I in young adults. Results
showed that muscle IGF-I content was significantly increased after high-intensity
resistance-exercise training, with greater gains observed from creatine supplementa-
tion than from placebo. IGF-I has been shown to increase muscle protein synthesis
and satellite-cell activity (Allen & Boxhorn, 1989) and stimulate the PI3K-Akt/
PKB-mTOR-signaling pathway involved in muscle hypertrophy (Deldicque et al.,
2005). In the current study, participants supplementing with creatine experienced a
greater increase in IGF-I than those on placebo (CR 78%, PL 55%; p = .06). These
results support the findings of Deldicque et al., who observed a 30% increase in
IGF-I mRNA expression at rest after 5 days of creatine supplementation in young
adults. Our results further suggest, however, that regular resistance-exercise-training
sessions for 8 weeks increase muscle IGF-I in adult humans, with greater gains
observed from creatine supplementation. Although the mechanism explaining the
Figure 2 — An image of one participant’s muscle cross-section stained for insulin-like
growth factor-I presupplementation (left) and after creatine supplementation (right).
396 Burke et al.
increase in IGF-I from creatine remains to be elucidated, the most plausible theory
involves high-energy phosphate metabolism and training intensity. As we have
previously shown, creatine supplementation increased both PCr and TCr content
to a greater extent than placebo (Burke et al., 2003). The increase in high-energy
phosphate metabolism might have allowed resistance training to be performed
with greater intensity as was observed in Weeks 2 and 7 of our resistance-exercise-
training program. The higher metabolic demand from more-intense resistance-
exercise-training sessions might explain the greater increase in muscle IGF-I content
from creatine supplementation found in the current study.
It is unclear why vegetarians did not experience a greater increase in IGF-I than
nonvegetarians. It has been shown that habitual dietary intake of reduced energy and
protein might reduce serum IGF-I in humans (Thissen, Ketelslegers, & Underwood,
1994). In particular, a diet low in essential amino acids reduces IGF- I production
(Harp, Goldstein, & Phillips, 1991), suggesting that essential amino acids are nec-
essary to maximize IGF-I production. For the current study, vegetarians consumed
approximately 2,200 kcal and 79 g of protein per day, compared with 2,650 kcal
and 139 g of protein per day for nonvegetarians. Although we cannot differentiate
between essential and nonessential amino acids in our dietary analyses, vegetarian
diets tend to be low in one or more essential amino acids that have been shown to
blunt IGF-I production (Clemmons, Seek, & Underwood, 1985) and might have
contributed to our lack of significant findings.
As previously reported, creatine supplementation resulted in greater increases
in lean-tissue mass and Type II fiber area than placebo (Burke et al., 2003). It is
difficult to determine whether the greater increase in lean-tissue mass and fiber area
with creatine was caused by greater muscle protein accretion. There was a trend
(p = .06) for a greater increase in muscle IGF-I content with creatine supplemen-
tation than with placebo, suggesting a greater muscle protein synthetic response
from creatine and exercise. The greater intramuscular IGF-I content (78%) from
creatine supplementation than with placebo (55%) might help explain the differ-
ences in muscle mass and exercise performance as previously reported (Burke et
al., 2003). The addition of creatine and subsequent increase in TCr and PCr might
have directly or indirectly stimulated production of muscle IGF-I concentration
and muscle protein synthesis, leading to muscle hypertrophy.
In summary, a structured resistance-exercise-training program increases
IGF-I content in men and women. The addition of creatine further augments the
physiological adaptations from resistance training, with no differences between
vegetarians and nonvegetarians. Future research should determine the mechanisms
explaining hormonal changes resulting from creatine supplementation alone and
in combination with resistance-exercise training.
Acknowledgments
This study was funded by a grant from Iovate Health Research and Development and the
University Council for Research, St Francis Xavier University, Canada.
Creatine and IGF-I 397
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