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Effect of Creatine Supplementation and Resistance-Exercise Training on Muscle Insulin-Like Growth Factor in Young Adults


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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 x/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.
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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.
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.
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
M/F Age Height (cm) Weight (kg) %
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.
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.
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).
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.
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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... A secondary purpose was to explore resting hormonal concentrations (i.e., IGF-1, testosterone, and cortisol), which may alter the anabolic/catabolic environment. Creatine supplementation has been shown to alter IGF-1 [27] and testosterone [20]; however, the effects of BA and Cr co-ingested on these hormones remains to be fully elucidated. ...
... There is limited evidence regarding BA and Cr supplementation on circulating IGF-1. Burke et al. (2008) reported that heavy resistance training increased muscle IGF-1 and supplementation with Cr resulted in greater increase [27]. This difference could be attributed to the duration of Cr supplementation and the exercise protocol. ...
... There is limited evidence regarding BA and Cr supplementation on circulating IGF-1. Burke et al. (2008) reported that heavy resistance training increased muscle IGF-1 and supplementation with Cr resulted in greater increase [27]. This difference could be attributed to the duration of Cr supplementation and the exercise protocol. ...
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The purpose was to investigate the effects of a 7-day creatine (Cr) loading protocol at the end of four weeks of β-alanine supplementation (BA) on physical performance, blood lactate, cognitive performance, and resting hormonal concentrations compared to BA alone. Twenty male military personnel (age: 21.5 ± 1.5 yrs; height: 1.78 ± 0.05 m; body mass: 78.5 ± 7.0 kg; BMI: 23.7 ± 1.64 kg/m2 ) were recruited and randomized into two groups: BA + Cr or BA + placebo (PL). Participants in each group (n = 10 per group) were supplemented with 6.4 g/day of BA for 28 days. After the third week, the BA + Cr group participants were also supplemented with Cr (0.3 g/kg/day), while the BA + PL group ingested an isocaloric placebo for 7 days. Before and after supplementation, each participant performed a battery of physical and cognitive tests and provided a venous blood sample to determine resting testosterone, cortisol, and IGF-1. Furthermore, immediately after the last physical test, blood lactate was assessed. There was a significant improvement in physical performance and mathematical processing in the BA + Cr group over time (p < 0.05), while there was no change in the BA + PL group. Vertical jump performance and testosterone were significantly higher in the BA + Cr group compared to BA + PL. These results indicate that Cr loading during the final week of BA supplementation (28 days) enhanced muscular power and appears to be superior for muscular strength and cognitive performance compared to BA supplementation alone.
... Therefore, It may be hypothesized that creatine consumption due to OMV, VGT and VEG nutritional habits may differently affect skeletal muscle adaptation. However, although IGF-1 accumulation in skeletal muscle fibers is indeed increased upon supplementation with creatine, VGT-related subjects showed similar responses to creatine supplementation compared to OMV-related subjects [144]. ...
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Muscular adaptations can be triggered by exercise and diet. As vegan and vegetarian diets differ in nutrient composition compared to an omnivorous diet, a change in dietary regimen might alter physiological responses to physical exercise and influence physical performance. Mitochondria abundance, muscle capillary density, hemoglobin concentration, endothelial function, functional heart morphology and availability of carbohydrates affect endurance performance and can be influenced by diet. Based on these factors, a vegan and vegetarian diet possesses potentially advantageous properties for endurance performance. Properties of the contractile elements, muscle protein synthesis, the neuromuscular system and phosphagen availability affect strength performance and can also be influenced by diet. However, a vegan and vegetarian diet possesses potentially disadvantageous properties for strength performance. Current research has failed to demonstrate consistent differences of performance between diets but a trend towards improved performance after vegetarian and vegan diets for both endurance and strength exercise has been shown. Importantly, diet alters molecular signaling via leucine, creatine, DHA and EPA that directly modulates skeletal muscle adaptation. By changing the gut microbiome, diet can modulate signaling through the production of SFCA.
... Interestingly, the results of our kinase enrichment analysis and the identification of hub nodes (downstream effectors of the MAPK and IGF-1/PI3K/Akt pathways) (Figure 3) are in high agreement with the available low-throughput, high-sensitivity experimental in vitro and in vivo evidence after Cr administration, such as qRT-PCR, Western blotting, and electrophoretic mobility shift assay. Several human and animal studies have shown that Cr brings higher growth hormone concentrations [107]; overexpression of IGF-1 [34,36,108,109]; upregulation and higher activity of Akt/PKB [70,110,111]; downregulation of myostatin and increase in GASP-1 [35]; overexpression of p38α (also called MAPK14) [69,112,113]; overexpression and higher activity of RPS6K and 4E-BP1 [37,38,114]; upregulation of myocyte enhancer factor isoforms [111,115]; overexpression of myogenic regulatory factors, such as MyoD, Myogenin, Myf5, and MRF4/Myf6/Herculin [32,33,36]; and overexpression of myosin heavy chain (MHC) isoforms [116]. Remarkably, our kinase enrichment analysis ( Figure 3C-D) showed high agreement with the protein kinase content after CrM supplementation, as reported by Safdar et al. (Figure A1) [70]. ...
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Creatine (Cr) and phosphocreatine (PCr) are physiologically essential molecules for life, given they serve as rapid and localized support of energy- and mechanical-dependent processes. This evolutionary advantage is based on the action of creatine kinase (CK) isozymes that connect places of ATP synthesis with sites of ATP consumption (the CK/PCr system). Supplementation with creatine monohydrate (CrM) can enhance this system, resulting in well-known ergogenic effects and potential health or therapeutic benefits. In spite of our vast knowledge about these molecules, no integrative analysis of molecular mechanisms under a systems biology approach has been performed to date; thus, we aimed to perform for the first time a convergent functional genomics analysis to identify biological regulators mediating the effects of Cr supplementation in health and disease. A total of 35 differentially expressed genes were analyzed. We identified top-ranked pathways and biological processes mediating the effects of Cr supplementation. The impact of CrM on miRNAs merits more research. We also cautiously suggest two dose–response functional pathways (kinase- and ubiquitin-driven) for the regulation of the Cr uptake. Our functional enrichment analysis, the knowledge-based pathway reconstruction, and the identification of hub nodes provide meaningful information for future studies. This work contributes to a better understanding of the well-reported benefits of Cr in sports and its potential in health and disease conditions, although further clinical research is needed to validate the proposed mechanisms.
... It is regularly reported that creatine supplementation, when combined with heavy resistance training leads to enhanced physical performance, fat free mass, and muscle morphology (15,16). Brief but heavy bouts of resistance exercise appear to promote cellular and subcellular adaptations, including more rapid ATP regeneration for muscle recovery, increased production of insulin-like growth factor, increased myogenic transcription factor signaling, and satellite cell proliferation, which are thought to further enhance anabolic performance (17,18). Absence of these changes seen in some studies has been attributed to lack of resistance exercise (19). ...
Creatine is a popular and widely used ergogenic dietary supplement among athletes, for which studies have consistently shown increased lean muscle mass and exercise capacity when used with short-duration, high-intensity exercise. In addition to strength gains, research has shown that creatine supplementation may provide additional benefits including enhanced postexercise recovery, injury prevention, rehabilitation, as well as a number of potential neurologic benefits that may be relevant to sports. Studies show that short- and long-term supplementation is safe and well tolerated in healthy individuals and in a number of patient populations.
... Supplementation also increases muscle GLUT-4 content and translocation to the sarcolemma which may increase glucose uptake and subsequent glycogen resynthesis [38,39]. Creatine supplementation facilitates calcium re-uptake via creatine kinase into the sarcoplasmic reticulum, and this may increase myofibrillar cross-bride cycling, cell swelling, the expression of myogenic transcription factors (i.e., Mrf4, myogenin), satellite cell proliferation, and the expression of growth factors (i.e., insulin-like growth factor-1) [40,41]. Creatine supplementation enhances the activation of protein kinases downstream in the mammalian target of rapamycin (mTOR) pathway, and this may subsequently reduce measures of muscle protein catabolism (i.e., leucine oxidation, urinary 3-methylhistidine) [25,31]. ...
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Creatine supplementation in conjunction with resistance training (RT) augments gains in lean tissue mass and strength in aging adults; however, there is a large amount of heterogeneity between individual studies that may be related to creatine ingestion strategies. Therefore, the purpose of this review was to (1) perform updated meta-analyses comparing creatine vs. placebo (independent of dosage and frequency of ingestion) during a resistance training program on measures of lean tissue mass and strength, (2) perform meta-analyses examining the effects of different creatine dosing strategies (lower: ≤5 g/day and higher: >5 g/day), with and without a creatine-loading phase (≥20 g/day for 5–7 days), and (3) perform meta-analyses determining whether creatine supplementation only on resistance training days influences measures of lean tissue mass and strength. Overall, creatine (independent of dosing strategy) augments lean tissue mass and strength increase from RT vs. placebo. Subanalyses showed that creatine-loading followed by lower-dose creatine (≤5 g/day) increased chest press strength vs. placebo. Higher-dose creatine (>5 g/day), with and without a creatine-loading phase, produced significant gains in leg press strength vs. placebo. However, when studies involving a creatine-loading phase were excluded from the analyses, creatine had no greater effect on chest press or leg press strength vs. placebo. Finally, creatine supplementation only on resistance training days significantly increased measures of lean tissue mass and strength vs. placebo.
... Beyond attenuating muscle damage, increased muscle creatine due to creatine supplementation alters the intramuscular milieu, which subsequently causes several changes beneficial to the adaptive response to resistance exercise. For example, creatine supplementation results in increased growth factor expression (e.g., myogenin, MRF-4, insulin-like growth factor I and II [IGF-I and IGF-II]) [38][39][40][41], increased satellite cell number and myonuclei concentration [42], and expression of multiple genes associated with adaptive processes related to exercise (e.g., osmosensing, cytoskeleton, remodeling, GLUT-4 translocation, glycogen and protein synthesis, satellite cell proliferation, and differentiation, DNA replication and repair, mRNA processing and transcription, and cell survival) [43]. It is possible that the increase in intramuscular water associated with creatine supplementation modulates some of the effects, as this is known to inhibit protein breakdown and RNA degradation and stimulate protein, DNA, RNA, and glycogen synthesis [33,44,45]. ...
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Numerous health conditions affecting the musculoskeletal, cardiopulmonary, and nervous systems can result in physical dysfunction, impaired performance, muscle weakness, and disuse-induced atrophy. Due to its well-documented anabolic potential, creatine monohydrate has been investigated as a supplemental agent to mitigate the loss of muscle mass and function in a variety of acute and chronic conditions. A review of the literature was conducted to assess the current state of knowledge regarding the effects of creatine supplementation on rehabilitation from immobilization and injury, neurodegenerative diseases, cardiopulmonary disease, and other muscular disorders. Several of the findings are encouraging, showcasing creatine’s potential efficacy as a supplemental agent via preservation of muscle mass, strength, and physical function; however, the results are not consistent. For multiple diseases, only a few creatine studies with small sample sizes have been published, making it difficult to draw definitive conclusions. Rationale for discordant findings is further complicated by differences in disease pathologies, intervention protocols, creatine dosing and duration, and patient population. While creatine supplementation demonstrates promise as a therapeutic aid, more research is needed to fill gaps in knowledge within medical rehabilitation.
The effect of a pre-workout supplement on anaerobic power output and muscular fatigue was examined. 18 participants took part in this double-blinded crossover study, reporting for testing on 3 occasions. Participants completed a 6×6 second repeated sprint test, with 20s recovery between sprints. Anaerobic power output was recorded as the highest power achieved during sprint test. Muscular fatigue was reported as a fatigue index across the six sprints ((maximum power - minimum power) ÷ total sprint time). During a baseline visit, participants consumed 250ml of water 30 minutes prior to testing, whilst in subsequent visits a taste-matched placebo (250ml water mixed with sugar-free juice) or a pre-workout supplement (250ml water mixed with one serving of 'THE PRE' Anaerobic power output increased following pre-workout ingestion (pre-workout supplement, 885.8 ± 216.9W; Placebo, 853.6 ± 206.5W; Baseline, 839.3 ± 192.6W). Baseline vs pre-workout supplement (p = 0.01, g = 0.30); Placebo vs pre-workout supplement (p = 0.01, g = 0.20); Baseline vs Placebo (p = 0.59 g = 0.09). Muscular fatigue was reduced following pre-workout ingestion (Baseline, 4.92 ± 1.83W.s; Placebo, 4.39 ± 1.93W.s; pre-workout supplement, 3.31 ± 1.34W.s). Baseline vs pre-workout supplement (p = < 0.01 g = 0.98); Placebo vs pre-workout supplement (p = 0.01, g = 0.63); Baseline vs Placebo (p = 0.20, g = 0.28). Acute ingestion of a pre-workout supplement significantly improves anaerobic power output and attenuates muscular fatigue during repeated sprint cycling.
This study was conducted to determine the optimum dietary glycine equivalent (Glyequi) level in low crude protein (LCP) diets of 181 g/kg containing varied concentrations of standardized ileal digestible (SID) methionine+cysteine (Met+Cys) for broiler chicks (1-21d old). A total of 1275, 1-d-old Cobb-Vantress® male broilers were distributed in a 5 × 3 factorial arrangement of completely randomized design of 15 treatments with five replicates of 17 birds each. Treatments consisted of 5 levels of dietary Glyequi (14.9, 16.4, 17.9, 19.4 and 20.6 g/kg) and three concentrations of SID Met+Cys (7.70, 9.0 and 10.3 g/kg). Interactions between Glyequi and SID Met+Cys levels were observed for feed:gain (P = 0.055) and breast meat yield (BMY) (P = 0.017). In 7.7 and 9.0 g SID Met+Cys/kg diets, optimal feed:gain and increased BMY were observed at the Glyequi level not lower than 17.9 g/kg. In 10.3 g SID Met+Cys/kg diet, a lower feed:gain was achieved at 19.4 g Glyequi/kg. Therefore, a minimum dietary level of 17.9 g Glyequi/kg is needed to increase growth of broilers fed diets containing 7.7 or 9.0 g/kg SID Met+Cys while 19.4 g/kg Glyequi is necessary in diets containing 10.3 g/kg SID Met+Cys for optimum growth.
Objective The objective of this scoping review was to examine the research question: In the adults with or without cardiometabolic risk, what is the availability of literature examining interventions to improve or maintain nutrition and physical activity related outcomes? Sub-topics included 1) behavior counseling or coaching from a dietitian/nutritionist or exercise practitioner; 2) mobile applications to improve nutrition and physical activity; and 3) nutritional ergogenic aids. Design This study is a scoping review. A literature search of the Medline Complete; CINAHL Complete; Cochrane Database of Systematic Reviews and other databases was conducted to identify articles published in the English language from January 2005 until May 2020. Data was synthesized using bubble charts and heat maps. Setting Out-patient, community and workplace. Participants Adults with or without cardiometabolic risk factors living in economically developed countries. Results Searches resulted in 19,474 unique articles and 170 articles were included in this scoping review, including one guideline, 30 systematic reviews, 134 RCTs and five non-randomized trials. Mobile applications (n=37) as well as ergogenic aids (n=87) have been addressed in several recent studies, including systematic reviews. While primary research has examined the effect of individual-level nutrition and physical activity counseling or coaching from a dietitian/nutritionist and/or exercise practitioner (n=48), interventions provided by these practitioners have not been recently synthesized in systematic reviews. Conclusion Systematic reviews of behavior counseling or coaching provided by a dietitian/nutritionist and/or exercise practitioner are needed and can inform practice for practitioners working with individuals who are healthy or have cardiometabolic risk.
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Creatine is a broadly used dietary supplement that has been extensively studied for its benefit on the musculoskeletal system. Yet, there is limited knowledge regarding the metabolic regulation of creatine in cells beyond the muscle. New insights concerning various regulatory functions for creatine in other physiological systems are developing. Here, we highlight the latest advances in understanding creatine regulation of T cell antitumor immunity, a topic that has previously gained little attention in the creatine research field. Creatine has been identified as an important metabolic regulator conserving bioenergy to power CD8 T cell antitumor reactivity in a tumor microenvironment; creatine supplementation has been shown to enhance antitumor T cell immunity in multiple preclinical mouse tumor models and, importantly, to synergize with other cancer immunotherapy modalities, such as the PD-1/PD-L1 blockade therapy, to improve antitumor efficacy. The potential application of creatine supplementation for cancer immunotherapy and the relevant considerations are discussed.
Purpose: Our goal was to determine the effects resistance training on circulating IGF-I and on two of its major binding proteins, IGFBP-1 and IGFBP-3. Additional goals were to compare the time course of hormonal changes with the time course of strength changes and to determine the effect of training volume on the extent of hormonal changes, Methods: Thirty-one men and women (mean age = 37 +/- 7 yr) completed a 25-wk, 3 d . wk(-1) program in which they performed single-set resistance training (I-SET, N = 11), multiple-set resistance training (3-SET, N = 11), or no exercise (Control, N = 9). Before training, and after 13 and 25 wk of training, blood hormones were analyzed and strength was assessed as the sum of one-repetition maximum (I-RM) far leg extension and chest press exercises. Results: During the first 13 wk of resistance training, circulating IGF-I increased by approximately 20% in both the I-SET and 3-SET groups (P = 0.041). No further increases occurred between 13 and 25 wk. In the 3-SET group, IGFBP-3 decreased 20% between 13 and 25 wk (P = 0.008). Training did not alter IGFBP-1. Increases in 1-RM strength occurred mainly during the first 13 wk of training and were significantly higher with 3-SET training compared to 1-SET. Conclusions: These findings indicate that increased circulating IGF-I may, at least in part, mediate increases in strength that result from resistance training.
Purpose: The purpose of this study was to examine the effect of creatine supplementation in conjunction with resistance training on physiological adaptations including muscle fiber hypertrophy and muscle creatine accumulation. Methods: Nineteen healthy resistance-trained men were matched and then randomly assigned in a double-blind fashion to either a creatine (N = 10) or placebo (N = 9) group. Periodized heavy resistance training was performed for 12 wk. Creatine or placebo capsules were consumed (25 g x d(-1)) for 1 wk followed by a maintenance dose (5 g x d(-1)) for the remainder of the training. Results: After 12 wk, significant (P < or = 0.05) increases in body mass and fat-free mass were greater in creatine (6.3% and 6.3%, respectively) than placebo (3.6% and 3.1%, respectively) subjects. After 12 wk, increases in bench press and squat were greater in creatine (24% and 32%, respectively) than placebo (16% and 24%, respectively) subjects. Compared with placebo subjects, creatine subjects demonstrated significantly greater increases in Type I (35% vs 11%), IIA (36% vs 15%), and IIAB (35% vs 6%) muscle fiber cross-sectional areas. Muscle total creatine concentrations were unchanged in placebo subjects. Muscle creatine was significantly elevated after 1 wk in creatine subjects (22%), and values remained significantly greater than placebo subjects after 12 wk. Average volume lifted in the bench press during training was significantly greater in creatine subjects during weeks 5-8. No negative side effects to the supplementation were reported. Conclusion: Creatine supplementation enhanced fat-free mass, physical performance, and muscle morphology in response to heavy resistance training, presumably mediated via higher quality training sessions.
Purpose: To study the effect of creatine (Cr) supplementation combined with resistance training on muscular performance and body composition in older men. Methods: Thirty men were randomized to receive creatine supplementation (CRE, N = 16, age = 70.4 +/- 1.6 yr) or placebo (PLA, N = 14, age = 71.1 +/- 1.8 yr), using a double blind procedure. Cr supplementation consisted of 0.3-g body weight for the first 5 d (loading phase) and 0.07-g body weight thereafter. Both groups participated in resistance training (36 sessions, 3 times per week, 3 sets of 10 repetitions, 12 exercises). Muscular strength was assessed by 1-repetition maximum (1-RM) for leg press (LP), knee extension (KE), and bench press (BP). Muscular endurance was assessed by the maximum number of repetitions over 3 sets (separated by 1-min rest intervals) at an intensity corresponding to 70% baseline 1-RM for BP and 80% baseline 1-RM for the KE and LP. Average power (AP) was assessed using a Biodex isokinetic knee extension/flexion exercise (3 sets of 10 repetitions at 60 degrees.s(-1) separated by 1-min rest). Lean tissue (LTM) and fat mass were assessed using dual energy x-ray absorptiometry. Results: Compared with PLA, the CRE group had significantly greater increases in LTM (CRE, +3.3 kg; PLA, +1.3 kg), LP 1-RM (CRE, +50.1 kg; PLA +31.3 kg), KE 1-RM (CRE, +14.9 kg; PLA, +10.7 kg), LP endurance (CRE, +47 reps; PLA, +32 reps), KE endurance (CRE, +21 reps; PLA +14 reps), and AP (CRE, +26.7 W; PLA, +18 W). Changes in fat mass, fat percentage, BP 1-RM, and BP endurance were similar between groups. Conclusion: Creatine supplementation, when combined with resistance training, increases lean tissue mass and improves leg strength, endurance, and average power in men of mean age 70 yr.
The study of the underlying mechanisms by which cells respond to mechanical stimuli, i.e. the link between the mechanical stimulus and gene expression, represents a new and important area in the morphological sciences. Several cell types (‘mechanocytes’), e.g. osteoblasts and fibroblasts as well as smooth, cardiac and skeletal muscle cells are activated by mechanical strain and there is now mounting evidence that this involves the cytoskeleton. Muscle offers one of the best opportunities for studying this type of mechanotransduction as the mechanical activity generated by and imposed upon muscle tissue can be accurately controlled and measured in both in vitro and in vivo systems. Muscle is highly responsive to changes in functional demands. Overload leads to hypertrophy, whilst decreased load force generation and immobilisation with the muscle in the shortened position leads to atrophy. For instance it has been shown that stretch is an important mechanical signal for the production of more actin and myosin filaments and the addition of new sarcomeres in series and in parallel. This is preceded by upregulation of transcription of the appropriate genes some of which such as the myosin isoforms markedly change the muscle phenotype. Indeed, the switch in the expression induced by mechanical activity of myosin heavy chain genes which encode different molecular motors is a means via which the tissue adapts to a given type of physical activity. As far as increase in mass is concerned, our group have cloned the cDNA of a splice variant of IGF that is produced by active muscle that appears to be the factor that controls local tissue repair, maintenance and remodelling. From its sequence it can be seen that it is derived from the IGF gene by alternative splicing but it has different exons to the liver isoforms. It has a 52 base insert in the E domain which alters the reading frame of the 3′ end. Therefore, this splice variant of IGF-1 is likely to bind to a different binding protein which exists in the interstitial tissue spaces of muscle, neuronal tissue and bone. This would be expected to localise its action as it would be unstable in the unbound form which is important as its production would not disturb the glucose homeostasis unduly. This new growth factor has been called mechano growth factor (MGF) to distinguish it from the liver IGFs which have a systemic mode of action. Although the liver is usually thought of as the source of circulating IGF, it has recently been shown that during exercise skeletal muscle not only produces much of the circulating IGF but active musculature also utilises most of the IGF produced. We have cloned both an autocrine and endocrine IGF-1, both of which are upregulated in cardiac as well as skeletal muscle when subjected to overload. It has been shown that, in contrast to normal muscle, MGF is not detectable in dystrophic mdx muscles even when subjected to stretch and stretch combined with electrical stimulation. This is true for muscular dystrophies that are due to the lack of dystrophin (X-linked) and due to a laminin deficiency (autosomal), thus indicating that the dystrophin cytoskeletal complex may be involved in the mechanotransduction mechanism. When this complex is defective the necessary systemic as well as autocrine IGF-1 growth factors required for local repair are not produced and the ensuing cell death results in progressive loss of muscle mass. The discovery of the locally produced IGF-1 appears to provide the link between the mechanical stimulus and the activation of gene expression.
1. The present study was undertaken to test whether creatine given as a supplement to normal subjects was absorbed, and if continued resulted in an increase in the total creatine pool in muscle. An additional effect of exercise upon uptake into muscle was also investigated. 2. Low doses (1 g of creatine monohydrate or less in water) produced only a modest rise in the plasma creatine concentration, whereas 5 g resulted in a mean peak after 1 h of 795 (sd 104) μmol/l in three subjects weighing 76–87 kg. Repeated dosing with 5 g every 2 h sustained the plasma concentration at around 1000 μmol/l. A single 5 g dose corresponds to the creatine content of 1.1 kg of fresh, uncooked steak. 3. Supplementation with 5 g of creatine monohydrate, four or six times a day for 2 or more days resulted in a significant increase in the total creatine content of the quadriceps femoris muscle measured in 17 subjects. This was greatest in subjects with a low initial total creatine content and the effect was to raise the content in these subjects closer to the upper limit of the normal range. In some the increase was as much as 50%. 4. Uptake into muscle was greatest during the first 2 days of supplementation accounting for 32% of the dose administered in three subjects receiving 6 × 5 g of creatine monohydrate/day. In these subjects renal excretion was 40, 61 and 68% of the creatine dose over the first 3 days. Approximately 20% or more of the creatine taken up was measured as phosphocreatine. No changes were apparent in the muscle ATP content. 5. No side effects of creatine supplementation were noted. 6. One hour of hard exercise per day using one leg augmented the increase in the total creatine content of the exercised leg, but had no effect in the collateral. In these subjects the mean total creatine content increased from 118.1 (sd 3.0) mmol/kg dry muscle before supplementation to 148.5 (sd 5.2) in the control leg, and to 162.2 (sd 12.5) in the exercised leg. Supplementation and exercise resulted in a total creatine content in one subject of 182.8 mmol/kg dry muscle, of which 112.0 mmol/kg dry muscle was in the form of phosphocreatine.
The poor growth associated with protein-calorie malnutrition occurs despite circulating growth hormone levels that are normal or elevated and is thought to be mediated partly by blunted generation of insulinlike growth factor I (IGF-I) in the liver. To explore underlying mechanisms, we asked whether altered availability of amino acids could regulate hepatic IGF-I release independent of the contributions of regulatory hormones. Normal rat hepatocytes were isolated by collagenase digestion and maintained in serum-free medium with fixed concentrations of insulin and dexamethasone. Levels of immunoassayable albumin and IGF-I accumulation in daily changes of medium were sustained for 3-5 days, and all studies were performed within this period. Cellular viability and content of DNA were unaffected by deprivation of the essential amino acids lysine or tryptophan and the nonessential amino acids cysteine and/or cystine. However, deletion of tryptophan or lysine from the culture medium led to 63 and 76% declines in IGF-I release, respectively (both P less than 0.001 vs. complete medium), although omission of cysteine or cysteine plus cystine produced no significant change. Over 5 days of culture, release of albumin was maintained in complete medium, but omission of tryptophan depressed albumin release over days 2-5 (P less than 0.001). In complete medium, IGF-I release rose for 3 days and then declined. In tryptophan-deficient medium, IGF-I levels were comparable to control values after 24 h but did not rise at 48 h and then fell rapidly after 72 h in culture, with values significantly below levels in complete medium (all P less than 0.005).(ABSTRACT TRUNCATED AT 250 WORDS)
Skeletal muscle satellite cells were cultured from mature rats and were treated in vitro with various combinations of transforming growth factor (TGF)-beta, fibroblast growth factor (FGF), and insulin-like growth factor I (IGF-I). In serum-free defined medium the following observations were made: TGF-beta depressed proliferation and inhibited differentiation; FGF stimulated proliferation and depressed differentiation; IGF-I stimulated proliferation to a small degree but demonstrated a more pronounced stimulation of differentiation. In evaluating combinations of these three factors, the differentiation inhibiting effect of TGF-beta could not be counteracted by any combination of IGF-I or FGF. The proliferation-depressing activity of TGF-beta, however, could not inhibit the mitogenic activity of FGF. Maximum stimulation of proliferation was observed in the presence of both FGF and IGF-I. The highest percentage fusion was also observed under these conditions, but differentiation with minimal proliferation resulted from treatment with IGF-I, alone. By altering the concentrations of TGF-beta, FGF, and IGF-I, satellite cells can be induced to proliferate, differentiate, or to remain quiescent.
Plasma somatomedin-C (Sm-C)/insulin-like growth factor I (IGF-I) concentrations have been shown to reflect changes in nitrogen balance induced by manipulation of nutrient intake. To assess the Sm-C/IGF-I response to refeeding a protein restricted diet in which the nitrogen source was supplemented with essential amino acids, six normal adults were fasted for five days, then refed for nine days diets consisting of 35 kcals/kg and 0.48 g protein/kg body weight. In one diet, 80% of the nitrogen was supplied as essential amino acids, and in the other, 80% was supplied as nonessential amino acids. Following the first fast/refeed cycle, a control diet was eaten for two weeks before the fast was repeated and the other test diet was ingested. The refeeding diets were given a random order. Plasma Sm-C/IGF-I fell from a pre-fast mean of 1.64 +/- 0.24 U/mL (mean +/- 1 SEM) to 0.67 +/- 0.18 (P less than 0.001) following fasting, and rose to 1.41 +/- 0.19 U/mL (P less than 0.001) following ingestion of the diet with supplemental essential amino acids. In contrast, when the same subjects were refed a diet in which 80% of the nitrogen was in the form of nonessential amino acids, the plasma Sm-C/IGF-I concentrations rose from 0.74 +/- 0.17 to 1.15 +/- 0.15 U/mL (P less than 0.01). This increase was significantly less than that observed after ingestion of the essential amino acid supplemented diet (0.74 +/- 0.10 U/mL v 0.40 +/- 0.11 U/mL; P less than 0.02).(ABSTRACT TRUNCATED AT 250 WORDS)
Several lines of evidence indicate that in the human, insulin-like growth factor-I (IGF-I) is nutritionally regulated. Both energy and protein availability are required for maintenance of IGF-I. Measurements of serum IGF-I constitute a sensitive means for monitoring the response of acutely ill patients to nutritional intervention. Serum IGF-I may also serve as a marker for evaluation of nutritional status. Our findings and those of others in animal models suggest that nutrients influence synthesis and action of IGF-I and its binding proteins (IGFBPs) at multiple levels. In fasting, liver growth hormone (GH) binding is decreased, providing one explanation for decreased IGF-I. In protein restriction, GH receptors are maintained, but there is evidence for a postreceptor defects. The latter results from pretranslational and translational defects. Amino acid availability to the hepatocytes is essential for IGF-I gene expression. Protein malnutrition not only decreases IGF-I production rate, but also enhances its serum clearance and degradation. Finally, there is evidence for selective organ resistance to the growth-promoting effects of IGF-I in protein-restricted rats.
Increased load on a muscle (synergistic overload or stretch) results in muscle hypertrophy. The expression of insulin-like growth factor I (IGF-I) mRNA in rat skeletal muscle is increased during synergistic overload-induced hypertrophy. Although it has also been established that fasting animals lose muscle protein, it has been shown that compensatory muscle hypertrophy occurs in adult fasting rats that are undergoing a net loss of body weight. The purpose of this investigation was to determine whether a relationship exists between IGF-I mRNA levels and muscle growth and regression. This was accomplished by examining whether IGF-I mRNA levels were altered during muscle hypertrophy after stretch and regression and the effect of fasting on IGF-I mRNA levels during stretch-induced hypertrophy. Patagialis (PAT) muscle weights increased 13 and 44% at 2 and 11 days of stretch, respectively. However, after removal of the stretch stimulus on day 11, PAT weights began to decrease, reaching control weights by 18 days. During the first time point (2 days), PAT muscle IGF-I mRNA remained constant. IGF-I mRNA abundance was threefold greater than contralateral control levels by 11 days of stretch. IGF-I mRNA levels decreased but remained significantly above control levels throughout the regression of hypertrophy (13, 18, and 25 days). Fasting did not alter PAT muscle response to stretch. After 11 days of stretch, PAT muscle weight increased 60% compared with contralateral control muscles and IGF-I mRNA levels increased three-fold. This study supports a role for IGF-I in muscle hypertrophy but not muscle atrophy.