Timing of Creatine Supplementation and Resistance Training: A Brief Review

Abstract

The combination of creatine monohydrate supplementation and resistance training increases muscle mass and strength. In this brief narrative review, we propose that the timing of creatine supplementation in relation to resistance training may be an important factor to optimize hypertrophy and strength gains. Meta-analyses indicated that creatine supplementation immediately after resistance training was superior for increasing muscle mass compared to creatine supplementation immediately before resistance training (3 studies, standard mean difference 0.52, 95% CI 0.03-1.00, p = 0.04); however, this did not translate into greater muscular strength (p > 0.05). Further research is needed to confirm these limited findings and to determine the mechanisms explaining the potential greater increase in muscle mass from post-exercise creatine.

Full text

2018, Volume 1 (Issue 5) OPEN ACCESS
Journal(of(Exercise(and(Nutrition(
!
Timing of Creatine Supplementation
and Resistance Training: A Brief
Review
Short Review,
Scott C. Forbes1, Darren G. Candow2
1Department of Physical Education, Brandon University, Brandon, Manitoba, Canada
2Faculty of Kinesiology & Health Studies, University of Regina, Regina, Saskatchewan, Canada
Abstract
The combination of creatine monohydrate supplementation and
resistance training increases muscle mass and strength. In this
brief narrative review, we propose that the timing of creatine
supplementation in relation to resistance training may be an
important factor to optimize hypertrophy and strength gains.
Meta-analyses indicated that creatine supplementation
immediately after resistance training was superior for increasing
muscle mass compared to creatine supplementation immediately
before resistance training (3 studies, standard mean difference
0.52, 95% CI 0.03 – 1.00, p = 0.04); however, this did not translate
into greater muscular strength (p > 0.05). Further research is
needed to confirm these limited findings and to determine the
mechanisms explaining the potential greater increase in muscle
mass from post-exercise creatine.!!
!
Key Words
: Supplements, Strength, Hypertrophy.
Corresponding author: Darren G. Candow, Darren.Candow@uregina.ca
Introduction
It is well established that resistance training increases muscle mass and strength over
time, possibly by increasing activation of the mammalian target of rapamycin
(mTOR) muscle protein synthetic pathway 1, satellite cell activation and proliferation
2, anabolic hormone production 3, and decreasing catabolic cytokine activity 4. The
combination of creatine supplementation and resistance training leads to greater
gains in muscle mass and strength compared to resistance training or creatine alone5.
Recent evidence suggests that the timing of ingestion may be an important factor
contributing to the greater gains in muscle mass and strength from creatine
supplementation 6,7,8,9. Specifically, (1) creatine supplementation immediately before
and immediately after resistance training sessions increases upper-and lower-body
strength more than placebo and resistance training 7, (2) post-exercise creatine
increases muscle mass compared to placebo 7, (3) pre-exercise and post-exercise
creatine supplementation increases muscle mass and strength compared to
consuming creatine in the hours (> 5) leading up to and following resistance training
9, and (4) post-exercise creatine increases muscle mass (trend) compared to pre-
exercise creatine 6.
The purpose of this review is to briefly outline the potential beneficial effects of
creatine supplementation and to evaluate the emerging evidence suggesting that the
timing of creatine ingestion may be an important factor to consider when designing

2018, Volume 1 (Issue 5) OPEN ACCESS
Journal(of(Exercise(and(Nutrition(
an effective creatine supplementation protocol. We performed meta-analyses to
assess the effect of creatine timing on muscle hypertrophy and strength.
Methods
We searched PubMed and SPORTDiscus databases using the key words “creatine
supplementation”, “timing”, and a variety of synonyms for “resistance training” (e.g.,
“strength training”) on August 21, 2018. Our inclusion criteria included i) a direct
evaluation of creatine timing ii) inclusion of a resistance training program, with
measures of lean tissue mass and/or strength, and iii) utilized a randomized, repeated
measures design. Mean changes and the standard deviation of mean changes were
extracted. If mean changes were not extractable, the authors were contacted to obtain
the raw data for calculations. The homogeneity of the effect size among studies was
assessed using a X2 test. Since the homogeneity was low, we used fixed effects models
to calculate the pooled mean net change of lean tissue mass and strength comparing
creatine supplementation provided before versus after resistance training. Mean
changes and standard deviations for mean changes for individual studies and the
pooled effects and their 95% confidence intervals were calculated and Forest plots
were generated using Review Manage 5.3 software. Meta-analyses for lean tissue mass
and maximum strength were only performed when 3 or more studies utilizing similar
interventions and outcomes were available. Significance was set at p ≤ 0.05.
Creatine Supplementation
Creatine or methyl-guanidino acetic acid, is a naturally occurring nitrogen-containing
compound found primarily in red meat and seafood 10. Creatine excretion typically
occurs at a rate of ~2 g·d-1 10. Creatine can be replaced via endogenous synthesis (1-
2 g·d-1) in the kidneys, liver, and pancreas or exogenously through dietary intake,
typically ~1-3 g·d-1 10,11. Ninety-five percent of creatine is stored in skeletal muscle,
of which 60-70% is phosphorylated (i.e. phosphocreatine; 12) and the remainder is
free creatine. Phosphocreatine rapidly re-synthesizes adenosine diphosphate (ADP)
to maintain adenosine triphosphate (ATP) during high intensity exercise 12. Elevated
phosphocreatine stores (via exogenous creatine) may increase exercise training
intensity and capacity leading to greater muscle accretion and strength over time
[reviewed in 13]. There are several purported mechanisms which may explain the
greater increase in muscle mass and strength observed from creatine
supplementation. Creatine supplementation elevates skeletal phosphocreatine and
total creatine stores 14, which increases phosphocreatine re-synthesis 15 and exercise
fatigue resistance 16. Creatine influences myocellular water retention due to increased
intracellular osmolarity and increases muscle glycogen storage 17. Muscle cell swelling
may stimulate genes (i.e., myosin heavy chain I and IIA) regulating various anabolic
signaling pathways 18. Furthermore, creatine increases satellite cell differentiation 19,
activity 20, and content 21; myogenic transcription factor activity 22, hormonal
secretions (e.g. IGF-1; 23), muscle protein kinetics 24, and decreases inflammation 25.
Creatine Timing
The timing of ingestion may be an important factor contributing to the greater gains
in muscle mass and strength from creatine supplementation (Table 1). Creatine
immediately before (~ 5 minutes) or immediately after (~ 5 minutes) resistance
training sessions for 8 months increased leg press strength (creatine before = 27%;
creatine after = 28%) and chest press strength (creatine before = 30%; creatine after
= 36%) compared to placebo (leg press: 4%; chest press: 4%; p < 0.05) in healthy
older adults 7. Interestingly, post-exercise creatine increased whole-body lean tissue
mass (6.4%) compared to placebo (1.2%; p<0.05), while there was no difference
between pre-exercise creatine and placebo 7. Furthermore, consuming creatine
immediately before (0.05 g·kg-1 of body weight) and immediately after (0.05 g·kg-1 of
body weight) resistance training sessions (3 days/week, 10 weeks) resulted in greater
muscle accretion (2.0 ± 0.3 cm) compared to placebo (0.8 ± 0.3 cm) in healthy older
males (59-77 years; 8). These results support previous findings of a significant

2018, Volume 1 (Issue 5) OPEN ACCESS
Journal(of(Exercise(and(Nutrition(
increase in lean tissue mass (6%), type II muscle fiber area (29%), and insulin growth-
factor I (78%) in adults (19-55 years) who ingested creatine before (0.03 g·kg-1 of
body weight) and after (0.03 g·kg-1 of body weight) resistance training for 8 weeks 23,
26. In addition, a creatine supplement (1 g·kg-1: supplement per 100 g = 40 g protein,
43 g glucose, 7 g creatine and <0.5 g fat) immediately before and immediately after
resistance training sessions for 10 weeks significantly increased intramuscular
creatine content, lean tissue mass, muscle cross sectional-area of type II fibers and
maximal strength in resistance trained body-builders compared to consuming
creatine > 5 hours before and after exercise (i.e., before breakfast and immediately
prior to sleep; 9).
In directly comparing pre-exercise creatine to post-exercise creatine, Antonio and
Ciccone 6 found a greater muscle benefit (i.e., fat-free mass and strength) from post-
exercise creatine (fat-free mass = 3% gain; 1 repetition maximum bench press =
7.5%) in young recreational male bodybuilders compared to pre-exercise creatine
supplementation (fat-free mass = 1.3% gain; 1 repetition maximum bench press =
6.8%). However, Candow et al. 7,8 found no statistical difference between pre-
exercise creatine and post-exercise creatine after either 12 weeks 8 or 8 months 7 of
resistance training in older adults. Results across studies suggest that pre-exercise and
post-exercise creatine supplementation has beneficial effects on muscle mass and
strength with slightly greater gains from post-exercise creatine.
Table 1. Studies investigation the effect of creatine ingestion before and after
resistance training.
FIRST
AUTHOR ,
YEAR
STUDY
POPULATION
INTERVENTION
DURATION
OUTCOME
MEASURES
ANTONIO
AND
CICCONE,
2013
N=19 Recreational Male
Bodybuilders; Age 23.1
± 2.9 yrs; Height: 166.0
± 23.2 cm; Weight: 80.18
± 10.43 kg
Randomly assigned:
CR (5g) PRE or CR
(5g) POST RT
sessions and anytime
on days off; 5 RT
sessions/wk
4 wks
↔FFM, FM, BM,
Bench Press 1RM
between groups;
Magnitude based
inference CR
POST possibly
more beneficial for
FFM, FM, 1RM BP
CANDOW
ET AL., 2014
N=22 (9 men; 13
women) non-RT healthy
older adults; Age 50-64
yrs
Randomly assigned:
CR before (n=11) (CR
0.1g/kg before +
0.1g/kg placebo after)
or CR after (n=11)
(0.1g/kg placebo
before + CR 0.1g/kg
after); RT 3d/wk
12 wks
↔ FFM, limb
muscle thickness,
BP and LP 1RM
and no difference
in protein
catabolism (but all
these parameters
were improved by
RT). No changes in
Kidney function
over time.
CANDOW
ET AL., 2015
N= 39 (22 women, 17
men); non-RT healthy
older adults, Age 50-71
yrs
Randomly assigned:
CR before (CR
0.1g/kg before +
0.1g/kg placebo after)
or CR after (0.1g/kg
placebo before + CR
0.1g/kg after) or
Placebo control; RT
3d/wk
8 months
CR After ↑ LBM
compared to
Placebo. CR Before
↔ LBM compared
to Placebo. ↔
Between CR
groups for 1RM
bench press, 1RM
leg press, LBM. CR
groups ↑ strength
compared to
Placebo.
Abbreviations: CR = creatine; RT = resistance training; FFM = fat free mass; FM = Fat
mass; BM = body mass; RM = repetition maximum; BP = bench press; LP = leg press;
LBM = lean body mass

2018, Volume 1 (Issue 5) OPEN ACCESS
Journal(of(Exercise(and(Nutrition(
Meta-Analysis Results
Mean changes and standard deviations for mean changes for individual studies and
pooled effects and their 95% confidence intervals are presented along with Forest
plots in Figures 1 and 2. When pooling the limited data, lean tissue mass (p = 0.04)
increased to a greater extent from post-exercise creatine compared to pre-exercise
creatine. These results provide preliminary evidence that creatine timing may be an
important factor to consider in designing a creatine supplementation protocol.
However, there were no differences between pre-exercise and post-exercise creatine
on maximal strength (Figure 2). It is important to note that only 3 trials were included
in the meta-analyses, which limits the statistical power to detect differences. Despite
this limitation, post-exercise creatine supplementation was statistically significant for
increasing lean tissue mass. However, additional research is needed to determine with
greater certainty whether post-exercise creatine is superior to pre-exercise creatine
for improving lean tissue mass.
Figure 1: Forest plot for absolute change in lean tissue mass. Comparing strategic
ingestion of creatine before versus after resistance training.
Figure 2: Forest plot for absolute change in 1 repetition maximum upper body
strength. Comparing strategic ingestion of creatine before versus after resistance
training.
Potential Mechanisms of Creatine Timing
The greater gains in muscle mass and strength observed from pre- and post-exercise
creatine may be due to an upregulation of the kinetics involved in creatine transport
27, by an increase in Na+-K+ pump function during exercise 27 and by an increase in
blood flow and delivery of creatine to exercising muscles 28. Tipton et al. 29 previously
showed that pre-exercise and post-exercise ingestion of an essential amino acid-
carbohydrate solution significantly increased net muscle protein synthesis in young
adults. The acute lower-body exercise session increased leg blood flow by 201-324%.
The authors concluded that providing amino acids at a time when blood flow is
elevated (i.e. during resistance training) maximizes delivery to muscle 29.
Conclusion
Based on the limited studies performed thus far, it appears that creatine
supplementation before and after resistance training sessions increases lean tissue
mass and strength. Our meta-analysis suggests that post-exercise creatine ingestion
provides greater muscle benefits than pre-exercise creatine. Further research is
warranted to confirm these findings and to elucidate the mechanisms explaining the
greater increase in muscle mass from post-exercise creatine.
Media-Friendly Summary

2018, Volume 1 (Issue 5) OPEN ACCESS
Journal(of(Exercise(and(Nutrition(
Creatine can enhance resistance training gains in muscle mass and strength. Presently,
there is limited data on when is the best time to take creatine in relation to training.
Based on the available evidence, it is recommended to take creatine after training to
maximize gains in muscle mass and strength; however, these findings are based on a
small sample size and precise mechanisms explaining these findings remain to be
determined.
Acknowledgements
The authors have no conflicts of interest.
Reference
1. Fujita, S, Dreyer, HC, Drummond, MJ, Glynn, EL, Cadenas, JG,
Yoshizawa, F, Volpi, E, and Rasmussen, BB. Nutrient signaling in the
regulation of human muscle protein synthesis. J Physiol, 2007;582(Pt2)(813-
823)
2. Verdijk, LB, Gleeson, BG, Jonkers, RA, Meijer, K, Savelberg, HH,
Dendale, P, and van Loon, LJ. Skeletal muscle hypertrophy following
resistance training is accompanied by a fiber type-specific increase in
satellite cell content in elderly men. J Geron. Series A Bio Sci Med Sci,
2009;64(332-339)
3. Smilios, I, Pilianidis, T, Karamouzis, M, Parlavantzas, A, and Tokmakidis,
SP. Hormonal responses after a strength endurance resistance exercise
protocol in young and elderly males. Int J Sports Med, 2007;28(401-406)
4. Cornish, SM and Chilibeck, PD. Alpha-linolenic acid supplementation and
resistance training in older adults. App Physiol Nutr Metab, 2009;34(49-59)
5. Chilibeck, PD., Kaviani, M., Candow, DG., and Zello GA. Effect of
creatine supplementation during resistance training on lean tissue mass and
muscular strength in older adults: a meta-analysis. J Sports Med, 2017;8(213-
226)
6. Antonio, J and Ciccone, V. The effects of pre versus post workout
supplementation of creatine monohydrate on body composition and
strength. J Int Soc Sports Nutr, 2013;10(36)
7. Candow, DG, Vogt, E, Johannsmeyer, S, Forbes, SC, and Farthing, JP.
Strategic creatine supplementation and resistance training in healthy older
adults. Appl Physiol Nutr Metab, 2015;40(689-694)
8. Candow, DG, Zello, GA, Ling, B, Farthing, JP, Chilibeck, PD, McLeod, K,
Harris, J, and Johnson, S. Comparison of creatine supplementation before
versus after supervised resistance training in healthy older adults. Res Sports
Med, 2014;22(61-74)
9. Cribb, PJ and Hayes, A. Effects of supplement timing and resistance
exercise on skeletal muscle hypertrophy. Med Sci Sports Exerc, 2006;38(1918-
1925)
10. Wyss, M and Kaddurah-Daouk, R. Creatine and creatinine metabolism.
Physiol Rev 2000;80(1107-1213)
11. Greenhaff, PL. Creatine and its application as an ergogenic aid. Int J Sport
Nutr, 1995;5 Suppl: S100-110.
12. Casey, A and Greenhaff, PL. Does dietary creatine supplementation play a
role in skeletal muscle metabolism and performance? Am J of Clin Nutr,
2000;72(607S-617S)
13. Kreider, RB, Kalman, DS, Antonio, J, Ziegenfuss, TN., Wildman, R,
Collins, R, Candow, DG, Kleiner, SM, Almada, AL, and Lopez, HL.
International Society of Sports Nutrition position stand: safety and efficacy
of creatine supplementation in exercise, sport, and medicine. J Int Soc Sports
Nutr, 2017;14(18)
14. Syrotuik, DG and Bell, GJ. Acute creatine monohydrate supplementation:
a descriptive physiological profile of responders vs. nonresponders. J
Strength Cond Res, 2004;18(610-617)

2018, Volume 1 (Issue 5) OPEN ACCESS
Journal(of(Exercise(and(Nutrition(
15. Greenhaff, PL, Bodin, K, Soderlund, K, and Hultman, E. Effect of oral
creatine supplementation on skeletal muscle phosphocreatine resynthesis.
Am J Physiol, 1994;266(E725-730)
16. Sahlin, K, Tonkonogi, M, and Soderlund, K. Energy supply and muscle
fatigue in humans. Acta Physiol Scand, 1998;162(261-266)
17. van Loon, LJ, Murphy, R, Oosterlaar, AM, Cameron-Smith, D, Hargreaves,
M, Wagenmakers, AJ, and Snow, R. Creatine supplementation increases
glycogen storage but not GLUT-4 expression in human skeletal muscle.
Clin Sci 2004;106(99-106)
18. Deldicque, L, Atherton, P, Patel, R, Theisen, D, Nielens, H, Rennie, MJ,
and Francaux, M. Effects of resistance exercise with and without creatine
supplementation on gene expression and cell signaling in human skeletal
muscle. J App Physiol, 2008;104(371-378)
19. Vierck, JL, Icenoggle, DL, Bucci, L, and Dodson, MV. The effects of
ergogenic compounds on myogenic satellite cells. Med Sci Sports Exerc,
2003;35(769-776)
20. Dangott, B, Schultz, E, and Mozdziak, PE. Dietary creatine monohydrate
supplementation increases satellite cell mitotic activity during
compensatory hypertrophy. Int J Sports Med, 2000;21(13-16)
21. Olsen, S, Aagaard, P, Kadi, F, Tufekovic, G, Verney, J, Olesen, JL, Suetta,
C, and Kjaer, M. Creatine supplementation augments the increase in
satellite cell and myonuclei number in human skeletal muscle induced by
strength training. J Physiol, 2006;573(525-534)
22. Willoughby, DS, and Rosene, JM. Effects of oral creatine and resistance
training on myogenic regulatory factor expression. Med Sci Sports Exerc,
2003;35(923-929)
23. Burke, DG, Candow, DG, Chilibeck, PD, MacNeil, LG, Roy, BD,
Tarnopolsky, MA, and Ziegenfuss, T. Effect of creatine supplementation
and resistance-exercise training on muscle insulin-like growth factor in
young adults. Int J Sports Nutr Exerc Metab, 2008;18(389-398)
24. Parise, G, Mihic, S, MacLennan, D, Yarasheski, KE, and Tarnopolsky, MA.
Effects of acute creatine monohydrate supplementation on leucine kinetics
and mixed-muscle protein synthesis. J App Physiol, 2001;91(1041-1047)
25. Bassit, RA, Curi, R. and Costa Rosa, LF. Creatine supplementation reduces
plasma levels of pro-inflammatory cytokines and PGE2 after a half-
ironman competition. Amino Acids, 2008;35(425-431)
26. Burke, DG, Chilibeck, PD, Parise, G, Candow, DG, Mahoney, D, and
Tarnopolsky, M. Effect of creatine and weight training on muscle creatine
and performance in vegetarians. Med Sci Sports Exerc, 2003;35(1946-1955)
27. Robinson, TM, Sewell, DA, Hultman, E, and Greenhaff, PL. Role of
submaximal exercise in promoting creatine and glycogen accumulation in
human skeletal muscle. J App Physiol, 1999;87(598-604)
28. Harris, RC, Soderlund, K, and Hultman, E. Elevation of creatine in resting
and exercised muscle of normal subjects by creatine supplementation. Clin
Sci, 1992;83(367-374)
29. Tipton, KD, Rasmussen, BB, Miller, SL, Wolf, SE, Owens-Stovall, SK,
Petrini, BE, and Wolfe, RR. Timing of amino acid-carbohydrate ingestion
alters anabolic response of muscle to resistance exercise. Am J Physiol. Endo
Metab, 2001;281(197-206)
Copyright, 2018. Published by Capstone Science Inc. under open access distribution rights. Articles are available for
download and proper distribution.