Strategic Ingestion of Creatine Supplementation

Creatine is a nitrogen-containing compound consumed in the diet primarily from red meat and seafood (i.e., 2-3 grams per day) or produced in the body from reactions involving the amino acids glycine, arginine, and methionine in the liver and kidney ³³. Typically, dietary creatine matches endogenous creatine degradation, resulting in the formation of creatinine ³⁰. Based on a 70 kg human with a total creatine pool of 120 grams, creatinine excretion typically amounts to 2 grams per day ^{26, 30}. Dietary creatine enters circulation and is transported to skeletal muscle, liver, kidney, and the brain ²¹. The majority of creatine is transported from areas of synthesis (i.e., liver, kidney) to areas of storage and utilisation (i.e. skeletal muscle) ²⁶. Skeletal muscle accounts for approximately 95% of all creatine stores in the body ²⁰. Skeletal muscle creatine content is dependent on muscle fiber composition 26. Type II muscle fibers have high levels of free creatine (Cr) and phosphocreatine (PCr). Intramuscular creatine stores range from 120-160 mmol/ kg dry muscle ¹² with approximately 60% being PCr ^{12, 22}. An increase in intramuscular creatine from creatine supplementation should theoretically increase PCr resynthesis during muscle contraction leading to greater muscle mass and strength.

Potential Mechanistic Actions of Creatine Supplementation

The potential mechanistic actions of creatine on skeletal muscle are multifactorial. Creatine increases intracellular osmolarity ³ which may in turn activate genes and signalling pathways ²⁷ involved in muscle protein synthesis. Creatine supplementation during resistance exercise training significantly increases the mRNA and protein expression of myogenic transcription factors ³² and mRNA expression of myosin heavy chain (MHC I and IIa) in young adults¹⁸ . Creatine supplementation increases satellite cell number and myonuclei concentration in muscle fibers following resistance exercise ²³ and the content of Akt/protein kinase B in humans ²⁷. Akt/Protein kinase B activates p70^s6k downstream in the mammalian target of rapamycin (mTOR) muscle protein synthetic pathway ¹⁹. Insulin-like growth factor 1 (IGF-1) stimulates the mTOR muscle protein synthetic pathway²⁸ and satellite cell proliferation and differentiation². Creatine supplementation (21 g·day-¹ for 5 days) augments IGF-1 mRNA in resting muscle and phosphorylation of eukaryotic initiation factor-4e binding protein-1 (4E-BP1) one day following an acute bout of resistance exercise in young adults ¹⁷. Over longer durations of training (i.e. 8 weeks), creatine supplementation increases intramuscular protein levels of IGF-1 7. Creatine may also have anti-catabolic properties. Creatine decreases urinary excretion of 3-methylhistidine, an indicator of muscle protein catabolism, in older men during resistance exercise training¹⁰ and whole body protein breakdown (e.g., plasma leucine rate of appearance) in younger men ²⁴.

Strategic creatine ingestion

Muscle hypertrophy following resistance training requires net synthesis of myofibrillar proteins and therefore, maximal stimulation of muscle protein synthesis is required for the development of muscle mass ⁹ . It is well established that the mechanical stimulus from resistance training results in increased protein catabolism and subsequent protein synthesis ²⁵. Although the machinery for stimulating the synthetic rate of muscle proteins is increased after exercise ³¹, it appears that this response may not be increased until some time after the resistance training session ²⁹. Recent evidence suggests that creatine ingestion, in close proximity to resistance training sessions (i.e., before and after exercise), may be more beneficial than ingesting creatine at other times of the day. For example, in the most recent study, creatine ingestion immediately before (0.1g∙kg^-1) and immediately after (0.1g∙kg^-1) resistance training sessions for 32 weeks in older adults increased lower and upper body strength compared to placebo ¹¹. While the mechanisms explaining the greater increase in maximal muscle strength from creatine remain to be elucidated, high-energy phosphate metabolism and actin-myosin cross-bridge cycling may be involved. Creatine is a component of phosphocreatine which rapidly rephosphorylates adenosine diphosphate to help maintain adenosine triphosphate during resistance training. Regarding actin-myosin cross bridge cycling, creatine may increase calcium re-uptake into the sarcoplasmic reticulum which would result in faster detachment of the actin-myosin cross-bridge and potentially augment force generating capacity ⁴. Interestingly, post-exercise creatine resulted in greater gains in lean tissue mass compared to placebo ¹¹. In comparing the effects of creatine (5 grams) immediately before and immediately after resistance training (20 sessions) in young males, Antonio and Ciccone ¹ found slightly greater increases in muscle mass and strength from post-exercise creatine ingestion. Potentially, the greater muscle benefits from post-exercise creatine may be due to an increase in skeletal muscle blood flow during resistance training which would result in greater creatine transport and accumulation in exercising muscles. With repeated training sessions, elevated intramuscular creatine stores may effectively influence genes, signalling pathways ²⁷, transcription factors ³², satellite cells ²³ and anabolic hormones (i.e. insulin-like growth factor 1; 7, 17) involved in skeletal muscle hypertrophy. Furthermore, creatine immediately before (0.05g•kg^-1) and immediately after (0.05g•kg^-1) resistance training sessions (3 days/week, 10 weeks) resulted in greater whole-body muscle hypertrophy (2.0 ± 0.3cm) compared to placebo (0.8 ± 0.3cm) and resistance training in healthy older males (59-77 years; 10). Older adults supplementing with creatine also had a reduction in urinary excretion of 3- methylhistidine, an indicator of muscle protein catabolism, by 40% compared to an increase of 29% for the placebo group; suggesting that creatine exhibits muscle anti-catabolic properties. These results support previous findings of a significant 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 (0.03g•kg^-1) and after (0.03g•kg^-1) resistance training (6 days/week, 8 weeks; 7). Interestingly, in comparing the effects of creatine ingestion before (0.5g•kg^-1) and after (0.5g•kg^-1) resistance training (10 weeks) to creatine ingestion in the morning and evening of training days, Cribb & Hayes ¹⁴ showed that creatine ingestion before and after exercise resulted in significantly greater intramuscular creatine content, lean tissue mass, and muscle cross sectional-area of type II fibers.
Results across studies suggest that the timing of creatine ingestion is important. Pre- and post-exercise creatine supplementation produce similar beneficial effects with slightly greater adaptations from post-exercise creatine. Independent of the timing of ingestion, creatine is superior to placebo for augmenting the physiological gains from resistance training in young and older adults.
The combination of creatine and whey protein may further enhance the physiological adaptations from resistance exercise. For example, healthy older males (n=10) who ingested creatine (0.1 g∙kg^-1) and whey protein (0.3 g∙kg^-1) during 10 weeks of supervised whole-body resistance training (3 sets of 10 repetitions to muscle fatigue, 3 days per week; exercises: leg press, chest press, lat pull-down, shoulder press, leg extension, leg curl, triceps extension, biceps curls, calf press) experienced a greater increase in lean tissue mass compared to older men who consumed creatine alone (n=12) or an iso-caloric carbohydrate placebo (n=13) ¹⁰. In younger men, the co-ingestion of creatine (0.1 g∙kg^-1) and whey protein (1.2 g∙kg^-1) during 6 weeks of heavy resistance training produced greater gains in lean tissue mass and bench press strength compared to men who consumed whey protein alone or placebo during training ⁸. Furthermore, trained bodybuilders who consumed creatine (0.1 g∙kg^-1) and whey protein (1.5 g∙kg^-1) during resistance exercise experienced greater gains in lean body mass, and maximum strength compared to bodybuilders who consumed protein or carbohydrate alone ^{14, 15}. Whey protein (a component of milk) has a high essential amino acid profile and is rapidly absorbed upon digestion ⁵ and increases the rates of muscle protein synthesis following resistance exercise ¹³. Therefore, the greater increase in muscle accretion from the co-ingestion of creatine and whey protein may be the result of a synergistic anabolic effect from these dietary compounds.

Practical Application and Take Home Points

1. Creatine increases muscle mass and muscle performance in young and older adults
2. A daily dosage of 8-10 grams appears optimal
3. Pre- and post-exercise creatine supplementation is important
4. Post-exercise creatine appears to be an optimal strategy
5. Combining creatine (8-10 grams) and whey protein (30-40grams) post-exercise is an effective strategy to maximise muscle mass and muscular performance.

Written by ACA Contributor Dr Darren Candow

Dr. Darren Candow, PhD, CSEP-CEP, is Professor and Associate Dean-Graduate Studies and Research in the Faculty of Kinesiology & Health Studies. Dr. Candow supervises the Aging Muscle and Bone Health Laboratory, and serves on the editorial board for the Journal of Aging and Physical Activity, Journal of the International Society of Sports Nutrition, and Biogerontology. Dr. Candow\’s research program involves the development of effective resistance training and nutritional intervention strategies for improving properties of muscle and bone health. Dr. Candow\’s research is funded by the Canadian Institutes of Health Research (CIHR), Canada Foundation for Innovation (CFI), the Saskatchewan Health Research Foundation (SHRF), and the Nutricia Research Foundation.

[reference]

REFERENCES

1. Antonio J, Ciccone V (2013) The effects of pre versus post workout supplementation of creatine monohydrate on body composition and strength. J Int Soc Sports Nutr 10:36.

2. Allen RE, Boxhorn LK (1989) Regulation of skeletal muscle satellite cell proliferation and differentiation by transforming growth factorbeta, insulin-like growth factor I, and fibroblast growth factor. J Cell Physiol 138:311-315.

3. Balsom PD, Soderlund K, Sjodin B, Ekblom B (1995) Skeletal muscle metabolism during short duration high-intensity exercise: influence of creatine supplementation. Acta Physiol Scand 154:303-310.

4. Bazzucchi I, Felici F, Sacchetti M (2009) Effect of short-term creatine supplementation on neuromuscular function. Med Sci Sports Exerc 41:1934-1941.

5. Burd NA, Tang JE, Moore DR, Phillips SM (2009) Exercise training and protein metabolism: influences of contraction, protein intake, and sex-based differences. J Appl Physiol 106(5): 1692-1701.

6. Burd NA, Wall BT, van Loon LJC (2012) The curious case of anabolic resistance: old wives\’ tales or new fables? J Appl Physiol 112(7): 1233-1235.

7. Burke DG, Candow DG, Chilibeck PD, MacNeil LG, Roy BD, Tarnopolsky MA, Ziegenfuss T (2008) Effect of creatine supplementation and resistance-exercise training on muscle insulin-like growth factor in young adults. Int J Sport Nutr Exerc Metab 18:389-398.

8. Burke DG, Chilibeck PD, Davison KS, Candow DG, Farthing J, Palmer TS (2001) The effect of whey protein supplementation with and without creatine monohydrate combined with resistance training on lean tissue mass and muscle performance. Int J Sport Nutr Exerc Metab 11:349-364.

9. Candow DG, Chilibeck PD, Facci M, Abeysekara S, Zello GA (2006) Protein supplementation before and after resistance training in older men. Eur J Appl Physiol 97:548-556.

10. Candow DG, Little JP, Chilibeck PD, Abeysekara S, Zello G, Kazachhov M, Cornish SM, Yu PH (2008) Low-dose creatine combined with protein during resistance training in older men. Med Sci Sports Exerc 40:1645-1652.

11. Candow DG, Vogt E, Johannsmeyer S, Forbes SC, Farthing JP (2015) Strategic creatine supplementation and resistance training in healthy older adults. Appl Physiol Nutr Metab 40(7):689-694.

12. Casey A, Constantin-Teodosiu D, Howell S, Hultman E, Greenhaff PL (1996) Creatine supplementation favorably affects performance and muscle metabolism during maximal exercise in human. Am J Physiol Endocrinol Metab 271: 31-37.

13. Churchward-Venne TA, Burd NA, Mitchell CJ, West DW, Philp A, Marcotte GR, Baker SK, Baar K, Phillips SM (2012) Supplementation of a suboptimal protein dose with leucine or essential amino acids: effects on myofibrillar protein synthesis at rest and following resistance exercise in men. J Physiol 1;590(11):2751-2765.

14. Cribb PJ, Hayes A (2006). Effects of supplement timing and resistance exercise on skeletal muscle hypertrophy. Med. Sci. Sports Exerc 38:1918-1925.

15. Cribb PJ, Williams AD, Hayes A (2007) A creatine-protein-carbohydrate supplement enhances responses to resistance training. Med Sci Sports Exerc 39(11):1960-1968.

16. Cribb PJ, Williams AD, Stathis CG, Carey MF, Hayes A (2007) Effects of whey isolate, creatine, and resistance training on muscle hypertrophy. Med Sci Sports Exerc 39(2):298-307.

17. Deldicque L, Louis M, Theisen D, Nielens H, Dehoux M, Thissen JP, Rennie MJ, Francaux M (2005) Increased IGF mRNA in human skeletal muscle after creatine supplementation. Med Sci Sports Exerc 37:731-736.

18. Deldicque L, Theisen D, Bertrand L, Hespel P, Hue L, Francaux M (2007) Creatine enhances differentiation of myogenic C2C12 cells by activating both p38 and Akt/PKB pathways. Am J Physiol Cell Physiol 293:C1263-1271.

19. Fujita S, Dreyer HC, Drummond MJ, Glynn EL, Cadenas JG, Yoshizawa F, Volpi E, Rasmussen BB (2007) Nutrient signalling in the regulation of human muscle protein synthesis. J Physiol 582:813-823.

20. Green AL, Hultman E, Macdonald IA, Sewell DA, Greenhaff PL (1996) Carbohydrate ingestion augments skeletal muscle creatine accumulation during creatine supplementation in humans. Am J Physiol 271: 821- 826.

21. Guerrero-Ontiveros ML, Wallimann T (1998) Creatine supplementation in health and disease. Effects of chronic creatine ingestion in vivo: Down–regulation of the expression of creatine transporter in skeletal muscle. Mol Cell Biochem 184: 427-437.

22. Harris RC, Soderland K, Hultman E (1992) Elevation of creatine in resting and exercise muscle of normal subjects by creatine supplementation. Clin Sci 83: 367-374.

23. Olsen S, Aagaard P, Kadi F, Tufekovic G, Verney J, Olsen JL, Suetta C, Kjaer M (2006) Creatine supplementation augments the increase in satellite cell and myonuclei number in human skeletal muscle induced by strength training. J Physiol 1:525-534.

24. Parise G, Mihic S, MacLennan D, Yarasheski KE, Tarnopolsky MA (2001) Effects of acute creatine monohydrate supplementation on leucine kinetics and mixed-muscle protein synthesis. J Appl Physiol 91:1041-1047.

25. Phillips SM (2004) Protein requirements and supplementation in strength sports. Nutr 20: 689-695.

26. Persky AM, Brazeau GA (2001) Clinical pharmacology of the dietary supplement creatine monohydrate. Pharmacol Rev 53: 161-176.

27. Safdar A, Yardley NJ, Snow R, Melov S, Tarnopolsky MA (2008) Global and targeted gene expression and protein content in skeletal muscle of young men following short-term creatine monohydrate supplementation. Physiol Genomics 32:219-228.

28. Sartorelli V, Fulco M (2004) Molecular and cellular determinants of skeletal muscle atrophy and hypertrophy. Sci STKE 244:re11.

29. Tipton KD, Rasmussen BB, Miller SL, Wolf SE, Owens-Stovall SK, Petrini BE, Wolfe RR (2001) Timing of amino acid-carbohydrate ingestion alters anabolic response of muscle to resistance exercise. Am J Physiol Endocrinol Metab 281:E197-206.

30. Walker JB (1979) Creatine: biosynthesis, regulation and function. Adv Enzymol Relat Areas Mol Biol 50: 177-242.

31. Welle S, Thornton CA. (1998) High-protein meals do not enhance myofibrillar synthesis after resistance exercise in 62- to 75-yr-old men and women. Am J Physiol 274: 677-683.

32. Willoughby DS, Rosene JM (2003) Effects of oral creatine and resistance training on myogenic regulatory factor expression. Med Sci Sports Exerc 35:923-929.

33. Wyss M, Kaddurah-Daouk R (2000) Creatine and creatinine metabolism. Physiol Rev 80:1107-1213.
[/reference]