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Ergogenic Aids: Creatine. What Is Creatine?. Amino acid derivative found mainly in skeletal muscle (90% to 95%) Small amounts in brain, testes, and cardiac muscle tissues Synthesized from glycine, arginine, and S-adenosylmethionine (1 to 2 g/day)
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What Is Creatine? • Amino acid derivative found mainly in skeletal muscle(90% to 95%) • Small amounts in brain, testes, and cardiac muscle tissues • Synthesized from glycine, arginine, and S-adenosylmethionine (1 to 2 g/day) • Found in meats (meat eaters consume 1 to 2 g/day) • Acts as a reservoir for high-energy phosphate needed for adenosine triphosphate (ATP) synthesis • Phosphorylated creatine (creatine phosphate, or phosphocreatine) can donate a phosphate group to adenosine diphosphate (ADP) to make ATP • Phosphocreatine stores depleted after 10 to 20 seconds of intense exercise Abbreviations: ADP, adenosine diphosphate; ATP, adenosine triphosphate. Juhn MS, et al. Clin J Sport Med. 1998;8(4):286-297.
The Creatine Phosphate Pathway • 3 different types (isoforms) of creatine kinase (CK) • CK-BB, or CK-1 (brain, lung) • CK-MB, or CK-2 (cardiac) • CK-MM, or CK-3 (skeletal muscle) Urinary excretion Abbreviations: ADP, adenosine diphosphate; ATP, adenosine triphosphate; BB, brain/brain; CPK, creatine phosphokinase; MB, muscle/brain; MM, muscle/muscle. Reprinted from Smith C, et al. Marks’ Basic Medical Biochemistry: A Clinical Approach. 2nd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2005:870-871.
Potential Mechanisms for Benefits of Creatine for Athletes • Loading can increase stores of phosphocreatine in muscle cells1 • Increased ATP production during high-intensity exercise • Diminished dependence on glycolysis and subsequent lactic acid formation • Indirect buffering of muscle pH • Faster re-synthesis of ATP after exercise • Affects muscle cell stretching, which may trigger cell growth2 • Osmotically active inside muscle cells; water follows it into the cell • Influences other pathways in the cell that increase the ratio of protein synthesis to protein breakdown3,4 • Increased myogenic regulatory factors • Increased insulin-like growth factor (IGF-1) expression • Decreased myostatin levels in blood (myostatin reduces muscle growth) • Decreased cellular damage following high-intensity exercise Abbreviations: ATP, adenosine triphosphate; IGF-1, insulin-like growth factor. 1. Terjung RL, et al. Med Sci Sports Exerc. 2000;32(3):706-717. 2. Haussinger D, et al. Lancet. 1993;341(8856):1330-1332. 3. Saremi A, et al. Mol Cell Endocrinol. 2010;317(1-2):25-30. 4. Deldicque L, et al. J Appl Physiol. 2008;104(2):371-378.
Typical Creatine Feeding Protocol • Loading period for rapid increase in muscle creatine • Approximately 20 g/day (~0.3 g/kg/day) for 3 to 5 days • 5 g, 4×/day • Maintenance phase • 2 to 5 g/day indefinitely • Slower increase in muscle creatine • 3 g/day for 28 days results in similar muscle creatine levels as in the loading phase Mc Ardle WD, et al. Sports and Exercise Nutrition, 3rd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2009:3476-377.
Evidence for Creatine Benefits on Performance and Strength/Muscle Mass • > 500 studies have evaluated the benefits of creatine in sports nutrition • None have shown detrimental effects • 300 examined performance: ~70% show significant improvements • Performance benefits include: • Maximal power/strength (5% to 15%) • Work performed during sets of maximal effort muscle contractions (5% to 15%) • Single-effort sprint performance (1% to 5%) • Work performed during repetitive sprint performance (5% to 15%) • Performance benefits generally limited to high-intensity, anaerobic exercise • Supplementation during training is associated with a 0.5- to 2-kg greater increase in body mass (BM) and/or fat-free mass (FFM) than training alone • Includes trained and untrained adolescent, adult, and elderly populations • Both males and females respond equally well Abbreviations: BM, body mass; FFM, fat-free mass. Kreider RB. Mol Cell Biochem. 2003;244(1-2):89-94.
Effects of Creatine Loading on Muscle Creatine Levels A 160 * 150 140 20 g creatine/day for 6 days, none after 130 Total creatine, mmol/kg dm 120 110 100 Day 0 Day 7 Day 21 Day 35 B 160 * * 150 * 140 20 g creatine/day for 6 days, then 2 g/day for remainder of study 130 Total creatine, mmol/kg dm 120 110 100 Day 0 Day 7 Day 21 Day 35 Abbreviation: dm, dry mass. *Significantly different from day 0, P < .05. Reprinted from Hultman E, et al. J Appl Physiol. 1996;81(1-2):232-237.
Influence of Creatine Loading on Myostatin Levels During 8 Weeks of Resistance Training (Typical 2 Phase Loading Protocol) Week 0 Week 4 140 Week 8 120 100 80 Myostatin, ng/mL 60 40 20 0 CON RT+PL RT+CR Abbreviations: CON, control; CR, creatine; PL, placebo; RT, resistance training. Reprinted from Saremi A, et al. Mol Cell Endocrinol. 2010;317(1-2):25-30.
Influence of Creatine on Markers of Muscle Damage After the Ironman Triathlon * * ns * *** ns 4000 700 ns 600 3000 ** 500 Plasma activity of CK, U/L 400 Plasma activity of LDH, U/L 2000 300 200 1000 100 0 0 Placebo Creatine supplemented Placebo Creatine supplemented Triathletes Triathletes 0 hours 36 hours 60 hours 0 hours 36 hours 60 hours Subjects: Ironman triathletes Treatments: 20 g/day creatine + 50 g carbohydrate for 5 days prior to the race Control: 50 g carbohydrate only Analysis: Markers of muscle damage measured at baseline and 36 or 60 hours after the race Abbreviations: CK, creatine kinase; LDH, lactate dehydrogenase; ns, not significant.*P < .05; **P < .01; ***P < .001. Reprinted from Bassit RA, et al. Eur J Appl Physiol. 2010;108(5):945-955.
Example of Anaerobic Performance Benefit From Creatine * Subjects: 14 active, but not “well-trained” males Treatments: 5 g creatine monohydrate + 1 g glucose polymer for 5 days Control: 6 g glucose polymer for 5 days Training: 10 sets of either 5 or 6 x6-second maximal bike sprints with varying recoveries (24, 54, or 84 seconds between sprints) over a period of 80 minutes Assessed before (pre-loading) and after (post-loading) 5 days of treatment Data are mean ± standard error. *P < .05 vs placebo.Data from Preen D, et al. Med Sci Sports Exerc. 2001;33(5):814-821.
Example of Creatine Effectiveness For Strength and Muscle Mass * * Subjects: 19 healthy, resistance-trained men Treatments: 25 g creatine/day for 7 days 5 g creatine/day for 11 weeks Controls: identical amounts of cellulose powder Training: 12-week resistance training Data are mean ± standard error. Abbreviations: BM, body mass; FFM, fat-free mass; FM, fat mass. *P ≤.05 vs placebo. Data from Volek JS, et al. Med Sci Sports Exerc. 1999;31(8):1147-1156.
Creatine Effects on Increase in Cross-Sectional Area in Different Muscle Fiber Types * * * Change in area from Week 0 to Week 12, µm2 Data are mean ± standard error. *P ≤.05 vs placebo.Data from Volek JS, et al. Med Sci Sports Exerc. 1999;31(8):1147-1156.
Is the Form of Creatine Important? • Creatine monohydrate by far the most commonly studied • Therefore, most evidence for efficacy • Creatine not stable in liquids over a period of time • Conversion to creatinine • Creatine liquids or serums not as effective as powder1 • Limited studies with other forms • Creatine ethyl ester, creatine pyruvate, creatine with D-pinitol, polyethylene glycosylated creatine, etc • No consistent improvements relative to creatine monohydrate • Hard to improve on bioavailability of creatine monohydrate • These forms are likely more expensive 1. Gill ND, et al. J Strength Cond Res. 2004;18(2):272-275.
Carbohydrate and Protein in the Facilitation of Muscle Creatine Uptake • 60% increase in total muscle creatine in experimental group1 • N = 24 males • 5 g creatine followed by 93 g glucose 30 minutes later; repeated 4×/day • Control was 5 g creatine 4×/day • Carbohydrate/Protein (carb/pro) and high-carbohydrate treatments had similar creatine retention2 • 5 g creatine 4×/day plus one of the following each time: • Placebo: 5 g glucose • Carb/pro: 47 g glucose and 50 g protein • High carb: 96 g glucose • Low carb: 50 g glucose • Low-carbohydrate treatment was not significantly different than placebo • The large insulin response to either the high-carbohydrate or carb/pro combination is likely responsible for driving further uptake of creatine by muscle cells Abbreviation: carb/pro, carbohydrate/protein. 1. Green AL, et al. Am J Physiol Endocrinol Metab.1996;271(5):E821-E826. 2. Steenge GR, et al. J Appl Physiol.2000;89(3):1165-1171.
Caffeine + Creatine: Is This a Concern? • Caffeine eliminated the positive effect of creatine on a knee extensor exercise in 1 study1 • High caffeine dose (5 mg/kg/day) • 0.5 g/kg/day creatine for 6 days • Caffeine did not inhibit the increase in muscle creatine concentration • Performance benefits shown in other studies of creatine2,3 • With lower doses of caffeine • With other nutrients 1. Vandenberghe K, et al. J Appl Physiol. 1996;80(5):452-457. 2. Kraemer WJ, et al. Eur J Appl Physiol.2007;101(5):637-646. 3. Smith AE, et al. J Int Soc Sports Nutr.2010;7:10 doi: 10.1186/1550-2783-7-10.
Creatine Nonresponders? • Individuals with high muscle levels of total creatine (> 120 mmol/kg dry matter) may not be as responsive to creatine supplementation1 • Conversely, vegetarians have lower creatine stores and may be more responsive to creatine supplementation (loading and performance)2 1. Greenhaff PL, et al. Am J Physiol Endocrinol Metab. 1994;266(5):E275-E730. 2. Burke DG, et al. Med Sci Sports Exerc.2003;35(11):1946-1955.
Creatine Side Effects • Generally well tolerated in the gastrointestinal tract when dose is ≤ 5 g1 at one time • Weight gain is common (may or may not be considered a “side effect”) • Early concern was potential muscle cramping and impaired temperature regulation2,3 • Possibly related to fluid shift to intracellular space (less circulating fluid) • Several recent studies have dispelled any concern regarding creatine with regard to muscle cramping, heat tolerance, and hydration status3,4,5 • May actually augment sprint performance and reduce cramping in the heat6 1. Ostojic SM, et al. Res Sports Med.2008;16(1):15-22. 2. Dalbo VJ, et al. Br J Sports Med. 2008;42(7):567-573. 3. Lopez RM, et al. J Athl Train. 2009;44(2):215-223. 4. Greenwood M, et al. J Athl Train. 2003;38(3):216-219. 5. Volek JS, et al. Med Sci Sports Exerc. 2001;33(7):1101-1108. 6. Wright GA, et al. J Strength Cond Res. 2007;21(3):655-660.
Creatine Safety • Most publicized potential safety concern is renal function • Long-term studies of the safety of creatine in athletes are lacking • The general safety of creatine is supported via several lines of evidence • Creatine supplementation (up to 5 years) in athletes have not shown impairment in renal function or other clinical markers with up to 20 g/day in healthy athletes1,2,3 • Short-term studies have shown no effects of creatine supplementation on renal parameters or hematologic indices4,5,6,7 • Loading: 15 to 20 g/day for 5 to 7 days • Maintenance: 3 to 10 g/day for up to 9 weeks • Comprehensive risk assessment showing an Observed Safe Level (OSL) of 5 g/day for chronic supplementation8 • Long-term studies of creatine use in clinical populations such as patients with Parkinson’s disease and gyrate atrophy of the choroid and retina have not shown adverse effects9,10,11 • Typically maintenance doses (1.5 to 4 g/day) have been used for up to 5 years 1. Poortmans JR, et al. Med Sci Sports Exerc. 1999;31(8):1108-1110; 2. Mayhew DL, et al. Int J Sport Nutr Exerc Metab.2002;12(4):453-460; 3. Kreider RB, et al. Mol Cell Biochem.2003;244(1-2):95-104; 4. Poortmans JR, et al. Eur J Appl Physiol Occup Physiol.1997;76(6):566-567; 5. Robinson TM, et al. Br J Sports Med.2000;34(4):284-288; 6. Gualano B, et al. Eur J Appl Physiol.2008;103(1):33-40; 7. Cancela P, et al. Br J Sports Med 2008;42(9):731-735; 8. Shao A, et al. Regul Toxicol Pharmacol.2006;45(3):242-251; 9. Bender A, et al. Nutr Res.2008;28(3):172-178; 10. Sipila I, et al. N Engl J Med.1981;304(15):867-870; 11. Vannas-Sulonen K, et al. Ophthalmology. 1985;92(12):1719-1727.
Creatine Safety (continued) • There have been a few isolated case reports of kidney dysfunction (interstitial nephritis) that have been associated with creatine supplementation1,2,3 • In each of these case studies, there are factors that greatly limit interpretation of the results • The patient had pre-existing kidney disease1 • The patient took 20 g/day for 4 weeks (exceeded recommended dose) and symptoms started 4 weeks after stopping creatine2 • The patient took only 15 g creatine/week and was on many other dietary supplements (17 amino acids, 18 herbal/plant extracts, and16 other nutritional supplements)3 • Symptoms resolved when ALL supplements were stopped • Causative agent could not be identified 1. Pritchard NR, et al. Lancet. 1998;351(9111):1252-1253. 2. Koshy KM, et al. N Engl J Med.1999;340(10):814-815. 3. Thorsteinsdottir B, et al. J Ren Nutr.2006;16(4):341-345.
Creatine Safety—Summary • Creatine has an excellent overall safety profile in a variety of healthy populations when taken as recommended • Do not exceed recommended doses: • Loading: 20 g/day • Maintenance: 5 g/day • Creatine should not be taken by persons with pre-existing kidney disease • As with any dietary supplement, the user’s physician should be made aware of its use in the rare event that an adverse effect is experienced