Creatine Transport into Muscle Cells from the Blood Stream

Creatine Transport into Muscle Cells from the Blood Stream
(bringing it all together)

Legend: Creatine harnesses the potential energy of sodium (Na) wanting to enter the muscle cell. Therefore, any agent that increases the extrusion of sodium, should likewise increase the transport of creatine into the muscle cell. Physiological agensts that are well known to increase sodium efflux include insulin and adrenalin (epinephrine).

Two sodiums need to accompany each creatine molecule being transported inward. Therefore, doubling the driving force for sodium inwardly will effectively increase creatine transport by 50%.

Creatine transporter expression is also greatest on type II muscle fibers. Recall that these are the muscle fibers with the greatest requirement for creatine.

Finally, due to its electrical charge creatine becomes trapped within the muscle cell once transported within. PCr is even more highly charged and likewise is trapped once produced. Creatinine, on the other hand, lacks electrical charges at physiological pH and hence is able to escape across the muscle cell membrane.

Creatine Synthesis from the Amino Acids

Creatine Synthesis from the Amino Acids,
Arginine, Glycine and Methionine

Legend: Reaction 1 (catalyzed by AGAT) is the rate limiting step in creatine biosynthesis. AGAT expression is also reduced by the presence of creatine. This raised concerns that prolonged creatine supplementation might inhibit endogenous creatine synthesis for an indefinite period of time.

Finally, notice that Glycine is completely incorporated into the creatine backbone, whereas Arginine and Methionine only contribute side groups.

Enzymatic Interconversion of PCr and ATP (Creatine Related)

Enzymatic Interconversion of PCr and ATP

Legend: ATP (Adenosine TriPhosphate) is the energy storage molecule of all cells. After donating its energy allotment to the contractile apparatus of muscle, ATP becomes ADP (Adenosine DiPhosphate). During intense physical exertion ATP is rapidly recreated from ADP by the donation of a phosphate group from Phosphocreatine (PCr).

Creatine kinase is the enzyme responsible for swapping the phosphate groups (shown in red) between PCr and ATP. The upward reaction predominates during strenuous exercise when energy (ATP) is needed to fuel explosive movements. The downward reactions primarily takes place during moments of rest and recreates our PCr reserves. The larger our PCr reserves, the longer we can sustain intense muscular activity. This is the basic premise behind creatine supplementation.

Creatine and PCr later spontaneously degrade into creatinine, which is able to escape from the cell.

The production of ATP from PCr has the added advantage that it also neutralizes muscle acidity (H+). This effect should heighten our fatigue threshold during moments of intense physical exertion.

Spontaneous one-way conversion of PCr and Creatine
into Creatinine

Legend: The presence of charged groups on creatine and PCr prevent them from transversing the muscle membrane. Creatinine, by contrast, has no charge and is thus able to freely slip through the muscle membrane escaping to the outside. This leakage pathway sets our requirement for new creatine (~2 grams per day).

Also note that most of the muscle creatine is in the form of PCr, which also degrades at twice the rate of creatine. Hence, degradation rates should be quite appreciable under resting conditions.

Creatine supplements

From Wikipedia, the free encyclopedia

For the biochemistry and physiology of creatine, please see Creatine.

Creatine supplements are athletic aids used to increase high-intensity athletic performance. Though researchers have known of the use of creatine as an energy source by skeletal muscles since the beginning of the 20th century, they were popularized as a performance-enhancing supplement in 1992.

Contents  [hide] 1 History of creatine supplements 2 Creatine and athletic performance 2.1 Creatine ethyl ester 3 Safety 4 Creatine and mental performance 5 References

[edit]History of creatine supplements

In 1912, Harvard University researchers Otto Folin and Willey Glover Denis found proof that ingesting creatine can dramatically boost the creatine content of the muscle^[1]. In the late 1920s, after finding that the intramuscular stores of creatine can be increased by ingesting creatine in larger than normal amounts, scientists discovered creatine phosphate, and determined that creatine is a key player in the metabolism of skeletal muscle. The substance creatine is naturally formed in vertebrates.

While creatine's influence on physical performance has been well documented since the early twentieth century, it only recently came into public view following the 1992 Olympics inBarcelona. An August 7, 1992 article in The Times reported that Linford Christie, the gold medal winner at 100 meters, had utilized creatine prior to the Olympics, and an article inBodybuilding Monthly named Sally Gunnell, gold medalist in the 400-meter hurdles, as another creatine user. Several medal-winning British rowers also used creatine during their preparations for the Barcelona games.

At the time, low-potency creatine supplements were available in Britain, but creatine supplements designed for strength enhancement were not commercially available until 1993 when a company called Experimental and Applied Sciences (EAS) introduced the compound to the sports nutrition market under the name Phosphagen.^[2] Research conducted afterward showed that the consumption of high glycemic carbohydrates in conjunction with creatine increases creatine muscle stores and performance. ^[3] In 1998, MuscleTech Research and Developmentlaunched Cell-Tech, the first creatine-carbohydrate-alpha lipoic acid supplement. Alpha lipoic acid has been demonstrated to enhance muscle phosphocreatine levels and total muscle creatine concentrations. This approach to creatine supplementation was validated in a study performed in 2003.^[4]

Another important event in creatine supplementation occurred in 2004 when the first creatine ethyl ester supplements were launched. Creatine ethyl ester (CEE) is becoming a widely used form of creatine, with many companies now carrying both creatine monohydrate-based supplements and CEE supplements, or combinations of both.

[edit]Creatine and athletic performance

This article needs additional citations for verification. Please help improve this article by adding reliable references. Unsourced material may be challenged and removed. (September 2007)

This article is in need of attention from an expert on the subject. WikiProject Pharmacology or the Pharmacology Portal may be able to help recruit one. (November 2008)

Creatine is often taken by athletes as a supplement for those wishing to gain muscle mass (bodybuilding). There are a number of forms but the most common are creatine monohydrate - creatine complexed with a molecule of water, and Creatine ethyl ester (CEE). A number of methods for ingestion exist - as a powder mixed into a drink, or as a capsule or caplet. Once ingested, creatine is highly bioavailable, whether it is ingested as the crystalline monohydrate form, the free form in solution, or even in meat. Creatine salts will become the free form when dissolved in aqueous solution. Conventional wisdom recommends the consumption of creatine with high glycemic index carbohydrates, though research indicates that the use of high GI carbs in combination with protein is also beneficial.^[5]

There is scientific evidence that taking creatine supplements can marginally increase athletic performance in high-intensity anaerobic repetitive cycling sprints, but studies in swimmers and runners have been less than promising, most likely because these activities are sustained at a given intensity and thus do not allow for significant intra-exercise synthesis of additional creatine phosphate molecules. Ingesting creatine can increase the level of phosphocreatine in the muscles up to 20%. It must be noted creatine has no significant effect on aerobicendurance, though it will increase power during short sessions of high-intensity aerobic exercise.^[6][7]

Since body mass gains of about 1 kg can occur in a week's time, many studies suggest that the gain is simply due to greater water retention inside the muscle cells. However, studies into the long-term effect of creatine supplementation suggest that body mass gains cannot be explained by increases in intracellular water alone.^[8] In the longer term, the increase in total body water is reported to be proportional to the weight gains, which means that the percentage of total body water is not significantly changed. The magnitude of the weight gains during training over a period of several weeks argue against the water-retention theory.

Also, research has shown that creatine increases the activity of satellite cells, which make muscle hypertrophy possible. Creatine supplementation appears to increase the number of myonuclei that satellite cells will 'donate' to damaged muscle fibers, which increases the potential for growth of those fibers. This increase in myonuclei probably stems from creatine's ability to increase levels of the myogenic transcription factor MRF4.^[9][10].

In another study, researchers concluded that changes in substrate oxidation may influence the inhibition of fat mass loss associated with creatine after weight training when they discovered that fat mass did not change significantly with creatine but decreased after the placebo trial in a 12-week study on ten active men. The study also showed that 1-RM bench press and total body mass increased after creatine, but not after placebo.^[11] The underlying effect of Creatine on body composition if there is indeed one has yet to be determined, as another study with a similar timeframe suggests no effect on body composition, but had less overall emphasis on metabolic effects. ^[12]

Creatine use is not considered doping and is not banned by the majority of sport-governing bodies. However, in the United States, the NCAA recently ruled that colleges could not provide creatine supplements to their players, though the players are still allowed to obtain and use creatine independently.

[edit]Creatine ethyl ester

Main article: Creatine ethyl ester

CEE is a form of commercially available creatine touted to have higher absorption rates and a longer serum half-life than regular creatine monohydrate by several supplement companies. No peer-reviewed studies have emerged on creatine ethyl ester to conclusively prove these claims, however, a study presented at the 4th International Society of Sports Nutrition (ISSN) annual meeting demonstrated that the addition of the ethyl group to creatine actually reduces acid stability and accelerates its breakdown to creatinine. The researchers concluded that creatine ethyl-ester is inferior to creatine monohydrate as a source of creatine.^[13]

As a supplement, the compound was patented, and licensed through UNeMed, the technology transfer entity of the University of Nebraska Medical Center.^[14]

[edit]Safety

Some current studies indicate that short-term creatine supplementation in healthy individuals is safe, although those with renal disease should avoid it due to possible risks of renal dysfunction, and before using it healthy users should bear these possible risks in mind.^{[7][15][16][17]} Small-scale, longer-term studies have been done and seem to demonstrate its safety.^[18][19][20] There have been reports of muscle cramping with the use of creatine, though a study showed no reports of muscle cramping in subjects taking creatine-containing supplements during various exercise training conditions in trained and untrained endurance athletes.^[21][22] The cause of the reported cramping by some users may be due to dehydration, and extra water intake is vital when supplementing with creatine.

In addition, experiments have shown that creatine supplementation improved the health and lifespan of mice.^[23] Whether these beneficial effects would also apply to humans is still uncertain. It also led to a rise in allergic lung reactions in an animal test on mice with pre-existent allergic disease.^[24]

Creatine supplementation, in the dosages commonly used, results in urinary concentrations that are 90 times greater than normal. The long term effects of this have not been investigated, but there is possibility for a variety of nephrotoxic, i.e., kidney damaging, events. There is potential for direct toxicity on renal tubules where urine is formed, and for acceleration of kidney stone formation.^[25] Creatine has been shown to accelerate the growth of cysts in rats with Polycystic Kidney Disease (PKD). ^[26] Studies have not yet determined if Creatine supplementation will accelerate the growth of cysts in humans with PKD. PKD is prevelant in approximately 1 in 1000 people and may not be detectable until affected individuals reach their thirties.

One case study suggested that there was increased risk of rhabdomyolysis and thence renal failure after the use of a tourniquet during surgery.^[27]

[edit]Creatine and mental performance

Creatine administration was shown to significantly improve performance in cognitive and memory tests in vegetarian individuals involved in double-blind, placebo-controlled cross-over trials.^[28] Vegetarian supplementation with creatine seems to be especially beneficial as they appear to have lower average body stores, since meat is a primary source of dietary creatine.^[28]

[edit]References

1. ^ Folin O, Denis W (1912). "Protein metabolism from the standpoint of blood and tissue analysis. Third paper, Further absorption experiments with especial reference to the behavior of creatine and creatinine and to the formation of urea.". Journal of Biological Chemistry 12 (1): 141–61.
2. ^ Stoppani, Jim (May, 2004), Creatine new and improved: recent high-tech advances have made creatine even more powerful. Here's how you can take full advantage of this super supplement, Muscle & Fitness, retrieved on 5 February 2008.
3. ^ Green AL, Hultman E, Macdonald IA, Sewell DA, Greenhaff PL (Nov 1996). "Carbohydrate ingestion augments skeletal muscle creatine accumulation during creatine supplementation in humans". Am. J. Physiol. 271(5 Pt 1): E821–6. PMID 8944667.
4. ^ Burke DG, Chilibeck PD, Parise G, Tarnopolsky MA, Candow DG (2003-09-01). "Effect of alpha-lipoic acid combined with creatine monohydrate on human skeletal muscle creatine and phosphagen concentration".International Journal of Sport Nutrition and Exercise Metabolism (Human Kinetics Publishers) 13 (3): 294–302. PMID 14669930.
5. ^ Steenge GR, Simpson EJ, Greenhaff PL (Sep 2000). "Protein- and carbohydrate-induced augmentation of whole body creatine retention in humans". J. Appl. Physiol. 89 (3): 1165–71. PMID 10956365.
6. ^ Engelhardt, M; Neumann G, Berbalk A, Reuter I (1998-07-01). "Creatine supplementation in endurance sports". Medicine & Science in Sports & Exercise (Lippincott Williams & Wilkins) 30 (7): 1123–9.doi:10.1097/00005768-199807000-00016. PMID 9662683.
7. ^ ^a b Graham AS, Hatton RC (1999). "Creatine: a review of efficacy and safety". J Am Pharm Assoc (Wash) 39 (6): 803–10; quiz 875–7. PMID 10609446.
8. ^ Powers, M; Arnold B et al (2003). "Creatine Supplementation Increases Total Body Water Without Altering Fluid Distribution". Journal of Athletic Training (National Athletic Trainers' Association, Inc) 38 (Jan-Mar): 44–50. PMID 12937471.
9. ^ Hespel, P; Eijnde BO, Derave W, Richter EA (2001). "Creatine supplementation: exploring the role of the creatine kinase/phosphocreatine system in human muscle". Canadian Journal of Applied Physiology (Human Kinetics Publishers, Inc.) 26 (Suppl.): S79–102. PMID 11897886.
10. ^ Olsen, S; Aagaard P, Fawzi K, et al (2006). "Creatine supplementation augments the increase in satellite cell and myonuclei number in human skeletal muscle induced by strength training". The Journal of Physiology573 (Jun 1): 525–34. doi:10.1113/jphysiol.2006.107359.
11. ^ Huso, ME; Hampl JS, Johnston CS, Swan PD (2002-08-16). "Creatine supplementation influences substrate utilization at rest". Journal of Applied Physiology 93 (6): 2018–22. doi:10.1152.
12. ^ Huso, ME; Hampl JS, Johnston CS, Swan PD (2007-12-01). "Effect of in-season creatine supplementation on body composition and performance in rugby union football players". Applied physiology, nutrition, and metabolism 32 (6): 1052–7. doi:10.1139/H07-072. PMID 18059577.
13. ^ Child, R. & Tallon, M.J. (2007). Creatine ethyl ester rapidly degrades to creatinine in stomach acid. International Society of Sports Nutrition 4th Annual Meeting
14. ^ UNeMed 2003 Annual Report, p.4
15. ^ Creatine's Side Effects. Fact or Fiction?, An interview of Professor Jacques R. Poortmans
16. ^ Poortmans J. R., Francaux, M. (September 2000). "Adverse effects of creatine supplementation. Fact or Fiction?". Sports Medicine. PMID 10999421.
17. ^ Robinson, T.M.; Sewell, D.A., Casey, A., Steenge, G. & Greenhaff, P.L. (2000). "Dietary creatine supplementation does not affect some haematological indices, or indices of muscle damage and hepatic and renal function". British Journal of Sports Medicine 34 (4): 284–288. doi:10.1136/bjsm.34.4.284. Retrieved on 12 April 2007.
18. ^ Mayhew DL, Mayhew JL, Ware JS (2002). "Effects of long-term creatine supplementation on liver and kidney functions in American college football players.". Int J Sport Nutr Exerc Metab. 12 (4): 453–60. PMID 12500988.
19. ^ Poortmans, J.R.; Francaux, M. (1999-08-01). "Long-term oral creatine supplementation does not impair renal function in healthy athletes". Medicine & Science in Sports & Exercise (Lippincott Williams & Wilkins, Inc.) 31 (8): 1108–1110. doi:10.1097/00005768-199908000-00005. Retrieved on 12 April 2007.
20. ^ Kreider, R.B.; Melton, C., Rasmussen, C.J., Greenwood, M., Lancaster, S., Cantler, E.C., Milnor, P. & Almada, A.L. (2004-11-01). "Long-term creatine supplementation does not significantly affect clinical markers of health in athletes". Molecular and Cellular Biochemistry (Springer Netherlands) 244 (1-2): 95–104. doi:10.1023. Retrieved on 12 April 2007.
21. ^ Kreider R. (1998). "Creatine: The Ergogenic/Anabolic Supplement". Mesomorphosis 1 (4). Retrieved on 12 April 2007.
22. ^ Kreider R, Rasmussen C, Ransom J, Almada AL. (1998). "Effects of creatine supplementation during training on the incidence of muscle cramping, injuries and GI distress.". Journal of Strength Conditioning Research12 (275).
23. ^ Bender A, Beckers J, Schneider I, et al (September 2008). "Creatine improves health and survival of mice". Neurobiol. Aging 29 (9): 1404–11. doi:10.1016/j.neurobiolaging.2007.03.001. PMID 17416441.
24. ^ Vieira RP, Duarte AC, Claudino RC, et al (Dec 2007). "Creatine supplementation exacerbates allergic lung inflammation and airway remodeling in mice". Am J Respir Cell Mol. Biol. 37 (6): 660–7.doi:10.1165/rcmb.2007-0108OC. PMID 17641295.
25. ^ http://www.rice.edu/~jenky/sports/creatine.html
26. ^ Edmunds JW, Jayapalan S, DiMarco NM, Saboorian MH, Aukema HM (2008). "Creatine supplementation increases renal disease progression in Han:SPRD-cy rats.". American Journal of Kidney Disease 37 (1): 157–9.PMID 11136170.
27. ^ Sheth NP, Sennett B, Berns JS (Feb 2006). "Rhabdomyolysis and acute renal failure following arthroscopic knee surgery in a college football player taking creatine supplements". Clin Nephrol. 65 (2): 134–7. PMID 16509464.
28. ^ ^a b Rae C, Digney AL, McEwan SR, Bates TC (Oct 2003). "Oral creatine monohydrate supplementation improves brain performance: a double-blind, placebo-controlled, cross-over trial". Proc Biol Sci. 270 (1529): 2147–50. doi:10.1098/rspb.2003.2492. PMID 14561278.

• Greenhaff PL et al. (1993). "Influence of oral creatine supplementation on muscle torque during repeated bouts of maximal voluntary exercise in men". Clinical Science 84: 565–71. PMID 8504634..

• Phillips, Bill. Sports Supplement Review 3rd issue. (2000).

• Stout JR et al. (1997). "The effects of a supplement designed to augment creatine uptake on anaerobic reserve capacity". NSCA National Conference Abstract.

• Benzi G. (2000). "Is there a rationale for the use of creatine either as nutritional supplementation or drug administration in humans participating in a sport?". Pharmacological Research 41 (3): 255–64.doi:10.1006/phrs.1999.0618. PMID 10675277.