Creatine - Your Arsenal Creates muscle

Summary:
1. Cell physiology has demonstrated that the cell will more likely take up a nutrient such as creatine if it is deficient in, or, has a low concentration of that nutrient.7,13 Especially if that nutrient cannot be synthesized by the cell.7 Muscles do not manufacture creatine, it must be synthesized and transported via the liver or kidneys.5

2. All cells have intricate, precise internal feedback-loop systems and a substrate like creatine is manufactured and transported to active muscle only when needed.13 An abundance of any end product will cause a halt to the enzymatic steps of its production.13

3. Research clearly demonstrates that while ATP levels remain fairly constant, both intense and prolonged exercise deplete total creatine stores.5,11 Total creatine (TCr) is free creatine and phosphocreatine (PCr)stores. PCr makes up the largest majority of TCr stores.11 Recent research shows PCr stores are depleted by up to 62% after only 1 heavy set in the gym!17. Yes PCr stores are replenished rapidly during the resting phase, however this resynthesis must come from free creatine stores.4,5,10 In fact very recent NMR studies on energy metabolism confirm that creatine supplementation does indeed serve to synthesize muscle PCr stores quicker and more effectively during exercise than no creatine supplementation.20 If there is no supplementation the muscle cells will eventually replenish these stores. It is a natural, critical process to sustaining life. While this homeostatic process ensures adequate supplies, it will never provide the super-compensatory effect we are after. Nothing great was ever built from anything adequate.

4. Research on the cellular mechanisms of creatine uptake clearly demonstrate that creatine uptake is determined by one thing - its own cellular concentration.3,7,14 Both inside and outside the cell.7,14 Transport of creatine into mammalian cells is meditated by a specific membrane-bound transport system.3 This system is regulated (upgraded or downgraded) purely by the extracellular and intracellular concentrations of creatine.7,14

Also the amount of creatine already inside the cell profoundly affects how much more creatine gets transported into the muscle cell.14 When concentrations of creatine are low the transport systems step up activity to drive more creatine into the cell.7 Animal invitro and invivo studies on the kinetics of creatine uptake show it is the initial creatine levels in the muscle that ultimately determine the degree of creatine uptake, and, the lower the initial concentration the better. It means the cell absorbs more creatine.3,7,14

By taking creatine at times muscle cells do not immediately require it, they can become easily saturated,7,14 as uptake is down regulated even when sustained, in low concentrations. 7,14 If the saturation continues, muscle cells actually lose their creatine transporters.7

Results consistently show that the subjects with the lowest pretreatment Cr concentrations demonstrate the greatest increases in total creatine uptake.4,6,9 Where as the subjects with very high pretreatment concentrations show little or no change.4,6,9

How much can a cell take?

Studies have indicated there may be a physiological limit to the amount of creatine that can be held within a cell, as current literature is showing a "ceiling-cap" is reached via conventional loading methods.11 However research on cellular amino acid transport and concentrations demonstrate that these physiological limits have rather wide ranges.1,2,10,14,15 There is room to substancially increase these amounts, and even the slightest increases toward upper physiological concentrations produce potent anabolic effects.1,2,8,14,15

Human studies that have examined the effects of weight training on amino acid transport in muscle demonstrate that after weight training amino acid uptake into the cell is dramatically enhanced under the right conditions.1,2,18 That being, high insulin levels combined with high concentrations of amino acids outside the cell directly after exercise.2,1018 If this environment is achieved at precisely the right time (when muscles are depleted) muscle cells become literally crammed with amino acid and glycogen to the upper limits of physiological concentrations.2,10 This "super-compensation" of cellular amino acids is itself, an extremely potent activator of muscle cell anabolism. It also serves to switch on other muscle growth mechanisms.2,8,10,14

[size=85]References
1. Bolio G, Tipton KD, Klein S and Wolfe RR. 1995 Increased rates of muscle protein turnover and amino acid transport after resistance exercise in humans. Am.J.Physiol.:268, E514-E520
2. Bolio G, Maggi P, Williams PD, Tipton KD, Wolfe RR. 1997 An abundant supply of amino acids enhances the metabolic effect of exercise on muscle protein. Am.J.Physiol.:273:E122-129
3. Dai W et al. 1999 Molecular characterization of the human CRT-1 creatine transporter expressed in Xenopus Oocytes. Arch. Of Biochem Biophys. vol 361.#1Jan. p75-84.
4. Greenhaff PL.1997. The nutritional chemistry of creatine. J.Nutr.Biochem.11:610-618
5. Greenhaff,P.L. et al. 1994 The effect of oral creatine supplementation on skeletal muscle phosphocreatine synthesis. Am.J.Physiol.266 (Endocrinol. Metab.29): E725-E730.
6. Gordon et al 1995. Creatine supplementation in chronic heart failure increases skeletal muscle creatine phosphate and muscle performance. Cardiovasc.Res.30:413-418
7. Guerrero-Ontivers, M.L. and Wallimann, T. 1998 Creatine supplementation in Health and Disease. Effects of chronic creatine ingestion in vivo: Down regulation of the expression of creatine transporter isoforms in skeletal muscle. Molecular and Cellular Biochemistry. 184: 427-437.
8. Haussinger D et al. 1998 Functional significance of cell volume regulatory mechanisms. Phys. Rev.vol78.#1.p247-290
9. Harris et al.1993 The effect of oral creatine supplementation on running performance during maximal short term exercise in man. J.Physiol. (Lond.) 467:74P
10. Hundal HS, Rennie MJ and Watt PW.1989 Characteristics of acid, basic and neutral amino acid transport in the perfused rat hindlimb. J.Physiol.408:93-114
11. Hultman,E. et al. 1996 Muscle creatine loading in man. J.Appl.Physiol. 81: 232-237
12. Jacobs I. Dietary creatine monohydrate supplementation.1999 Can.J.Appl.Physiol.24(6):503-514
13. Lehninger, Nelson and Cox. Principles of Biochemistry 2nd Ed. 1997.Ch8:211-215.
14. Loike JD et al. 1988 Extracellular creatine regulates creatine transport in rat and human cells.Proc.Natl.Acad.Sci.USA.vol.85 p807-811
15. Low SY et al. 1997 Signaling elements involved in amino acid transport reponses to altered muscle cell volume. FASEBJ. vol11.p1111-1117.
16. Low SY et al. 1998 Intergrin and cytoskeletal involvement in signaling cell volume to glutamine changes in cell volume. J.Physiol. vol512 #2 p481-485
17. MacDougall et al.1999 Muscle substrate utilization and lactate production during weightlifting. Can.J.Appl.Physiol.24(3):209-215.
18. Miers WR and Barrett EJ. 1998 The role of insulin and other hormones in the regulation of amino acid and protein metabolism in humans. Journal of Basic Clin Physiol & Pharm. Vol 9 #2-4:235-253.
19. Vandeburie,F et al.1998 Effect of creatine loading on endurance capacity and sprint power in cyclists. Int.J.Sports Med;19490-495.
20. Creatine reduces human muscle PCr ad pH decrements and Pi accumulation during low-intensity exercise. Published in APStracts on 10 January 2000. J.Appl. Physiol.
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The Belgium research.

Study: Belgium scientists examined the effects of creatine supplementation on 25 men undertaking a structured weight training program.(1)

Design:The creatine group ingested 21gms of creatine a day for the first 5 days then a maintenance dose of 3 gms/day for 42 days.(1) Examination of the experimental protocol showed a control group was used and the supplements were taken in a manner that allowed neither the researchers nor subjects (double blind) to know whom was taking what until after the study. This sets the scene for credible, unbiased scientific research.
Now our bodies are basically hairy, salty bags of water (around 70% H2O). Therefore, the most accurate methods of assessing body composition rely on determination of where this water resides.
Outcomes: Bio-impedance spectroscopy was the method used to measure body water compartments. It determines very accurately if water is held within or outside the muscle cell and therefore, if any increases in body weight are merely water retention or gains in lean muscle mass.(1)
The results showed the control and non-creatine group exhibited no change in body mass after the six-week training program.(1) However, the body mass of the creatine-fed group increased by 2kgs in only six weeks.(1) The majority of this increase was due to an increase in water content, inside the cells. Increasing the amount of water held within the cell is a critical mechanism of muscle growth (cell volumizing). Cell volumizing is the increasing of muscle cell's water content and this phenomenon is demonstrated by research to literally "turbo charge" protein synthesis rates.(3)

Most importantly, examination of the data reveals that while the absolute value of total body water and intracellular water content increased, the relative values did not.(1) This means the body mass gains seen with creatine supplementation were not only due to increases in intracellular water content. Because the relative volumes of water within the body remained constant the researchers stated "the gains cannot be attributed to water retention, they are due to dry matter (muscle fiber) growth accompanied by a normal volume of cellular water."(1) In fact, only 55% of body mass increase was water weight. The remaining 45% was an increase in actual muscle fiber growth!(2) Over the training period of 6 weeks the creatine subjects gained an average of 2 kgs and most of this was muscle [~0.9g].(1,2)

The researchers concluded the gains in body mass seen after the 6-week training period using creatine were not from water retention but actual increases in muscle fiber growth! (1,2)

In another experiment the same researchers examined two weeks of creatine loading on accumulation of phosphorylcreatine (PCr) levels in working muscle.(2) PCr is the energy substrate that directly replenishes ATP during intense muscle contraction. The more PCr in a muscle cell, the longer and harder a muscle can work. This is due to a more rapid, higher rate of ATP replenishment. In this study 21gms a day were ingested (3 doses of 7gms) for the two-week duration.(2) Body mass was again measured using the same body water content procedure.

Results showed this dosage pattern increased resting PCr levels by at least 20%.(2) It also increased the rate of ATP replenishment during repeated muscle contractions of both high intensity and submaximal intensity.(2) This means creatine may play a big part in endurance events. Even in submaximal exercise ATP levels are regenerated faster.(2) However, this time there were no significant increases in body mass despite an increase in PCr levels of 20%. No gains in muscle or volume of water compartments were seen.(2) Does this refute the findings of the previous study? No, in fact it substantiates the fact any gains in body mass seen with creatine supplementation are due to muscle growth.(1,2)

If gains in mass were seen immediately with the rise in muscle creatine content they would be due to water retention. The process of building muscle, protein synthesis, is a long-term phenomenon. The delay between the rise in muscle PCr content (2 weeks) and gains in body mass (6-9 weeks) with a normal cellular water content indicates the cellular uptake of creatine temporarily modifies (increases) cell volume. This triggers accelerated protein synthesis rates. The cell then, slowly regulates its normal water volume once again, but with a net increase in contractile fiber growth!

The delay between the rise in muscle PCr content (2 weeks) and gains in body mass (6-9 weeks) with a normal cellular water content indicates true growth of contractile matter. Protein synthesis (growth of muscle) is a long-term phenomenon.

Further evidence.

William Kraemer and colleagues at Pennsylvania and Ball State Universities directly substantiated these findings this year utilizing direct analyses of muscle fibers.(4) These researchers were the first to obtain direct data on skeletal muscle morphology and creatine supplementation by examining muscle biopsies from athletes to see exactly what's happening inside the muscle as a result of creatine supplementation. This study used a one-week loading period (25 gms/day) then another 11 weeks on a maintenance dosage (5 gms/day) while weight training hard for 12 weeks.

After the 12 weeks the body mass of both the creatine-fed group and the placebo (sugar) group increased equally! However the increase in fat-free mass (muscle) in the creatine group (4.3 kgs) was more than double that of the placebo group (2.1 kgs).(4) The creatine-fed group kept growing lean tissue right through the 12-week study.(4) They did not plateau after 4 or even 10 weeks of training.(4) The scientists commented these dramatic gains could have kept going even longer. Also, the scientists concluded the lean body mass gains were a result of greater skeletal muscle growth. Here's why:

The information derived from the muscle biopsies revealed the creatine supplementation increased the cross sectional area (size) of all fiber types, not just the fast twitch (the one predominantly associated with muscle growth).(4) These increases were more than double that of the placebo group.(4) The creatine group initially possessed smaller muscle fiber areas before training and the ramifications of this are not yet known.(4) However, as a direct result of the creatine supplementation, all muscle fiber types grew dramatically. This implies greater myofibrillar synthesis or reduced degradation.(4) Either way, this is an accelerated physiological adaptation to training. This accelerated adaptive mechanism induced by creatine supplementation was substantiated by the fact the creatine group lifted more weight for more reps during the later stages of the study. This is particularly evident in the data on the bench press exercise.(4)

Not only did the creatine group grow bigger muscles, they performed more reps with heavier weight in the later stages of the study.(4) An example of accelerated recovery/adaptation process.


[size=85]References:
1. M Francaux & JR Poortmans. Effects of training and creatine supplement on muscle strength and body mass. Eur. J. Appl Physiol. 80: 165-168, 1999.
2. M Francaux, R Demeure, JF Goudemant & JR Poortmans. Effect of exogenous creatine supplementation on muscle PCr Metabolism. Int J. Sports Med. 21:139-145, 2000.
3. D.Haussinger et al. Functional Significance of Cell Volume Regulatory Mechanisms. Physiol Rev. Vol78.No1:247-272. 1998.
4. JS Volek et al. Performance and muscle fiber adaptations to creatine supplementation and heavy resistance training. Med.Sci.Sport Exerc. Vol 31.No8:1147-1156, 2000.
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Scientific literature clearly demonstrates that creatine increases:
• Strength
• power out-put and
• lean body weight,

Increasing the branching network and number of these myotube channels would theoretically, provide a larger, stronger, more extensive contraction within muscle fibers. The ability to do this is basically what strength training is all about! Creatine supplementation also increased phosphocreatine levels (energy) and the survival rate of these dystrophic muscle cells.2

Before we get too excited, we must remember dystrophic muscle cells are not healthy ones, there is a big physiological difference. Put very simply; Dystrophin is associated with a complex of transmembrane glycoproteins that acts as a link between the muscle sarcolemmal matrix and the extracellular matrix. Loss of this complex results in the instability of the sarcolemma to hold and control flow of Ca2+. The muscle loses the ability to control muscle contraction.2 However, the possibility that the results exhibited in this study may be reproduced in other conditions cannot and should not be discounted.
This report demonstrates that creatine supplementation dramatically affects human Ca2+ transport cells in muscle in a very positive manner. Human muscle myotube cells treated with creatine grew, dramatically and survived longer.2

[size=85]References
Ingwall et al. 1974. Specificity of Creatine in the Control of Muscle Protein Synthesis. Journ. Of Cell Biol.63.p145-151
S.M.Pulido et al. 1998. Creatine supplementation improves intracellular Ca2+ handling and survival in mdx skeletal muscle cells. FEBS Letters 439:357-362.
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