2. Why supplement with creatine? The energy that fuels most metabolic functions comes from the splitting of high-energy phosphate compounds. ATP is the major source of fuel for metabolism. ATP is constantly resynthesized so that there is a continual source of ATP for biologic work. The major energy sources for ATP resynthesis are fats and carbohydrates. However, phosphocreatine (PCr) is another high-energy phosphate that can be hydrolyzed to provide the energy to form ATP from ADP+P (it is often called an “energy reservoir”).

3. Creatine is found in meat, poultry, and fish. Until recently, scientists believed that vegetarians had normal levels of muscle creatine because the body synthesizes creatine from amino acids in the diet. However, a study published in 2003 offers the first evidence that vegetarians have lower muscle creatine. Tarnopolsky et al MSSE 2003

4. amino acid excreted in the urine

5. About 95% of the body’s total creatine is contained in skeletal muscle as one of two forms. –PCr (~60%) and free creatine (~40%). CK stimulated to hydrolyze PCr to Cr by buildup of ADP. This makes sense since a large amount of ADP is indicative of low energy in the cell and PCr is used to create more ATP. PCr is referred to as “buffering” the ATP levels in the cell - meaning the presence of PCr keeps ATP levels from falling.

6. Creatine Metabolism CreatinePhosphocreatine Creatinine ATPADP PiPi H2OH2O H2OH2O + H + Creatine Kinase (CK)

7. PCr is used as an energy source for quick, intense bouts of work. H + + PCr + ADP  ATP + Cr enzyme is creatine kinase (CK) The idea behind creatine supplementation is that increasing the body’s stores of PCr will provide an advantage for high power, short-duration work. The key was thought to be an increase in PCr.

8. As the data below show, PCr is the predominant energy source for ATP synthesis for very short duration, high intensity muscle contraction. Rate of ATP production (mmol/sec/kg) during maximal contraction in human muscle Duration PCr glycolysis 0-1.3 sec 9.0 2.0 1.4-2.5 sec 7.5 4.3 2.6-5 sec 5.3 4.4 5-10 sec 4.2 4.5 10-20 sec 2.2 4.5 20-30 sec 0.2 2.1 Greenhaff, Int. J. Sport Nutr. 1995

9. PCr may also shuttle intramuscular phosphate between the mitochondria and muscle filament cross-bridge sites (the actual sites of muscle contraction). Theoretically, high levels of PCr should also lessen the reliance on anaerobic glycolysis. Remember that H+ ions are produced during glycolysis which are buffered by pyruvate which reduces to lactate. The rate controlling step of glycolysis is catalyzed by an enzyme called phosphofructose kinase (PFK). PCr levels exert some control over the activity of this enzyme. As PCr levels decrease the activity of PFK goes up, increasing the rate of glycolysis.

10. Potential mechanism ATP  ADP   ATP  ADP Cr  CrP   Cr  CrP ATP  ADP mitochondria Actin and myosin

11. Summary: Role of PCr in Muscle 1. Fast production of ATP (maximal work?) 2. Buffers change in ATP/ADP (maintain high rate of work?) 3. Faster high energy phosphate diffusion (faster recovery?) 4. Buffers intracellular hydrogen ions (less fatigue?) 5. Reduced PCr, increased Pi may activate glycolysis (less reliance on glycolysis – less glycogen use?

12. Cr Supplementation Era 1993 - 2000 ??? human studies Major focus –Exercise performance –Body composition –Optimizing uptake Recent Studies –Clinical - elderly, muscle disease, CHF, COPD, Arthritis, Gyrate Atrophy & other diseases

13. Cr Supp & Performance Exercise performance involving short periods of extremely powerful activity can be enhanced, especially during repeated bouts. ….enhanced accrual of strength in strength- training programs. Terjung et al. ACSM Creatine Roundtable. MSSE, 2000

14. Creatine and Performance N = 8 fit men/group Randomized, double-blind 30 g Cr/d for 6 d 4 familiarization trials 10 x 6s maximal cycling; 30s rest intervals Target rpm = 140/min Balsom et al., Scand. J. Med. Sci. Sports 3:143-149, 1993

15. Kreider et al (1998) “Effects of creatine supplementation on body composition, strength, and sprint performance”. Creatine (16 g/d): 11 football players Placebo: 14 “ “ (matched on body weight) Resistance training: 4 d/wk monitored Sprint/agility training: 3 d/wk; Diets: monitored Addition of creatine to the glucose/taurine/electrolyte supplement promoted greater gains in fat/bone- free mass, isotonic lifting volume, and sprint performance during intense resistance/agility training.

16. Becque et al. ”Effects of oral creatine supplementation on muscular strength and body composition”. MSSE, 2000 Biceps training for 6 weeks with either Cr (20g/d for 5 days and then 2g/d) or placebo. After 6 weeks: increase of 2.0 kg in Cr group (+0.4 with placebo) with FFM increasing 1.6 kg. Upper arm area incr. 8 cm 3 with Cr and 2.5 cm 3 with placebo. 1 RM incr. 2x more with Cr than with training alone. Authors conclude “creatine supplementation during arm flexor strength training lead to greater increases in arm flexor muscular strength, upper arm muscle area, and fat- free mass than strength training alone”

17. Cr Supp & Body Mass Consistent  in body mass (1 - 3 kg) Acute - Most likely water retention –  urine vol. during Cr supp (Hultman et al. 1996) Water retention 1st? Protein synthesis 2nd? Both together?

18. Cr & Protein Synthesis  synthesis of myosin, actin, & CK in vitro & in vivo (Ingwall et al. 1972 -1976) Rat Studies –  protein content (Flisinska - Bojanowska 1996) –Ø in CK or myosin (Brannon et al. 1997) –  satellite cell activity (Dangott et al. 2000)

19. How to use creatine effectively... Remember, the benefits of creatine are related to an athlete’s ability to train harder. –This means that creatine alone (without training) likely won’t increase strength. Most common creatine supplementation regime: 1.LOADING PHASE: 5-10 days (20-25g/day) 2.MAINTENANCE PHASE: (2-5g/day) -Goal of maintenance phase is maintain muscle saturation. Creatine absorption appears to be enhanced when the supplement is taken with a high CHO drink (ex: juice) - Tarnopolsky et al., 2001

20. Cr uptake and Glucose ingestion

21. Creatine and Body Mass Conclusions 1.Body mass does tend to increase with creatine supplementation. 2. The increase is almost exclusively fat free mass 3. Although there may be some retention water in the short-term, there is some evidence that longer- term use (>6-8 weeks) may increase myofibrillar protein? 4. Do size and strength gains result because creatine allows faster recovery between bouts so that people can train at a higher intensity/longer duration?

22. Creatine and Caffeine Vandenberghe et al. (1996) looked at whether combining Cr and caffeine would increase Cr uptake by muscle. –0.5g/kg BW of Cr –0.5mg/kg BW of caffiene (equivalent to about 3 cups of coffee for 70kg male) Expected additive effect but Cr in muscle was same with or w/o caffeine. Unexpectedly, addition of caffeine eliminated ergogenic effects of creatine on knee extensor force.

23. This recent work suggests that caffeine ingestion disrupts the mechanism through which creatine ingestion increases muscle creatine levels. May be due to muscle contraction relaxation time being prolonged (Hepsel et al 2002) thereby interrupting recovery of PCr? Based on these and other studies, athletes who use creatine are often told to abstain from caffeine during the loading phase of creatine supplementation when loading the muscle Caffiene known to enhance prolonged bouts of exercise, not necessarily high intensity exercise

24. Side Effects Anecdotally reported: Gastrointestinal distress Nausea Dehydration Muscle cramping Long term effects of creatine supplementation have not been documented in healthy individuals but no adverse events have been linked to creatine use > 5yrs. Individuals with pre-existing kidney or liver dynsfunction often not recommended to ingestion Cr supplementation Not reported in scientific literature

25. Conclusions from a host of different studies 1.Creatine supplementation increases total Cr, but not necessarily CR-P in skeletal muscle 2. Size of the increase is related to initial Cr levels (start low = bigger response) and individual responses vary a lot 3. In many people, Cr supplementation enhances performance of repeated, high-intensity exercise 4. Caffeine use (and probably hard training) probably reduce the size of the creatine effect

26. Conclusions from a host of different studies 5. Supplementation results in an initial increase in body mass (likely due to water retention) 6.May have an age related effect. Older individuals may show greater improvement compared to younger individuals. Not clearly shown. 7.Seems that there is no clear effect of training status or gender on performance outcomes after creatine supplementation. (Due to large variance among individuals taking creatine)