Lecture 22 Creatine

							       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”).
•   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
 amino acid




excreted in the urine
•   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.
            Creatine Metabolism
H 2N                                                  H2N     HN   PO3
             NH2
       CH              ATP          ADP                     CH

H 3C N                                                H3C N              + H+
       CH2         Creatine Kinase (CK)                     CH2
       COO                                                  COO

Creatine                                              Phosphocreatine
                                                 Pi
              H 2O              H
                       HN       N         H 2O
                                     O
                            N
                     H 3C

                        Creatinine
• 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.
•   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
• 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.
ATP  ADP            mitochondria

      
ATP  ADP
 Cr  CrP
               Potential mechanism
      
      
 Cr  CrP
ATP  ADP
            Actin and myosin
     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?
    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
    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
           Creatine and Performance
•   N = 8 fit men/group
•   Randomized, double-blind
•   30 g Cr/d for 6 d
•   4 familiarization trials                         145




                                     Pedaling Rate
•   10 x 6s maximal cycling;
•   30s rest intervals                               140
•   Target rpm = 140/min                             135
                                                               Creatine
                                                     130
                                                               Placebo
                                                     125
Balsom et al., Scand. J. Med. Sci.
Sports 3:143-149, 1993                               120
                                                           0 1 2 3 4 5 6 7 8 9 10
                                                             Number of Cycling Bouts
   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


                                                         2.5




                                     CHANGE AFTER 28 d
Addition of creatine to the                                2                                             Placebo
glucose/taurine/electrolyte
                                                         1.5
supplement promoted                                                                                      Creatine
                                                           1
greater gains in fat/bone-
free mass, isotonic lifting                              0.5

volume, and sprint                                         0

performance during intense                               -0.5
resistance/agility training.                              -1
                                                                Body Mass   Fat Mass   Fat-and-Bone-   Body Water
                                                                                         Free Mass
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 cm3 with Cr and 2.5 cm3 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”
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?
         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)
            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
Cr uptake and Glucose ingestion




                QuickTime™ and a
       TIFF (Uncompressed) decompressor
         are needed to see this picture.
   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?
             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.
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
                        Side Effects
Anecdotally reported:

•   Gastrointestinal distress
•   Nausea                                  Not reported in
•   Dehydration                            scientific literature
•   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
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
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)