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The ATP-PCr system
The creatine kinase-phosphocreatine system plays a key role in the control of ATP levels in tissues that have a high and fluctuating energy demand (Ponticos et al., 1998; McLeish & Kenyon, 2005). Phosphocreatine (PCr) is a high-energy phosphate molecule used to store energy within muscle cells. Although it cannot be used as an immediate source of energy, the ATP molecule can be reconstructed by reducing PCr to Cr and phosphate (Pi), thereby providing energy for ATP production (Meyer et al., 1984). Energy transfer from PCr is crucial during transitions from low to high energy demand, such as at the beginning of exercise (McArdle et al., 2001). The sarcoplasmic enzyme creatine kinase (CK) catalyses the reversible transfer of Pi between PCr and ATP. This is a dead-end reaction in the sense that there is no other known reaction utilising PCr in cells (Meyer et al., 1984). ATP generated in the mitochondria during rest (from the oxidation of fats and carbohydrates), is utilised to resynthesise Cr released during muscle contraction back to PCr.
Muscle cells store substantial amounts of PCr. In resting muscle the PCr concentration is approximately three to four times that of ATP (Maughan, 1995). At rest 60 to 90% of muscle Cr is in the form of PCr (Harris, 1993; Wyss & Kaddurah-Daouk, 2000), ensuring that ATP broken down during muscle contraction is rapidly (almost immediately) restored. Resting PCr concentrations are higher, and the rate of degradation greater, in type II (fast) muscle fibres compared with type I (slow) fibres (Casey et al., 1996; Kraemer & Volek, 1999). Together, ATP and PCr provide energy fuelling maximum muscle power for about 15 to 20 seconds (Marieb, 2004). The initial store of PCr, and the rate at which it is resynthesised, must be optimal for the muscle to effectively maintain a high ATP content. During intense activity, however, the PCr support for ATP resynthesis will begin to fail. The subsequent build-up of adenosine diphosphate (ADP) is the starting point for further degradation of adenine nucleotide, with the formation of adenosine monophosphate (AMP) and membrane-damaging free radicals (Harris, 1993). This will challenge the normal functioning of the muscle cell and ultimately lead to fatigue
Duration and time course of physical activity
Firstly, substrate choice is dependent on the duration and time course of physical activity. Although it is common to speak of aerobic versus anaerobic exercise, in reality the energy to perform most types of exercise comes from a combination of aerobic/anaerobic energy sources (Powers & Howley, 2009). Indications are that the duration of an event will determine the utilisation of energy sources. Events of five to ten seconds are mainly dependent on ATP and PCr. Whereas events of 40 to 60 seconds mainly depend on anaerobic glycolysis, events of two minutes require almost equal amounts of both anaerobic and aerobic energy, and events lasting more than two minutes depend increasingly on aerobic energy as the event continues (Thoden, 1991). Table 2-1 presents the relative contributions of the different energy systems during continuous activity of a specific duration. However, this table is not meant to apply directly to sports events that last two to three hours at a stretch, but are made up of five- to 20-second bursts at higher rates of energy release, interspersed with recovery periods of lower intensity (eg. tennis and rugby).
Furthermore, substrate availability depends on the time course of physical activity. The anaerobic pathways often kick in temporarily at an early stage in the exercise event as a result of the minuscule store of oxygen available to the muscle cells and a delay caused in the activation of mitochondrial respiration by ADP and inorganic phosphate. High-energy phosphates and glycogen are the immediately available substrates for energy production. They are stored in muscle tissue itself, and are therefore in close contact with the contractile units of the muscle cells. Endogenous hexose phosphates and free glucose inside muscle cells are additionally available for immediate anaerobic utilisation. The penetration by blood glucose of the plasma membrane is a slow process and will therefore only be available as substrate during prolonged exercise (Hultman & Sjöholm, 1983).
Respiratory exchange ratio (RER)
The respiratory exchange ratio (RER) is a variable that indicates substrate utilisation during incremental exercise. RER is the ratio between the amount of carbon dioxide (CO2) produced and the amount of oxygen (O2) consumed. The RER value provides information regarding the proportion of energy derived from various nutrients at rest and during steady-state sub-maximal exercise. It also indicates the attainment of exhaustion. RER values of less than 1.0 at peak exercise generally signify inadequate effort or poor motivation on the part of the participant (Franklin et al., 1989), while values exceeding 1.0 indicate metabolism beginning to rely mainly on anaerobic processes (McArdle et al., 2001). When the RER value exceeds 1.0, as when the individual approaches exhaustion, an accurate estimate of the fuel type being used is no longer possible. Elevations of 1.1 or higher during recovery are associated with an unloading of the excess CO2 that accumulated in the blood during exercise (Wilmore & Costill, 2008). In general, the amount of carbon within a molecule of carbohydrate or fat is proportional to the amount of oxygen needed to oxidise the fuel completely.
Although the body derives more energy when it metabolises a given amount of fat than when it metabolises the same amount of carbohydrate, it takes proportionally more oxygen to oxidise fat (Marieb, 2004). Wilmore and Costill (2008) observe that it is impossible to calculate the use of protein from the RER since protein oxidises less completely than carbohydrate and fat. But, according to Franklin et al. (1989), the RER value for protein metabolism is approximately 0.8. Although, protein has been thought to contribute little to energy used in short duration activities, it may well contribute eight to nine percent of the total energy used in bouts of exercise lasting several hours (Wilmore & Costill, 2008; Williams, 2010). Indeed, Janssen (1987) speculated that for endurance sport, five to 15 percent of the energy supplied is derived from proteins (Janssen, 1987). This percentage may even rise when some very strenuous workouts are done successively, or when the duration of the exertion increases further (Williams, 2010). Table 2-2 shows that the RER will vary with the substrates being used for energy.
Effect of Cr on muscle hypertrophy
Increases in muscle fibre hypertrophy and muscle protein content have been observed with Cr supplementation, especially when combined with resistance training (Table 2-5). However, the supplementation regimen seems to play an important role in facilitating these outcomes. Shortterm Cr loading in humans did not result in net gains in muscle protein synthesis or hypertrophy (Louis et al., 2003b; Louis et al., 2003c; Kinugasa et al., 2004; Deldicque et al., 2005). It was found that Cr loading followed by an extended maintenance period (6 – 15 weeks) induced muscle hypertrophy (Volek et al., 1999; Burke et al., 2003; Chilibeck et al., 2004; Souza-Junior et al., 2011), as well as an amplified muscle hypertrophy response (Olsen et al., 2006) in subjects who participated in an associated resistance training programme. Prolonged lowdosage Cr supplementation also proved effective in supporting muscle hypertrophy in that it increased myofibrillar protein content (Sipilä et al., 1981; Willoughby & Rosene, 2001; Jäger et al., 2008) and the expression of myoregulatory factors (Willoughby & Rosene, 2003). Some of the studies that reported gains in muscle protein also reported gains in muscle strength (Volek et al., 1999; Willoughby & Rosene, 2001; Brose et al., 2003; Burke et al., 2003; Chilibeck et al., 2004; Olsen et al., 2006; Souza-Junior et al., 2011). However, the underlying physiological mechanism(s) to explain this ergogenic effect remain unclear. In essence, a Crinduced enhancement of strength and particularly muscle fibre area must depend on interaction in some manner between Cr and known or postulated mechanisms of muscle-fibre hypertrophy (Volek & Rawson, 2004). As explained in the previous paragraphs, one of the explanatory mechanisms applied to Cr, namely cellular hydration and swelling, has been difficult to validate.
Another theory to consider here is that Cr supplementation combined with resistance training may influence the expression of certain myogenic regulatory factors (MRF), which may increase myosin heavy chain (MHC) synthesis. This theory is supported by study results achieved by Willoughby and Rosene (2001; 2003), Louis et al. (2004), Deldicque et al. (2005) and Saremi et al. (2010). However, further research is needed to clarify whether oral Cr supplementation has a direct effect on the expression of MRF and MHC, or whether the effect is indirectly mediated through a greater training volume resulting in increased stimulation of muscle hypertrophy (Burke et al., 2003; Louis et al., 2003b; Chilibeck et al., 2004; Volek & Rawson, 2004; Rahimi et al., 2010; Souza-Junior et al., 2011), in which case it may either be that acute exercise unmasks some anabolic effect of Cr not seen at rest (Schedel et al., 2000), or that, because Cr increases force development through increases in muscle PCr stores, work output during training can be increased during Cr supplementation with a benefit to muscle accretion (Louis et al., 2003c; Souza-Junior et al., 2011). An increase in myonucleus number is not a permissive factor to achieve muscle fibre hypertrophy, but it may set the limit for muscle hypertrophy by regulating the nuclear domain of the muscle cell (Olsen et al., 2006). It has been found that Cr supplementation combined with resistance training elevates myonucleus number respectively by 14% and 17% at weeks 4 and 16 (Olsen et al., 2006). The authors attributed the accelerated time course and more marked muscle-fibre hypertrophy of the Cr group to this phenomenon. The study (Olsen et al., 2006) also reported increased satellite cell numbers of myofibres. This effect may have been mediated, at least in part, via Cr-induced facilitation of MRF pathways. The results of the study therefore support a role for Cr in activating myogenic satellite cells (Olsen et al., 2006). These activated cells then donate their nuclei to muscle fibres, thereby augmenting repair and recovery of muscle fibres and the training-induced accretion of muscle mass, especially in the early part of the training bout (Olsen et al., 2006).
Other safety concerns
In his letter to the editor of the Clinical Journal of Sport Medicine, Archer (1999) pointed out that under the conditions that exist in the human stomach (high acidity, supply of nitrite from food and saliva) Cr can react to form N-nitrosarcosine. He (Archer, 1999) argued that the deleterious effects of the presence of this carcinogenic compound would only become apparent after many years, and thus warranted consideration by those advocating the use of Cr as an ergogenic compound. Tarnopolsky (1999) indicated in his reply to these comments that under ideal conditions approximately one gram of N-nitrosarcosine can be formed in vivo from five grams of Cr. This would amount to one sixteenth of the dose used to induce carcinoma in experiments (Tarnopolsky, 1999). The author did, however, recommend that detailed pathologic studies be performed to determine whether an increase in carcinogenesis is associated with Cr supplementation in humans (Tarnopolsky, 1999).
Rhabdomyolysis is a serious condition that results from a breakdown of the muscle cell wall, which leads to cell necrosis (Juhn, 2000). Two case studies have raised concerns about the possibility of this serious adverse effect of Cr supplementation. Robinson (2000) reported acute quadriceps compartment syndrome and rhabdomyolysis in a weight-lifter using high-dosage Cr supplementation. Potteiger et al. (2001) also reported elevated lower-leg anterior compartment pressure in a healthy physically active male subject during and after Cr supplementation, although rhabdomyolysis was absent. Both authors (Robinson, 2000; Potteiger et al., 2001) attributed the increased compartmental pressure to the potential water retention properties of Cr. Thus, individuals susceptible to compartment syndrome and rhabdomyolysis due to dehydration, illicit drug use, trauma or strenuous exercise (Juhn, 2000) should be closely monitored during Cr supplementation. According to Juhn (2000) the question they should be asking is: “Is it really worth it?”
2-1 Work time partitioned into aerobic and anaerobic contributions
2-2 The Respiratory Exchange Ratio (RER) and fraction (%) of energy derived from the oxidation of carbohydrates and fat
2-3 Effect of Cr ingestion on body weight, fat-free weight and fat% – a summary of the literature
2-4 Effect of Cr ingestion on body water compartments – a summary of the literature
2-5 Effect of Cr supplementation on muscle morphology – a summary of the literature
3-1 Training programme in preparation for the Comrades Marathon (March – May)
3-2 Chemical pathology analyses
3-3 Between-group analysis of the change in body composition of the CRE group compared to that of the PLA group
3-4 Between-group analysis of the change in recorded scores associated with maximal aerobic capacity of the CRE group compared to that of the PLA group
3-5 Between-group analysis of the change in recorded scores associated with the sub-maximal running economy of the CRE group compared to those of the PLA group
3-6 Between-group analysis of the change in recorded scores associated with the serum chemical pathology of the CRE group compared to those of the PLA group
3-7 Comparison of the change in body composition of ultradistance runners in the CRE and PLA groups across test intervals
3-8 Comparison of the change in recorded values associated with maximal aerobic capacity of ultradistance runners in the CRE and PLA groups across test intervals
3-9 Comparison of the change in recorded scores associated with sub-maximal running economy of ultradistance runners in the CRE and PLA groups across test intervals
3-10 Comparison of the change in recorded scores associated with chemical pathology of ultradistance runners in the CRE and PLA groups across test intervals
4-1 Participant activity level
4-2 Haematology and biochemistry performed on full blood
4-3 Product information per 2 capsules Creatine Forte (NRF Sport, Centurion)
4-4 Descriptive statistics for general measurements during baseline testing of the EX group and CO group
4-5 Between-group analysis of the change in recorded scores associated with the serum biochemical pathology of the EX group compared to that of the CO group
4-6 Between-group analysis of a change in measurement scores associated with isokinetic strength/power expressed relative to body weight for the EX group compared to the CO group
