The creatine‐phosphocreatine system: there's more than one song in its repertoire

As you read this you are probably well aware of the principal role of phosphocreatine (PCr) in skeletal muscle energy metabolism, namely that of a ‘temporal’ energy buffer at sites of high energy translocation which operates when the rate of ATP utilisation outstrips the rate of production by mitochondrial respiration. Thus, at the onset of steady-state contraction, or during non-steady-state conditions, PCr maintains ATP homeostasis at specific sites of high energy turnover (e.g. myofibrils; Fig. 1, Function 1), particularly in fast contracting skeletal muscle. Figure 1 Probably fewer of you are aware of the growing evidence that is emerging pointing to much more complex, elegant and versatile roles for the creatine-phosphocreatine (Cr-PCr) system in skeletal muscle (for excellent reviews see Wallimann et al. 1992; Saks & Ventura-Clapier, 1994). Fortunately, a paper published by Walsh et al. in this volume of The Journal of Physiology offers me a good opportunity to highlight some of these new emerging roles. A second role proposed for the Cr-PCr system is that of a cellular energy transport system (the Cr-PCr shuttle). Mainstream scientific opinion leads us to believe that intracellular energy translocation is entirely dependent on the diffusion of ATP and ADP from sites of energy production to sites of energy utilisation and vice versa (Meyer et al. 1984). However, in 1966, Samuel Bessman introduced the concept of the Cr-PCr shuttle (Bessman & Fonyo 1966), which was presented as an alternative explanation of movement of cellular chemical energy. In this model, which has now evolved to its current intricate and elegant compartmentalised state (Wallimann et al. 1992; Saks & Ventura-Clapier 1994), Cr and PCr are designated as cellular ‘energy carriers’, based on observations that creatine kinase isoforms exist in discrete cellular locations, and thereby have different metabolic roles, with the outer mitochondrial membrane relatively impermeable to adenine nucleotides, thereby making Cr and PCr more plausible ‘energy carriers’. The model shows that the role of the ‘classical’ ATP-ADP system is somewhat reversed, so that ATP and ADP became co-factors functioning in discrete cellular compartments (Fig. 1, Function 2). The relative importance of each of these models to cellular spatial energy transfer is still hotly debated. For example, it has been proposed that there is no major loss of muscle function in creatine kinase knock-out animals and animals fed creatine analogues (to replace muscle Cr and PCr stores), indicating that neither creatine kinase nor PCr are central to cellular energy transduction. Conversely, creatine kinase knock-out and creatine analogue feeding have been shown to result in marked myofibrillar and mitochondrial remodelling (suggesting energy transduction is altered), and the impairment of muscle function during near maximal, rather than submaximal, contraction. A third role for the Cr-PCr system that I would like to highlight is that of a low threshold ADP sensor that functions to maintain [ATP]/[ADP] ratios in subcellular locations where creatine kinase is functionally coupled to ATP-consuming and -producing pathways. In the context of mitochondrial respiration, therefore, it is proposed that Cr would react with ATP derived from mitochondrial respiration in a reaction catalysed by mitochondrial creatine kinase (and functionally coupled to adenine nucleotide translocase), thereby resulting in an increase in the local ADP concentration and the stimulation of mitochondrial respiration (Fig. 1, Function 3). In this volume of the Journal of Physiology, the elegant paper by Walsh et al. lends considerable evidence in support of this premise, and what is more, the experiment was performed using human skeletal muscle. In line with previous work by this group using the skinned muscle fibre preparation, and by others, the authors were able to show that when creatine was added to a mitochondrial incubation medium ADP- stimulated respiration was increased. However, the novel and most exciting finding presented was that PCr was able to reduce ADP-stimulated mitochondrial respiration, and that this effect was equal to, or greater than, the opposite effect of Cr on respiration. What does this tell us? We now know that PCr per se can exert a regulatory effect on mitochondrial respiration. Indeed, based on Walsh et al. it appears that PCr may be a more potent regulator of mitochondrial respiration than Cr. Furthermore, it is now clear that cellular [PCr]/[Cr] ratios will impact on mitochondrial respiration, which is directly in line with the proposed role for the Cr-PCr system as a low threshold ADP sensor which functionally couples ATP-consuming and -producing pathways at discrete subcellular locations. The other important roles for the Cr-PCr system in skeletal muscle that I would like to identify, but unfortunately do not have the space to highlight in detail are its role in preventing substantial increases in cellular free ADP concentrations, and thereby minimising cellular adenine nucleotide loss; its role in maintaining pH homeostasis, particularly at the onset of exercise; and finally, its role in activating glycogenolysis and glycolysis at the onset of contraction by liberating Pi, thereby integrating PCr and carbohydrate degradation to maintain ATP provision at the onset of exercise. Lastly, given that debate about the regulation of skeletal muscle energy metabolism has raged for well over half a century, we need to ask ourselves why it has taken us so long to identify these important roles for the Cr-PCr system in skeletal muscle? The paper of Walsh et al. offers us one good explanation, as it highlights that at least some of our current understanding of the control of mitochondrial respiration has been constrained because information has been gleaned from experiments performed in vitro using isolated mitochondrial preparations. As the authors themselves indicate, this procedure is limited by having a relatively low mitochondrial yield, but perhaps more important to the present setting, because ‘the sensitivity of respiration to ADP and the effect of creatine (on mitochondrial respiration) appear to be altered during the isolation period’. The lesson to be learnt perhaps by all of us from this is that the experimental approach utilised by researchers can often limit our understanding, and we should all endeavour to try to keep something of an open mind when possible. In this respect, the innovative approach of Walsh et al. offers good guidance to us all.