The creatine kinase system and pleiotropic effects of creatine

Abstract

The pleiotropic effects of creatine (Cr) are based mostly on the functions of the enzyme creatine kinase (CK) and its high-energy product phosphocreatine (PCr). Multidisciplinary studies have established molecular, cellular, organ and somatic functions of the CK/PCr system, in particular for cells and tissues with high and intermittent energy fluctuations. These studies include tissue-specific expression and subcellular localization of CK isoforms, high-resolution molecular structures and structure–function relationships, transgenic CK abrogation and reverse genetic approaches. Three energy-related physiological principles emerge, namely that the CK/PCr systems functions as (a) an immediately available temporal energy buffer, (b) a spatial energy buffer or intracellular energy transport system (the CK/PCr energy shuttle or circuit) and (c) a metabolic regulator. The CK/PCr energy shuttle connects sites of ATP production (glycolysis and mitochondrial oxidative phosphorylation) with subcellular sites of ATP utilization (ATPases). Thus, diffusion limitations of ADP and ATP are overcome by PCr/Cr shuttling, as most clearly seen in polar cells such as spermatozoa, retina photoreceptor cells and sensory hair bundles of the inner ear. The CK/PCr system relies on the close exchange of substrates and products between CK isoforms and ATP-generating or -consuming processes. Mitochondrial CK in the mitochondrial outer compartment, for example, is tightly coupled to ATP export via adenine nucleotide transporter or carrier (ANT) and thus ATP-synthesis and respiratory chain activity, releasing PCr into the cytosol. This coupling also reduces formation of reactive oxygen species (ROS) and inhibits mitochondrial permeability transition, an early event in apoptosis. Cr itself may also act as a direct and/or indirect anti-oxidant, while PCr can interact with and protect cellular membranes. Collectively, these factors may well explain the beneficial effects of Cr supplementation. The stimulating effects of Cr for muscle and bone growth and maintenance, and especially in neuroprotection, are now recognized and the first clinical studies are underway. Novel socio-economically relevant applications of Cr supplementation are emerging, e.g. for senior people, intensive care units and dialysis patients, who are notoriously Cr-depleted. Also, Cr will likely be beneficial for the healthy development of premature infants, who after separation from the placenta depend on external Cr. Cr supplementation of pregnant and lactating women, as well as of babies and infants are likely to be of benefit for child development. Last but not least, Cr harbours a global ecological potential as an additive for animal feed, replacing meat- and fish meal for animal (poultry and swine) and fish aqua farming. This may help to alleviate human starvation and at the same time prevent over-fishing of oceans.

Creatine in health, medicine and sport: an introduction to a meeting held at Downing College, University of Cambridge, July 2010

“…From examination of the dynamics and distribution of CK, it is evident that the Cr/PCr/CK system contributes to cellular metabolism in at least three fundamental ways; as (1) an immediately available temporal energy buffer at sites of rapid ATP turnover, (2) a spatial energy buffer or intracellular energy transport system (i.e., the CK/PCr energy shuttle or circuit), and (3) as a metabolic regulator of oxidative phosphorylation (Guzun et al 2011;Wallimann et al 2011). As a temporal buffer, Cr/PCr/CK both regenerates ATP and maintains ADP at a low concentration.…”

“…The CK/PCr energy shuttle connects sites of ATP production (glycolysis and mitochondrial oxidative phosphorylation) with subcellular sites of ATP utilization (ATPases). Thus, limitations imposed by the diffusion of ATP, and in particular ADP, are overcome by Cr and PCr with much higher diffusion rates and present in a combined concentration, for instance in muscle, up to six times higher than that of the adenine nucleotide pool (Wallimann et al 2011). Mitochondrial CK in the mitochondrial outer compartment is tightly coupled to ATP export via adenine nucleotide carrier (ANT) and thus ATP-synthesis and respiratory chain activity, releasing PCr into the cytosol.…”

“…Aging and reduced physical activity are associated with decreases in muscle mass, bone mineral density, and strength (Rawson and Venezia 2011;Tarnopolsky 2011;Wallimann et al 2011). However, there is increasing evidence that Cr supplementation may slow and even reverse some of these changes.…”

“…However, for the most part we have overlooked in our debate on Cr that for much of hominid evolution this was a normal component of the diet and at levels comparable with those when Cr supplements are taken (Wallimann et al 2011). Indeed, on a mg/kg body weight basis, the ''high'' levels taken by athletes when ''Cr loading'' are close to and even surpassed by those ingested by any carnivorous animal.…”

“…While it is evident that humans can function in the absence of a dietary supply of Cr, there are likely to be instances, for example in the elderly, those on a protein restricted diet, vegans, pregnant and lactating women, and in the premature and new born (Wallimann et al 2011) where consideration perhaps should be given to inclusion of Cr in the diet. Certainly, this would seem to be the case for the otherwise-healthy elderly population where age progression, and age-related changes, for example in bone mineral density appear to benefit from Cr supplementation (Wallimann et al 2011).…”