Cerebral energetic effects of creatine supplementation in humans

Abstract

There has been considerable interest in the use of creatine (Cr) supplementation to treat neurological disorders. However, in contrast to muscle physiology, there are relatively few studies of creatine supplementation in the brain. In this report, we use high-field MR 31 P and 1 H spectroscopic imaging of human brain with a 7-day protocol of oral Cr supplementation to examine its effects on cerebral energetics (phosphocreatine, PCr; ATP) and mitochondrial metabolism (N-acetyl aspartate, NAA; and Cr). We find an increased ratio of PCr/ATP (day 0, 0.80 Ϯ 0.10; day 7, 0.85 Ϯ 09), with this change largely due to decreased ATP, from 2.7 Ϯ 0.3 mM to 2.5 Ϯ 0.3 mM. The ratio of NAA/Cr also decreased (day 0, 1.32 Ϯ 0.17; day 7 1.18 Ϯ 0.13), primarily from increased Cr (9.6 Ϯ 1.9 to 10.1 Ϯ 2.0 mM). The Cr-induced changes significantly correlated with the basal state, with the fractional increase in PCr/ATP negatively correlating with the basal PCr/ATP value (R ϭ Ϫ0.74, P Ͻ 0.001). As NAA is a measure of mitochondrial function, there was also a significant negative correlation between basal NAA concentrations with the fractional change in PCr and ATP. Thus healthy human brain energetics is malleable and shifts with 7 days of Cr supplementation, with the regions of initially low PCr showing the largest increments in PCr. Overall, Cr supplementation appears to improve high-energy phosphate turnover in healthy brain and can result in either a decrease or an increase in high-energy phosphate concentrations. high-energy phosphates; brain; N-acetyl aspartate; metabolism SEVERAL GROUPS HAVE SHOWN that oral creatine (Cr) supplementation can affect energy dynamics and performance in muscle (4,17,22) and brain (7,12,16,24). In both of these tissues where energy demand and ATP consumption may be temporally dynamic, relatively higher concentrations of creatine and phosphocreatine are found, presumably for its physiological role as a buffer for ATP. Also found in these tissues are mitochondrial and cytosolic creatine kinase isoforms that serve to transfer high-energy phosphate equivalents between the sites of production and consumption. Thus, as suggested in muscle (3, 18), Cr supplementation may enhance both the spatial and chemical buffering of high-energy phosphates, and this effect may contribute to the functional consequences of supplementation. For example, Watanabe et al. (24) used a double-blind placebo-controlled study of short-period creatine supplementation (5 days) to affect cognitive performance, finding that the cognitive decline associated with mental fatigue was reduced with a brief period of creatine supplementation (8 g/day for 5 days). Although these considerations have contributed to the therapeutic use of creatine in neurological diseases in which metabolic and mitochondrial dysfunction is pertinent [e.g

Proton magnetic resonance spectroscopic creatine correlates with creatine transporter protein density in rat brain

“…Our result fits nicely to the known effect of oral creatine supplementation: there is evidence from preclinical and human studies that excessive oral creatine supplementation increases regionally dependent brain tCr levels (Michaelis et al, 1999;Dechent et al, 1999;Lyoo et al, 2003;Pan and Takahashi, 2007). In those studies supplementation usually took place for at least 1 week, sometimes several weeks, which may suggest an upregulation of the CrT under constant excessive creatine supply.…”

Adverse Stress, Hippocampal Networks, and Alzheimer’s Disease

“…Lifestyles that incorporate mild intermittent beneficial stressors (exercise, dietary energy restriction and cognitive challenges) and minimize adverse chronic stressors (psychosocial stress, sleep deprivation and the like) provide the first line of defense. Improving peripheral and brain cell energy metabolism through dietary supplementation (with creatine, for example) or drugs (exendin-4, for example) is another approach that may be used in individuals at risk (Sullivan et al, 2000; Pan et al, 2007; Li et al, 2009; Martin et al, 2009). Suppressing glucocorticoid production pharmacologically would be expected to counteract the adverse effects of chronic stress on neural networks in the brain (Smith-Swintosky et al, 1996), although such drugs may compromise the beneficial effects of glucocorticoids in acute stress conditions.…”

A Potential Role for Creatine in Drug Abuse?

“…The therapeutic value of oral creatine supplementation to treat brainrelated disorders is underscored by the ability of creatine to permeate the blood-brain barrier and increase cellular energy reserves [8,[58][59][60][61]. The beneficial effects of creatine are also connected to its role as a buffer in metabolic processes needed to prevent energy depletion and neuronal loss.…”