Creatine: prescription for bad genes and a hostile environment?

Creatine is a molecule that has recently received considerable attention in the lay press because of its use as a dietary supplement by athletes in an effort to enhance their performance. For nearly 70 years it has been known that tissues such as muscle contain high concentrations of creatine and phosphocreatine, which are used as a source of ‘high-energy phosphate’ that serves as a cellular energy buffer. Creatine can be produced from the amino acid arginine or can be obtained in the diet. Many tissues, including the brain, contain high levels of creatine kinase and are therefore capable of producing phosphocreatine. Studies by Matthews et al.1xNeuroprotective effects of creatine and cyclocreatine in animal models of Huntington's disease. Matthews, R.T. et al. J. Neurosci. 1998; 18: 156–163PubMedSee all References1 showed that dietary supplementation with creatine can increase concentrations of phosphocreatine in rodent brains, and that cellular ATP levels can be maintained and mitochondrial function preserved by creatine administration in neurons subjected to excitotoxic and metabolic insults. Impaired energy metabolism, resulting in depletion of ATP in neurons, appears to be a major factor leading to neuronal dysfunction and death in Huntington's disease (HD), an inherited and always fatal disorder caused by expanded trinucleotide (CAG) repeats in the huntingtin gene that results in degener-ation of striatal neurons that control body movements. Ferrante et al.2xNeuropro-tective effects of creatine in a transgenic mouse model of Huntington's disease. Ferrante, R.J. et al. J. Neurosci. 2000; 20: 4389–4397PubMedSee all References2 have now employed a transgenic mouse model of HD to determine whether creatine supplementation might counteract the neurodegener-ative cascade induced by the HD mutation.Transgenic mice expressing exon 1 of the human HD gene produce huntingtin protein that contains polyglutamine expansions, and develop a progressive neurological syndrome characterized by resting tremor and an abnormal gait. Extensive death of striatal neurons does not occur in the HD mice, but they do exhibit degenerative changes, including intraneuronal inclusions containing huntingtin and ubiquitin. Importantly, there is evidence for cellular energy deficits in the HD mice prior to behavioral alterations and degenerative changes. When HD mice were fed a diet containing 1–3% creatine (beginning at weaning age), the development of motor dysfunction was delayed and their survival was significantly increased. Analysis of the mice brains showed that those fed creatine developed fewer intraneuronal inclusions and decreased neuronal atrophy; and contained increased levels of creatine and N-acetylaspartate levels (a measure of cellular energy status). These striking results provide a strong rationale for clinical trials of creatine in human HD patients.If creatine can counteract bad genes, might it also protect neurons against a harsh environment? Traumatic injuries to the brain and spinal cord are major causes of death and long-term disability and, although good animal models of such injuries are available, few treatments have proven effective in these models. Sullivan et al.3xSee all References3 have found that rats fed a diet supplemented with creatine for one month exhibit reduced brain damage and improved synaptic mitochondrial function after traumatic brain injury. These findings are particularly good news for athletes because they suggest that creatine supplementation could not only enhance their performance, but might also reduce the severity of their injury should they suffer a severe blow to the head or spinal cord.