Role of Creatine in Health and Disease
Creatine (Cr) is an essential component of cellular energy storage and production in tissues with high energy requirements. Cr deficiency in humans is caused by a small group of rare inborn errors of metabolism involving synthesis and transport. In contrast, Cr supplementation is purported to have a protective effect on neurologic progression in disease models of amyotrophic lateral sclerosis, Huntington disease, and Parkinson disease. Furthermore, prophylactic Cr administration in animals appears to be neuroprotective in animal models of traumatic and ischemic brain injuries.
The most significant utilization of Cr occurs in muscle and brain. In these organs, Cr and phosphocreatine, together with creatine kinase isozymes and ATP/ADP, provide the major reserve of energy. Deficiency of the first enzyme in the Cr synthetic pathway, arginine:glycine amidinotransferase (AGAT), in humans leads to complete deficiency of Cr synthesis and severe neurological sequelae, including mental retardation and autistic features. However, newborns appear normal and early treatment may eliminate neurologic injury. Thus, Cr deficiency appears to be an excellent candidate for newborn screening.
Using a mouse model of AGAT deficiency, our goal is to provide insights into the pathologic mechanisms of this inherited metabolic disease with regard to learning and synaptic plasticity. We will use behavioral testing in conjunction with electrophysiology to examine the neurologic phenotype and its response to Cr supplementation.
We are also interested in understanding the effect of Cr deficiency on muscle bioenergetics using various physiologic and biochemical assays, including exercise testing, tissue and fluid analytes, magnetic resonance spectroscopy and mitochondrial respiration using skinned muscle fibers. We will investigate the effects of oral Cr administration as a neuroprotective agent by determining the threshold for seizure induction and examining sensitivity to hypoxic injury.
These studies will provide insights into a screenable human disorder and more broad biomedical issues.
Relevance of the project to IDDRC mission:
Energy homeostasis is central to the nervous system and this project is directed at understanding whether cratin metabolism is relevant to both developmental and homeostatic processes in the brain. Creatine may have a protective role in disease mechanisms and help inrecovery from injuries such as hypoxic-ischemic events.