The role of creatine in health and disease

说明(申请人提供)：肌酸(肌酸)是细胞能量储存和高能量需求组织中产生的重要成分。人类的肌酸缺乏症是由一小群罕见的先天性代谢错误引起的，涉及合成和运输。相比之下，在肌萎缩侧索硬化症、亨廷顿病和帕金森病的疾病模型中，肌酸补充剂据称对神经进展具有保护作用。此外，在动物中预防性给予肌酸似乎在创伤性和缺血性脑损伤模型中具有神经保护作用。 肌酸利用最显著的部位是肌肉和大脑。在这些器官中，肌酸和磷酸肌酸，以及肌酸激酶同工酶和ATP/ADP，提供了主要的能量储备。肌酸合成途径中的第一个酶-精氨酸：甘氨酸氨基转移酶(AGAT)的缺失会导致肌酸合成的完全缺陷和严重的神经后遗症，包括智力低下和自闭症特征。然而，新生儿看起来正常，早期治疗可能会消除神经损伤。因此，肌酸缺乏症似乎是一个很好的新生儿筛查对象。 利用AGAT缺乏的小鼠模型，这项应用的目标是提供关于学习和突触可塑性的这种遗传性代谢性疾病的病理机制的见解。研究人员将使用行为测试和电生理学相结合的方法来检查神经表型及其对补充肌酸的反应。他们还有兴趣通过各种生理和生化分析来了解肌酸缺乏对肌肉生物能量学的影响，这些分析包括运动测试、组织和液体分析、磁共振波谱以及剥离肌肉纤维的线粒体呼吸。此外，还将研究口服肌酸作为神经保护剂的效果，方法是确定癫痫发作的诱导阈值和对缺氧性损伤的敏感性。这些研究将为可筛查的人类疾病以及更广泛的生物医学问题提供见解。

DESCRIPTION (provided by applicant): Creatine (Cr) is an essential component of cellular energy storage and production in tissues with high energy requirements. Creatine deficiency in humans is caused by a small group of rare inborn errors of metabolism involving synthesis and transport. In contrast, creatine supplementation is purported to have a protective effect on neurologic progression in disease models of amyotrophic lateral sclerosis, Huntington's disease, and Parkinson's disease. Furthermore, prophylactic creatine administration in animals appears to be neuroprotective in models of traumatic and ischemic brain injuries. The most significant utilization of creatine occurs in muscle and brain. In these organs, creatine and phosphocreatine, together with creatine kinase isozymes and ATP/ADP, provide the major reserve of energy. Deficiency of the first enzyme in the creatine synthetic pathway, arginine:glycine amidinotransferase (AGAT), in humans leads to complete deficiency of creatine synthesis and severe neurological sequelae, including mental retardation and autistic features. However, newborns appear normal and early treatment may eliminate neurologic injury. Thus, creatine deficiency appears to be an excellent candidate for newborn screening. Using a mouse model of AGAT deficiency, the goal of this application is to provide insights into the pathologic mechanisms of this inherited metabolic disease with regard to learning and synaptic plasticity. The investigators will use behavioral testing in conjunction with electrophysiology to examine the neurologic phenotype and its response to creatine supplementation. They are also interested in understanding the effect of creatine deficiency on muscle bioenergetics using various physiologic and biochemical assays, including exercise testing, tissue and fluid analytes, magnetic resonance spectroscopy, and mitochondrial respiration with skinned muscle fibers. Also to be investigated are the effects of oral creatine administration as a neuroprotective agent by determining the threshold for seizure induction and sensitivity to hypoxic injury. These studies will provide insights into a screenable human disorder as well as broader biomedical issues.