In vivo Mapping of Muscle Specific Metabolism

肌肉特异性代谢的体内作图 摘要 长期以来，磷-31磁共振波谱（31 P-MRS）一直是研究 人体肌肉生物能量学31 P-MRS测量磷酸肌酸（PCr）和腺苷的相对量 三磷酸（ATP），并且可用于估计肌肉肌酸激酶（CK）动力学。运动期间，PCr，a ATP高能量“储备”源被耗尽以满足瞬时能量需求。PCR再合成率 通常用作骨骼肌氧化磷酸化（OXPHOS）能力的量度。 使用31 P-MRS和多种其他方式的研究表明，肌酸代谢异常和 缺乏OXPHOS可能导致衰老的病理生理学。此外，众所周知，肌肉 不同的群体在这些代谢特性以及对衰老的反应方面各不相同。尽管它的优势， 31 P-MRS具有低解剖分辨率，并且不容易提供肌群特异性肌酸估计 新陈代谢.目前可用的测量肌肉群特异性代谢的选择是侵入性活检。 因此，对于评估肌肉代谢的高分辨率、非侵入性策略存在明显未满足的需求 同时在不同的肌肉群中运动。 我们小组最近介绍了一种新的磁共振成像（MRI）技术，称为铬胺 化学交换饱和转移（CrCEST），其测量由PCr利用形成的游离Cr。CrCEST 与31 P-MRS相比，提供了超过三个数量级的高灵敏度， 研究CK动力学和肌肉生物能量学。 在这项提案中，我们进一步开发和优化用于人类的CrCEST，通过提高时间分辨率， 表征再现性，并评估pH值的影响。作为询问优化的 CrCEST技术，我们将测试年龄，性别，种族和体力活动对高分辨率CrCEST的影响， 健康成人我们希望证明肌群特异性肌酸代谢的差异， OXPHOS能力使用非侵入性技术，这是不可行的，直到现在。 该项目的成功完成将i）产生肌肉肌酸的定量成像生物标志物 代谢，乳酸代谢和OXPHOS能力，提供解剖特异性，而没有 基于活检的方法的侵入性; ii）提供参考数据，以支持未来使用CrCEST的研究 信号作为老化和其它条件下肌肉质量的非侵入性指标，包括但不限于 糖尿病、肌营养不良、外周动脉疾病和遗传性线粒体疾病。我们预计 CrCEST（iii）也将作为一种非侵入性肌肉群特异性监测工具， 针对衰老、神经肌肉疾病和无数疾病中异常肌肉代谢的潜在疗法 其他条件。因此，基于CrCEST的技术有潜力满足许多重要的未满足的需求 预计将对实地产生持续影响。

In vivo Mapping of Muscle Specific Metabolism ABSTRACT Phosphorus-31 magnetic resonance spectroscopy (31P-MRS) has long been the method of choice to study muscle bioenergetics in humans. 31P-MRS measures relative amounts of phosphocreatine (PCr) and adenosine triphosphate (ATP), and can be used to estimate muscle creatine kinase (CK) kinetics. During exercise, PCr, a high-energy “reserve” source of ATP, is depleted to meet transient energy demands. The rate of PCr re-synthesis after exercise is commonly used as a measure of skeletal muscle oxidative phosphorylation (OXPHOS) capacity. Studies using 31P-MRS and multiple other modalities have suggested that abnormal creatine metabolism and deficient OXPHOS may contribute to the pathophysiology of aging. In addition, it is well established that muscle groups vary with respect to these metabolic properties, and also in their response to aging. Despite its strengths, 31P-MRS has low anatomic resolution, and does not readily provide muscle group specific estimates of creatine metabolism. The currently available option for measuring muscle group specific metabolism is invasive biopsy. Thus, there is a clear unmet need for high-resolution, non-invasive strategies to assess muscle metabolism simultaneously across heterogeneous muscle groups. Our group recently introduced a new magnetic resonance imaging (MRI) technique known as the Cr-amine chemical exchange saturation transfer (CrCEST), which measures free Cr formed from PCr utilization. CrCEST provides over three orders of magnitude higher sensitivity compared to 31P-MRS and can also be used to investigate CK kinetics and muscle bioenergetics. In this proposal, we further develop and optimize the CrCEST for use in humans, by improving time resolution, characterizing reproducibility, and assessing the effects of pH. As a critical part of interrogating the optimized CrCEST technique, we will test the effects of age, sex, race and physical activity on high-resolution CrCEST in healthy adults. We expect to demonstrate muscle group specific differences in creatine metabolism and OXPHOS capacity using non-invasive techniques that were not feasible until now. Successful accomplishment of this project will i) yield quantitative imaging biomarkers of muscle creatine metabolism, lactate metabolism and OXPHOS capacity that provide anatomic specificity without the invasiveness of biopsy-based approaches; ii) provide reference data to support future studies using CrCEST signal as a non-invasive index of muscle quality in aging and other conditions, including but not limited to diabetes, muscular dystrophy, peripheral arterial disease, and genetic mitochondrial disorders. We anticipate that CrCEST (iii) will also serve as a non-invasive muscle group specific monitoring tool to evaluate response to potential therapies targeting abnormal muscle metabolism in aging, in neuromuscular disorders, and myriad other conditions. Thus, CrCEST based technologies have the potential to fill a number of important unmet needs and are expected to exert sustained impact on the field.