In vivo Mapping of Muscle Specific Metabolism

肌肉特异性代谢的体内图谱 摘要 磷 31 磁共振波谱 (31P-MRS) 长期以来一直是研究的首选方法 人类肌肉生物能学。 31P-MRS 可测量磷酸肌酸 (PCr) 和腺苷的相对量 三磷酸 (ATP)，可用于估计肌肉肌酸激酶 (CK) 动力学。运动期间，PCr ATP 的高能量“储备”来源已耗尽，无法满足瞬时能量需求。 PCR重合成率 运动后通常用作衡量骨骼肌氧化磷酸化（OXPHOS）能力的指标。 使用 31P-MRS 和多种其他方式的研究表明，肌酸代谢异常和 OXPHOS 缺陷可能会导致衰老的病理生理学。此外，众所周知，肌肉 不同群体的这些代谢特性以及对衰老的反应也各不相同。尽管其实力雄厚， 31P-MRS 的解剖分辨率较低，并且不容易提供肌酸的特定肌肉群估计值 新陈代谢。目前测量肌肉群特异性代谢的可用选择是侵入性活检。 因此，对于评估肌肉代谢的高分辨率、非侵入性策略的需求显然尚未得到满足 同时跨越不同的肌肉群。 我们的小组最近推出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)，测量 PCr 利用过程中形成的游离 Cr。 CrCEST 与 31P-MRS 相比，其灵敏度高出三个数量级，并且还可用于 研究 CK 动力学和肌肉生物能学。 在此提案中，我们通过提高时间分辨率，进一步开发和优化用于人类的 CrCEST， 表征重现性并评估 pH 值的影响。作为询问优化的关键部分 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 健康的成年人。我们希望证明肌酸代谢和肌群特异性差异 使用迄今为止还不可行的非侵入性技术来实现 OXPHOS 能力。 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，而无需 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 信号作为衰老和其他条件下肌肉质量的非侵入性指标，包括但不限于 糖尿病、肌营养不良症、外周动脉疾病和遗传性线粒体疾病。我们预计 CrCEST (iii) 还将作为一种非侵入性肌肉群特定监测工具来评估对 针对衰老、神经肌肉疾病和多种疾病中肌肉代谢异常的潜在疗法 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需求 并有望对该领域产生持续影响。

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.