In vivo Mapping of Muscle Specific Metabolism

肌肉特异性代谢的体内图谱

基本信息

批准号：
10553616
负责人：
Ravinder Reddy
金额：
$ 63.66万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-02-01 至 2026-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10553616
关键词：
Adenosine Triphosphate Adult Aerobic Affect Age Aging Amines Anatomy Bioenergetics Biopsy Blood flow Cell Respiration Chemicals Chronic Chronic Disease Clinical Computer software Creatine Creatine Kinase Data Diabetes Mellitus Disease Elderly Evaluation Exercise Fiber Functional disorder Future Gastrocnemius Muscle Genetic Goals Human Image Imaging Techniques Individual Kinetics Location MM form creatine kinase Magnetic Resonance Imaging Magnetic Resonance Spectroscopy Maps Measures Metabolic Metabolism Methods Mitochondria Mitochondrial Diseases Modality Monitor Motion Muscle Muscle Mitochondria Muscle function Muscular Dystrophies Neuromuscular Diseases Outcome Oxidative Phosphorylation Oxidative Phosphorylation Deficiency Peripheral arterial disease Phosphocreatine Phosphorus Physical activity Population Positioning Attribute Procedures Property Publishing Race Recovery Reproducibility Research Resolution Rest Signal Transduction Skeletal Muscle Slice Soleus Muscle Source Specificity Strenuous Exercise Supplementation Techniques Technology Testing Time age effect age group clinically relevant cohort data exchange design diagnostic tool efficacy evaluation imaging biomarker improved in vivo indexing magnetic field muscle form muscle metabolism non-invasive imaging noninvasive diagnosis novel nutrition quantitative imaging response sedentary lifestyle sex spatiotemporal targeted treatment temporal measurement tool treatment strategy

项目摘要

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.

肌肉特异性代谢的体内图谱抽象的磷 31 磁共振波谱 (31P-MRS) 长期以来一直是研究的首选方法 31P-MRS 测量人体肌肉生物能量学中磷酸肌酸 (PCr) 和腺苷的相对含量。三磷酸 (ATP)，可用于估计运动期间的肌肉肌酸激酶 (CK) 动力学。 ATP 的高能量“储备”来源已被耗尽以满足瞬时能量需求 PCr 再合成率。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，肌酸代谢异常和缺乏 OXPHOS 可能会导致衰老的病理生理学。此外，众所周知，肌肉。尽管有其优势，但不同群体的这些代谢特性以及对衰老的反应也各不相同。 31P-MRS 的解剖分辨率较低，并且不容易提供肌酸的肌群特异性估计值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。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。在本提案中，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，表征再现性并评估 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 的影响我们希望展示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使用 CrCEST 的未来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，包括但不限于我们预计会出现糖尿病、肌营养不良、外周动脉疾病和遗传性线粒体疾病。 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因此，基于 CrCEST 的技术有潜力满足许多重要的未满足的需求。并有望对该领域产生持续影响。