In vivo Mapping of Muscle Specific Metabolism

肌肉特异性代谢的体内图谱

• 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
• 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

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.

体内肌肉特异性代谢 抽象的 磷-31磁共振光谱（31p-MR）长期以来一直是研究的方法 人类的肌肉生物能学。 31p-MRS测量磷酸蛋白（PCR）和腺苷的相对量 三磷酸（ATP），可用于估计肌肉创造激酶（CK）动力学。在锻炼过程中，PCR，一个 ATP的高能“储备”来源耗尽以满足瞬时能源需求。 PCR重新合成的速率 运动后通常用作骨骼肌氧化磷酸化（OXPHOS）能力的量度。 使用31p-MR和其他多种模式的研究表明，异常的创造代谢和 缺乏OXPHOS可能有助于衰老的病理生理学。此外，肌肉已经很好地确定 各组因这些代谢特性以及对衰老的反应而有所不同。尽管有优势， 31p-MRs的解剖分辨率较低，并且不容易提供肌肉组的特定估计值 代谢。目前可用于测量肌肉组特定代谢的选择是侵入性活检。 这是对评估肌肉代谢的高分辨率，非侵入性策略的明显未满足的需求 同样，各种异质肌肉群。 我们的小组最近引入了一种新的磁共振成像（MRI）技术称为CR-AMINE 化学交换满意度转移（CRCEST），它测量了由PCR利用形成的自由CR。 crcest 与31p-Mrs相比，提供三个数量级以上的数量级以上，也可以用于 研究CK动力学和肌肉生物能学。 在此建议中，我们通过改善时间分辨率，进一步开发和优化用于人类使用的CRCEST， 表征可重复性，并评估pH的影响。作为审问优化的关键部分 CRCEST技术，我们将测试年龄，性别，种族和体育活动对高分辨率CRCEST的影响 健康的成年人。我们希望在创造代谢和 使用非侵入性技术的OXPHOS容量到现在不可行。 成功完成该项目i）产生肌肉创造的定量成像生物标志物 新陈代谢，新陈代谢和OXPHOS能力，可提供解剖学特异性 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 信号是衰老和其他条件下肌肉质量的无创指数，包括但不限于 糖尿病，肌肉营养不良，周围动脉疾病和遗传线粒体疾病。 该crcest（iii）也将作为一种非侵入性肌肉群特定的监测工具，以评估对 靶向异常肌肉代谢在衰老，神经肌肉疾病和无数的潜在疗法 其他条件。这是基于CRCEST的技术有可能满足许多​​重要的未满足需求 并有望对该领域持续影响。