In vivo Mapping of Muscle Specific Metabolism

肌肉特异性代谢的活体定位 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 人体肌肉生物能量学。31P-MRS测定磷酸肌酸和腺苷的相对含量 三磷酸腺苷(ATP)，并可用于估计肌肉肌酸激酶(CK)的动力学。在运动过程中，聚合酶链式反应，a 高能“储备”来源的三磷酸腺苷，被耗尽，以满足瞬变的能源需求。聚合酶链式反应重新合成的速度 运动后常被用作衡量骨骼肌氧化磷酸化(OXPHOS)能力的指标。 使用31P-MRS和多种其他方法的研究表明，异常的肌酸代谢和 OXPHOS的缺乏可能参与了衰老的病理生理过程。此外，很好地确定了肌肉 不同的群体在这些代谢特性方面存在差异，对衰老的反应也不同。尽管它有自己的优势， 31P-MRS具有较低的解剖分辨率，并且不容易提供肌酸的特定肌群估计。 新陈代谢。目前可用于测量肌肉群特异性代谢的方法是侵入性活检。 因此，对评估肌肉新陈代谢的高分辨率、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。 我们小组最近推出了一种名为铬胺的新磁共振成像(MRI)技术 化学交换饱和转移(CrCEST)，测量利用聚合酶链式反应形成的游离铬。CrCEST 提供比31P-MRS高三个数量级的灵敏度，还可用于 研究CK动力学和肌肉生物能量学。 在这个建议中，我们进一步开发和优化了用于人类的CRCEST，通过提高时间分辨率， 表征重复性，并评估pH的影响。作为审问优化的 ，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。我们希望展示肌肉组在肌酸代谢和肌酸代谢方面的特定差异 使用非侵入性技术提高OXPHOS的能力，这到目前为止是不可行的。 这个项目的成功完成将i)产生肌肉肌酸的定量成像生物标记物 代谢、乳酸代谢和OXPHOS能力提供解剖特异性，而不是 以活检为基础的方法的侵袭性；二)提供参考数据，以支持使用CRCEST的未来研究 在衰老和其他情况下，信号作为肌肉质量的非侵入性指标，包括但不限于 糖尿病、肌肉营养不良、外周动脉疾病和遗传性线粒体疾病。我们期待着 CrCEST(III)还将作为一种非侵入性肌群特异性监测工具来评估对 针对衰老、神经肌肉疾病和各种疾病中肌肉代谢异常的潜在治疗方法 其他条件。因此，基于CRCEST的技术有可能满足许多重要的未得到满足的需求 预计将对这一领域产生持续的影响。

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.