MR & Optical Diagnosis of Muscle Metabolism and Function

描述(申请人提供)：本申请提出了一种新的磁共振(MRS)和近红外光学(NIRS)光谱的组合，用于研究正常和异常人体肌肉的能量代谢。我们的目标是根据能量平衡原理及其规则开发人体肌肉功能的诊断程序，这些原理和规则是通过先前在这项拨款上的工作而开发的。新陈代谢、能量学和肌肉功能是紧密结合在一起的，为定义完整的人类肢体的正常和异常的肌肉功能提供了关键的信息。在此应用程序中，我们添加了小鼠肌肉研究，以测试我们的定量光谱方法的有效性和准确性。前三个具体目标是利用前几年在本赠款中开发的综合质量和能量平衡的概念来量化氧通量在控制氧化和糖酵解能量代谢中的作用。首先，我们问线粒体如何将O2与氧化磷酸化中的ATP通量联系起来(目标1)。我们通过实验来评估磷酸化和氧化之间的耦合，这些实验集中在完整的人类肌肉中的细胞呼吸作为氧气张力的函数。这些实验可能会建立对线粒体供氧和细胞内氧分压在[ADP]氧化磷酸化调节中的作用的新观点。其次，我们研究了肌肉扩散电导如何将氧气输送与线粒体需求联系起来(目标2)。这个目的是比较氧气压力梯度的大小与氧气吸收通量中的扩散电导的大小。第三，我们评估氧摄取的扩散电导对糖酵解通量和H&乳酸外流之间的平衡有多大影响(目标3)。如果我们的假设被支持，扩散电导将被发现在H&乳酸平衡和氧平衡中起着类似的作用。最后，目标4展示了这种整合是如何独特地解释衰老过程中异常的肌肉能量变化的。因此，这个项目将能量平衡中控制ATP供应的所有主要组成部分与细胞ATPase的需求连接成一个连贯的整体，并以老年肌肉为例，测试这些联系及其调节的改变如何影响功能。

DESCRIPTION (provided by applicant):This application proposes a novel combination of magnetic resonance (MRS) and near infrared optical (NIRS) spectroscopy for studying energy metabolism in normal and abnormal human muscle. Our goal is to develop diagnostic procedures for human muscle function from principles of energy balances and their regulation developed by prior work on this grant. Metabolism, energetics and function of muscle are tightly integrated and provide crucial information needed to define normal and interpret abnormal muscle function in the intact human limb. In this application we add mouse muscle studies to test efficacy and accuracy of our quantitative spectroscopic methods. The first three specific aims exploit the notions of an integrative mass and energy balance developed in prior years of this grant to quantify the role of oxygen flux in the control of oxidative and glycolytic energy metabolism. First, we ask how mitochondria link O2 with ATP fluxes in oxidative phosphorylation (Aim 1). We evaluate the coupling between phosphorylation and oxidation with experiments that focus on cellular respiration in intact human muscle as a function of oxygen tension. These experiments are likely to establish new views of oxygen supply to mitochondria and the role of intracellular partial pressure of oxygen in the regulation of oxidative phosphorylation by [ADP]. Second, we examine how muscle diffusion conductance links O2 delivery with mitochondrial demand (Aim 2). This aim compares the magnitude of the oxygen pressure gradient versus the diffusive conductance in oxygen uptake flux. Third, we evaluate how much the diffusion conductance for oxygen uptake influences the balance between glycolytic flux and H+ & lactate efflux (Aim 3). If our hypothesis is supported, diffusive conductance will be found to play a similar functional role for H+ & lactate balances and for oxygen balance. Finally, Aim 4 shows how this integration uniquely accounts for abnormal muscle energetics in aging. Thus this project links all the major components of energy balance governing the supply of ATP to the demands of cellular ATPases into a coherent whole and tests how alteration of these linkages and their regulation influences function, using elderly muscle as an example.